bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2560: IKKα inactivation predisposes to spontaneous lung squamous cell carcinomas
Authors: Xiao Zuoxiang , Jiang Qun , Willette-Brown Jami , Zhu Feng , Young Howard A. , Lin Fanching , Burkett Sandra , Datla Mahesh , Xi Sichuan , Schrump David S. , Wiltrout Robert H. , Hu Yinling 
Published: August 2012

Abstract
Lung cancer is the leading cause of cancer deaths worldwide. To advance the understanding of this disease, various genetically engineered and chemical induced mouse models have been established. However, most animal models resemble human lung adenocarcinoma, and spontaneous lung squamous cell carcinomas (SCCs) mouse models are very rare. Here, we generated Ikkα-KA/KA knock-in mice (KA/KA) in which an ATP binding site of IKKα, Lys 44 was replaced by alanine. The knock-in mice develop severe skin lesions and begin to die after 6 months. We found lung SCCs in some of the mice. To study lung SCC development, we decided to stabilize the skin condition by reintroducing transgenic IKKα by crossing KA/KA with Lori.IKKα transgenic mice to generate KA/KA/Lori.IKKα (KA/KAL) mice. Almost all the KA/KAL (100%) mice at 4 to 6 months of age developed spontaneous lethal lung SCCs. The endogenous IKKα protein level generally markedly declined in an age dependent manner in these IKKα mutant mice. Progenitor cell related markers Sox2, OCT3/4 and Nanog were only increased in the lung SCC tissue but not in the tumor adjacent tissues, implying the involvement of cancer stem cells in lung SCC. Furthermore, we detected substantial increases in Ras and CyclinD1 levels and EGFR, ERK and p38 activities in lung SCCs. On the other hand, we detected reduction in tumor suppressor gene Rb and IαBβ accompanying with reduced IKKα levels in KA/KAL lungs as well as in lung SCCs. Importantly, we observed a similar alteration pattern in mouse and human lung SCCs. Finally, reintroducing IKKα into lung epithelial cells prevented lung SCC development in mice. Collectively, our study supports the tumor suppressing role of IKKα in lung tumorigenesis. This novel lung SCC mouse model may facilitate investigations in pathogenesis, diagnosis, and treatment of human lung SCC disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2560. doi:1538-7445.AM2012-2560
Abstract 2561: IKKα links inflammation and tumorigenesis in a mouse model of lung squamous cell carcinoma
Authors: Jiang Qun , Xiao Zuoxiang , Willette-Brown Jami , Back Timothy , Wiltrout Robert H. , Hu Yinling 
Published: August 2012

Abstract
NF-kB plays critical roles in linking inflammation and carcinogenesis. The activation of NF-kB is regulated by the IkB Kinase Complex (IKK), composed of IKKα, IKKα, and NF-κB essential modulator (NEMO). We have established a mouse model of lung squamous cell carcinoma (SCC) by inactivating IKKα in vivo. However, IKKα's attributes relating to linkage between inflammation and lung SCC have not yet been well-defined. We now show that inactivation of IKKα in mice causes systemic chronic inflammation, which consequently promotes lung SCC initiation and progression. In mice with mutated IKKα, CD4 T cells, dendritic cells, and macrophages are all significantly increased in the spleen and lung. Proinflammatory cytokines and chemokines are also remarkably elevated in the lungs of these mice. An M2 macrophage phenotype is observed only in the lungs of old IKKα mutant mice, not in younger mice, suggesting the M1/M2 polarization may be driven by the proinflammatory microenvironment in these mice. Production of Th2 cytokines and IL-10 are elevated in CD4 T cells from the lungs of mice with mutated IKKα, and may contribute to M2 polarization during the chronic inflammation. In addition, depletion of macrophages in these mice can significantly reduce Th2 cytokine production, oxidative DNA damage, and shut down SCC development in the lungs, suggesting their important roles in inflammation-associated lung carcinogenesis. Together, our data suggest that IKKα may play important roles in linking inflammation and lung SCC tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2561. doi:1538-7445.AM2012-2561
Abstract 258: Development of death receptor agonists - A novel therapy for breast cancer
Authors: Srivastava Rakesh , Shankar Sharmila 
Published: August 2012

