bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Proteomic Approach for the Identification of Vascular Markers of Liver Metastasis
Authors: Borgia Beatrice , Roesli Christoph , Fugmann Tim , Schliemann Christoph , Cesca Marta , Neri Dario , Giavazzi Raffaella 
Published: December 2009

Abstract
Vascular proteins expressed at liver metastasis sites could serve as prognostic markers or as targets for pharmacodelivery applications. We employed a proteomic approach to define such proteins in three syngeneic mouse models of liver metastasis. Vascular structures were biotinylated in vivo by a terminal perfusion technique, followed by mass spectrometric analysis of accessible biotinylated proteins. In this manner, we identified 12 proteins for which expression was selectively associated with liver metastasis, confirming this association by tissue immunofluorescence or in vivo localization with radiolabeled antibodies. In summary, our findings identify vascular proteins that may have prognostic or drug-targeting use in addressing liver metastases, a common issue in many advanced cancers. Cancer Res; 70(1); 309–18
Increased Prevalence of Precursor Lesions in Familial Pancreatic Cancer Patients
Authors: Shi Chanjuan , Klein Alison P. , Goggins Michael , Maitra Anirban , Canto Marcia , Ali Syed , Schulick Richard , Palmisano Emily , Hruban Ralph H. 
Published: December 2009

AbstractPurpose: Histologic findings in 51 pancreata resected from patients with a strong family history of pancreatic cancer were compared with the findings in 40 pancreata resected from patients with sporadic pancreatic cancer. None of the patients in the familial group had a known inherited syndrome other than familial pancreatic cancer.Experimental Design: Precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and incipient IPMN, were quantified. Invasive cancers were classified using established histologic criteria.Results: The individual precursor lesions identified in both groups were histologically similar. Precursor lesions were more common in the familial cases than in the sporadic cases. The relative rate of PanINs per square centimeter was 2.75-fold higher (95% confidence interval, 2.05-3.70; adjusted for age) in familial compared with sporadic cases. PanIN-3 lesions were more common in familial versus sporadic pancreatic cancer patients (relative rate, 4.20; 95% confidence interval, 2.22-7.93; adjusted for age). High-grade incipient IPMNs were only observed in the familial cases. Nine of the 51 (18%) familial pancreatic cancers and 4 of the 40 (10%) sporadic cancers arose in association with an IPMN. No significant differences were found in the types of invasive cancers.Conclusions: Noninvasive precursor lesions are more common in patients with a strong family history of pancreatic cancer than in patients with sporadic disease, and precursor lesions are of a higher grade in patients with a strong family history of pancreatic cancer. These findings can form a basis for the design of screening tests for the early detection of pancreatic neoplasia. (Clin Cancer Res 2009;15(24):7737–43)
Transforming Growth Factor-β–Stimulated Clone-22 Is an Androgen-Regulated Gene That Enhances Apoptosis in Prostate Cancer following Insulin-Like Growth Factor-I Receptor Inhibition
Authors: Sprenger Cynthia C.T. , Haugk Kathleen , Sun Shihua , Coleman Ilsa , Nelson Peter S. , Vessella Robert L. , Ludwig Dale L. , Wu Jennifer D. , Plymate Stephen R. 
Published: December 2009

Abstract
Purpose: Inhibition of insulin-like growth factor (IGF) signaling using the human IGF-I receptor monoclonal antibody A12 is most effective at inducing apoptosis in prostate cancer xenografts in the presence of androgen. We undertook this study to determine mechanisms for increased apoptosis by A12 in the presence of androgens.
Experimental Methods: The castrate-resistant human xenograft LuCaP 35 V was implanted into intact or castrate severe combined immunodeficient mice and treated with A12 weekly. After 6 weeks of tumor growth, animals were sacrificed and tumors were removed and analyzed for cell cycle distribution/apoptosis and cDNA arrays were done.
Results: In castrate mice, the tumors were delayed in G2 with no apoptosis; in contrast, tumors from intact mice underwent apoptosis with either G1 or G2 delay. Transforming growth factor-β–stimulated clone-22 (TSC-22) was significantly elevated in tumors from the intact mice compared with castrate mice, especially in those tumors with the highest levels of apoptosis. To further determine the function of TSC-22, we transfected various human prostate cancer cell lines with a plasmid expressing TSC-22. Cell lines overexpressing TSC-22 showed an increase in apoptosis and a delay in G1. When these cell lines were placed subcutaneously in athymic nude mice, a decreased number of animals formed tumors and the rate of tumor growth was decreased compared with control tumors.
Conclusions: These data indicate that IGF-I receptor inhibition in the presence of androgen has an enhanced effect on decreasing tumor growth, in part, through increased expression of the tumor suppressor gene TSC-22. (Clin Cancer Res 2009;15(24):7634–41)
Noninvasive Prediction of Fracture Risk in Patients with Metastatic Cancer to the Spine
Authors: Snyder Brian D. , Cordio Marsha A. , Nazarian Ara , Kwak S. Daniel , Chang David J. , Entezari Vahid , Zurakowski David , Parker Leroy M. 
Published: December 2009