Abstract
Binding of TRAIL to death receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5) induces apoptosis in cancer cells without affecting normal cells. The purpose of this study was to identify and characterize TRAIL-death receptor agonist (DRA) that induces apoptosis in breast cancer cells. DRA is a small organic molecule. The pharmacokinetics of the DRA with a single oral dose was also characterized in nude mice. Blood was collected over 72-hour period after DRA administration, and analyzed by HPLC-MS/MS for plasma drug concentration. The Cmax, tmax, and AUC of DRA were measured. DRA inhibited cell viability and colony formation, and induced apoptosis in estrogen-dependent (MCF-7) and independent (MDA-MB-231 and MDA-MB-468) human breast cancer cell lines, but had no effect on human normal mammary epithelial cells and hepatocytes. The combination of DRA with paclitaxel or doxorubicin had synergistic effects on apoptosis in breast cancer cell lines. DRA formed active TRAIL-DISC (death-inducing signaling complex) similar to that of TRAIL. DRA inhibited the growth of orthotopically implanted MDA-MB-231 and MDA-MB-468 tumors in nude mice. Histological examination of tumor tissues derived from DRA-treated nude mice revealed massive caspase-3 activation and apoptosis. Pharmacokinetic data demonstrate that DRA possesses a long terminal half-life, which is acceptable for further clinical development. In conclusion, we have identified DRA that can be used either alone or in combination with chemotherapeutic drugs for the treatment of human breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 258. doi:1538-7445.AM2012-258
Abstract 2655: Esophagectomy with extended 2-field lymph node dissection for patients with thoracic esophageal carcinoma
Authors: Xue Hengchuan , Wu Changrong , Zhu Zonghai , Zhang Zhenbin , Ma Zhenkai , Gao Jie 
Published: August 2012

Abstract
Objective: To summarize the surgical effect and clinical application of esophagectomy with extended 2- field lymph node dissection for patients with thoracic esophageal carcinoma. Methods: From June, 1987 to December, 2008, 1690 patients with thoracic esophageal cancer underwent esophagectomy with extended 2-field (thoracic and abdominal) dissection of lymph nodes were recruited and followed up. Patients with the middle and lower thoracic esophageal cancer underwent Ivor-Lewis esophagectomy, while patients with upper thoracic esophageal cancer underwent Akiyama esophagectomy. Both thoracic and abdominal lymph node metastases were recorded. Survival rates on 1, 3, 5, and 10 years were analyzed respectively. Results: Totally, 1690 eligible patients were recruited and successfully followed. Lymph node metastases were found in 713 patients, with the proportion of 42.2%(713/1690). Thoracic lymph node metastasis rate was 39.3%(665/1690), of which 20.7%(349/1690) were found in the right apical pleural para-tracheal triangle, 26.3%(444/1690) were found in the posterior upper mediastinum, and 18.2%(307/1690) were found in the lower mediastinum. Abdominal lymph node metastasis rate was 20.1%(339/1690). Out of 1690 patients underwent esophagectomy, 278 patients were reported postoperative complications, among which the pulmonary complication was ranked as the first one (43.6%). The death rate due to operation was 0.2%.The l-year, 3-year, 5-year and 10-year survival rates were 88.2%, 63.5%, 54.8% and 30.8%, respectively. Patients without lymph node metastasis had higher 5-year survival rate (76.2%), as compared to those with lymph node metastases (36.8%). Conclusion: Findings from this study demonstrated that Ivor-Lewis and Akiyarna esophagectomy with 2-field lymph node dissection could expose the operation fields clearly and make radical lymphadenectomy thoroughly, which was useful for observing the lymph nodes in the posterior upper mediastinum around the recurrent laryngeal nerve and in the right pleural apical para-tracheal triangle. We believe that esophageal cancer patients with potential lymph node metastases could benefit from esophagectomy with extended 2-field dissection of lymph nodes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2655. doi:1538-7445.AM2012-2655
Abstract 2659: Cilastatin attenuates cisplatin-induced proximal tubular cell damage without compromising antitumoral activity
Authors: Humanes Blanca , Blanco-Codesido Montserrat , Lazaro Alberto , Camaño Sonia , Tejedor Alberto 
Published: August 2012

Abstract
Introduction: Cisplatin (CDDP) is a very effective and common treatment in solid malignancies. One of the most important side effects of CDDP is the nephrotoxicity. Nephrotoxicity is a limitating side effect on treatment with CDDP, preventing patients with limit kidney function of receiving the drug and stopping treatment once kidney function has worsened. Cilastatin (Cls) is a specific inhibitor of renal dedydrodipeptidase I (DHP-I) which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. In this work we hypothesized that Cls acts as a nephroprotector against CDDP-induced damage without compromising antitumor activity. Methods: Primary cultures of proximal tubular cells (PTCs) and cell lines of different malignancies (colon, breast, ovarian, bladder) were cultured with different concentrations of CDDP (1, 10 and 30 μM) in the presence or absence of Cls. Cell viability was assessed with MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. Raft staining was measured with toxine B choleric and FasL by confocal microscopy. Results: Cls interfered with CDDP-induced FasL signalling at raft level on PTCs brush border. Concomitant treatment with Cls reduced CDDP-induced changes. Several tumoral cell lines were tested with CDDP and Cls together. Cls did not increase or decreased tumor growth alone or in combination with CDDP. CDDP sensitivity was not affected by Cls. Conclusion: By binding a DHP-I, Cls blocks CDDP-induced PTCs apoptosis but it does not affect the CDDP antitumoral activity. Our findings suggest that the affinity of Cls for renal DHP-I make this effect specific for proximal tubular cells and may be related to a reduction in intracellular drug accumulation. Cls administration might represent a novel strategy in the prevention of CDDP-induced acute renal injury. Cls treatment could potentially increase the number of patients undergoing CDDP treatment or maintaining treatment. Further clinical trials for renal function preservation in cancer patients are warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2659. doi:1538-7445.AM2012-2659
Abstract 2662: Racial disparities in the surgical outcomes after esophagectomy for esophageal cancer
Authors: Akateh Clifford , Zhao Lili , Orringer Mark B. , Chang Andrew C. , Lin Jules , Reddy Rishindra M. 
Published: August 2012

Abstract
Introduction: Despite advances in the management of esophageal cancer, African American patients continue to have poorer outcomes following esophagectomy for esophageal cancer. The reasons for this are multifactorial, including access to care and cultural perceptions of treatments. For those patients who underwent esophagectomy, we sought to evaluate if there were disparities in outcomes for African American patients. Method: We identified African American and Caucasian patients who underwent esophagectomy for esophageal cancer at a single, high volume institution. from 1974 to 2011. Using Chi-square and Fisher's exact test, we evaluated for differences in perioperative risk factors, postoperative complications and long term survival. Results: 2090 (2.7% African Americans, 97.3% Caucasians) patients were included in the study. No significant difference was seen in anastomotic leaks, chylothoraces, hoarseness, or other postop complications. However, more African Americans were sent to the intensive care unit during their postop hospitalization (62% versus 46%, p= 0.02). In addition, African Americans had a significantly longer hospitalization compared to their Caucasian counterparts (19 versus 12 days, p&lt;0.0001). This difference persisted even after adjusting for histology, preoperative staging, age, gender, alcohol and tobacco use. Squamous cell cancer was more likely to be seen in African Americans than in Caucasians (79% versus 20% respectively, p&lt;0.0001). Adenocarcinoma was more often seen in Caucasians than African Americans (78% vs 21%, p&lt;0.0001) as were Barrett's changes (33% versus 10%, p=0.003). Despite the longer hospitalizations, there was no significant difference in the long term survival (weeks) between African Americans and Caucasians. Conclusion: African Americans have equal survival to Caucasians after esophagectomy for esophageal cancer at single, high volume institution. Despite having longer hospitalizations with more ICU admissions after surgery, there were no significant differences in postoperative complications or long term survival based on race. Differences in outcomes in patients with esophageal cancer may be related to initial access to care, but there doesn't appear to be a difference in outcomes once patients proceed to surgery at an experienced center.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2662. doi:1538-7445.AM2012-2662
Abstract 2669: Early-phase trials in patients with advanced gallbladder cancer and cholangiocarcinoma: The MD Anderson Clinical Center for Targeted Therapy experience
Authors: Subbiah Ishwaria M. , Tsimberidou Apostolia M. , Naing Aung , Subbiah Vivek , Kaseb Ahmed O. , Falchook Gerald S. , Fu Siqing , Hong David S. , Piha-Paul Sarina A. , Wheler Jennifer J. , Janku Filip , Kurzrock Razelle 
Published: August 2012

Abstract
BACKGROUND: Patients with cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few effective therapeutic options in the relapsed and/or metastatic setting. With that purpose, we analyzed the characteristics and outcomes of patients with advanced CC and GC treated on early-phase clinical trials in the Clinical Center for Targeted Therapy at MD Anderson Cancer Center. METHODS: We searched an electronic database of consecutive pts with GC and CC referred to the Clinical Center for Targeted Therapy starting in November 2004. We assessed the relationship between types of clinical trial and pts’ tumor types, progression-free survival, and mutations. RESULTS: Of the 72 patients with CC and GC referred to the clinic, 32 (44%) were not enrolled in a clinical trials mainly due to deterioration of performance status (n=25), decision to pursue alternate therapies (n=6), and insurance denial (n=1). Forty pts (5 w GC; 35 w CC) who received treatment on early clinical trials are included in this analysis. The median age was 60.2 yrs (range, 41.4-73.6 yrs). ECOG performance status (PS) was 0-1 in 36 pts (90%) and 2 in 4 (10%). Median number of prior therapies was 3 (range 0-17). Six pts were not restaged due to early disease progression. Of the 40 pts evaluable for response, 8 (20%) had stable disease (SD) &gt; 6 months and 3 (8%) had a partial response (PR) (total SD &gt; 6 mos/PR = 28%). Highest rates of SD &gt; 6 mos/PR were observed in patients treated with protocols that included hepatic arterial infusion drug administration (7/17 = 41%) or anti-angiogenic agents (9/24 = 38%) (with 6 of these pts receiving treatment that included hepatic arterial infusion chemotherapy combined with a systemic anti-angiogenic agent). SD lasting 9 months was also seen in 1 pt treated with a MEK inhibitor. Median progression-free survival for the 40 pts was 2.0 months 9 (95% CI 1.7, 2.8) on early-phase clinical trials versus 3.0 months on their last FDA-approved treatment before Phase I referral (95% CI 2.3, 3.7). CONCLUSIONS: About one-third of patients with CC and GC referred for early-phase trials cannot be enrolled because of poor performance status. Twenty-eight percent of patients who met eligibility criteria achieved SD &gt; 6 mos/PR, with responses predominantly observed in regimens that contained locoregional treatment, anti-angiogenic agents, or a targeted MEK inhibitor.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2669. doi:1538-7445.AM2012-2669
Abstract 2671: CYP2D6 polymorphisms are not associated with tamoxifen outcome in premenopausal women with ER positive breast cancer of the POSH cohort
Authors: Saladores Pilar H. , Schroth Werner , Eccles Diana , Tapper William , Gerty Sue , Brauch Hiltrud B. 
Published: August 2012

Abstract
Long-term adjuvant tamoxifen therapy for five years is the anti-estrogenic standard of care for ER-positive breast cancer in premenopausal patients. The metabolic activation of tamoxifen into the active metabolite endoxifen is mediated by Cytochrome P450 (CYP) 2D6 and it has been shown that CYP2D6 polymorphims can influence the clinical outcome of postmenopausal breast cancer patients (Schroth et al. JAMA 2009, Mürdter et al.CPT 2011). While this is currently still under debate awaiting the denouement (Brauch et al. JCO 2011), no such relationship has been investigated for premenopausal patients. We used the Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH) collection to explore the pharmacogenetic relationship between CYP2D6 polymorphisms and tamoxifen outcome in premenopausal patients. POSH is an observational cohort study established to explore the effect of genetic factors on breast cancer prognosis (Eccles et al. BMC Cancer 2007). We genotyped genomic DNA of 772 patients with adjuvant tamoxifen (age 18 to 41 years) for CYP2D6 and other CYP enzymes by MALDI TOF-MS. Patients were assigned for CYP2D6 metabolizer status, poor (PM), intermediate (IM), and extensive (EM), and tested for clinical associations using Kaplan-Meier and Cox regression analyses. After a median follow-up of 4 years (0.1 - 8 years) with 24.6% of study participants reporting a relapse, Kaplan Meier survival analysis did not show an association between CYP2D6 metabolizer status and the occurrence of relapse. In contrast, CYP3A5 functional status predicted by the *1 genotype was associated with worse outcome compared to the CYP3A5 deficient status (*3). Since chemotherapy is a suggested confounder of the CYP2D6 tamoxifen pharmacogenetic effect and the majority of POSH patients had received chemotherapy prior to tamoxifen, there is a possibility that variation in the metabolism and cytotoxic effects of these agents may mask CYP2D6 dependent tamoxifen outcome. However, in premenopausal patients due to higher plasma estrogen concentrations, the inhibition of tumor ER signaling may likely depend on factors other than endoxifen formation. While this is currently being explored with respect to the underlying ER pharmacodynamic effects, the polymorphic CYP3A5, one of the major drug metabolizing enzymes, appears to be a candidate marker for the prognosis of premenopausal breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2671. doi:1538-7445.AM2012-2671
Abstract 2677: Determination of the optimal route of administration of Salmonella typhimurium A1-R to target breast cancer in nude mice
Authors: Zhang Yong , Suetsugu Atsushi , Zhang Nan , Zhang Lei , Hoffman Robert M. , Zhao Ming 
Published: August 2012

Abstract
We have previously developed the genetically-modified strain Salmonella typhimurium A1-R that selectively targets tumors. S. typhimurium A1-R is auxotrophic for leu and arg, which precludes it from growing in normal tissues but allows high tumor virulence. We report here the efficacy and safety of three different routes of S. typhimurium A1-R delivery oral (p.o.), intravenous (i.v.), and intra-tumor (i.t.) in nude mice with orthotopic human breast cancer. Nude mice with MDA-MB-435 human breast cancer expressing red fluorescence protein (RFP) were administered S. typhimurium A1-R by either of 3 routes: (p.o.: 2 × 108 CFU/200 αl; i.v.: 2.5 × 107 CFU/100 αl; i.t.: 2.5 × 107 CFU/50 µl) twice a week. Tumor growth was monitored by florescence imaging and caliper measurement in two dimensions. Treatment with S. typhimurium A1-R via all three routes resulted in effective targeting and tumor growth inhibition. Efficacy was observed earliest in the animals treated by i.v. injection. GFP-expressing S. typhimurium A1-R were imaged to target, colonize, and replicate in the human breast tumor, liver, and spleen as observed by fluorescence imaging. Bacterial colonization of tumor and normal organs at different time points were determined after S. typhimurium delivery by either of the 3 routes. S. typhimurium A1-R targeted tumors at much higher levels than normal organs with all 3 routes of administration. The bacteria replicated and survived longer in the tumor than normal organs with all 3 routes of administration. Two weeks after bacteria administration by all 3 routes, the bacteria disappeared from normal organs, but grew continuously in the tumor. The fewest bacteria were detected in normal organs after oral administration, which suggests oral administration has the highest safety. The i.v. route had the greatest anti-tumor efficacy. There were no obvious toxic effects on the host with any of the routes of administration. Non-tumor-bearing mice tolerated S. typhimurium A1-R, p.o., twice weekly treatment and could survive as long as untreated mice. The results of this study suggest that oral administration was the most safe to the host and the i.v. route was most effective for tumor targeting with S. typhimurium A1-R.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2677. doi:1538-7445.AM2012-2677