Abstract
Purpose: Skeletal metastases affect up to 85% of breast cancer patients by the time of their death. This prospective in vivo study evaluated the diagnostic performance of computed tomography–based structural rigidity analysis (CTRA) to predict vertebral fracture risk in breast cancer patients with skeletal metastasis and in comparison with the current standard of care.
Experimental Design: Torso CT scans of 94 women with vertebral metastatic breast cancer were obtained as part of routine screening for lung and liver metastases. The load-bearing capacity (LBC) and axial (EA) and bending (EI) rigidities of vertebrae T8 to L5 were calculated from CT images. The LBC was normalized by patient body mass index (BMI) to account for height and mass variations. Vertebral fracture risk was also calculated using the current radiographic-based criteria based on lesion size and location. The actual occurrence of a new vertebral fracture was assessed radiographically over the ensuing 4 months.
Results: Eleven vertebral fractures occurred in 10 patients. The structural parameters EA, EI, LBC, and LBC/BMI were all 100% sensitive and 55%, 53%, 44%, and 70% specific to predict fracture risk, respectively. Although radiographic criteria correctly predicted all fracture cases (100% sensitive), only 48 of the 236 spinal segments that did not have a fracture were correctly predicted not to fracture (20% specific).
Conclusions: CTRA, using CT scans as part of routine screening for lung and liver metastasis, is shown to be as sensitive as, and significantly more specific than, the current radiographic criteria for predicting vertebral fracture in breast cancer patients with skeletal metastasis. (Clin Cancer Res 2009;15(24):7676–83)
The Ligamp TP53 Assay for Detection of Minimal Residual Disease in Head and Neck Squamous Cell Carcinoma Surgical Margins
Authors: Poeta M. Luana , Manola Judith , Goldenberg David , Forastiere Arlene , Califano Joseph A. , Ridge John A. , Goodwin Jarrard , Kenady Daniel , Saunders John , Westra William , Sidransky David , Koch Wayne M. 
Published: December 2009

Abstract
Purpose: Detect tumor-related DNA using LigAmp in histologically clear margins and associate results with clinical outcome.
Experimental Design: Patients with head and neck cancer were registered for molecular analysis of surgical margins. Adequacy of resection was ensured using histologic margin analysis. Further margins were then harvested and DNA extracted. TP53 mutations in tumor were determined using Affymetrix p53 GeneChip. Margins were analyzed by Ligamp in comparison with standard curves for quantification of mutant DNA. Ligation used two oligonucleotides to isolate DNA targeting the mutation. Ligated DNA was amplified using real-time PCR. The quantity of mutation in the margin was determined as percent of mutant species relative to plasmid and relative to tumor. Cutpoints were identified and defined groups were evaluated for local failure-free, cancer-specific, and overall survival. Study margins were examined for presence of tumor by light microscopy.
Results: Tissue from 95 patients with common mutations was analyzed. Fifteen experienced local recurrence. Cutpoints of 0.15% for mutant species relative to plasmid and 0.5% for mutant species relative to tumor were chosen as most selective of recurrent cases. LigAmp had slightly better area under the receiver operator characteristic curve (P = 0.09) than light microscopy correctly predicting 9 of 15 recurrent tumors. There were 6 false negative cases and 26 false positive results. No statistically significant distinctions were observed in cancer-specific or overall survival in this limited cohort.
Conclusions: Ligamp provides quantifiable, sensitive detection of mutant DNA in histologically normal margins. Detection of mutant species in margins may identify patients at risk of local recurrence. (Clin Cancer Res 2009;15(24):7658–65)
Relationship between Topoisomerase 2A RNA Expression and Recurrence after Adjuvant Chemotherapy for Breast Cancer
Authors: Sparano Joseph A. , Goldstein Lori J. , Childs Barrett H. , Shak Steven , Brassard Diana , Badve Sunil , Baehner Frederick L. , Bugarini Roberto , Rowley Steve , Perez Edith , Shulman Lawrence N. , Martino Silvana , Davidson Nancy E. , Sledge George W. , Gray Robert 
Published: December 2009

Abstract
Purpose: To perform an exploratory analysis of the relationship between gene expression and recurrence in operable hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–normal breast cancer patients treated with adjuvant doxorubicin-containing chemotherapy.
Experimental Design: RNA was extracted from archived tumor samples derived from 378 patients with stage I to III HR-positive, HER2-normal breast cancer and analyzed by reverse transcription-PCR for a panel of 374 genes, including the 21-gene recurrence score (RS). Patients were randomized to receive adjuvant doxorubicin plus cyclophosphamide or docetaxel in trial E2197, with no difference in recurrence seen in the treatment arms. All available recurrent cases were selected plus a nonrecurrent cohort. Cox proportional hazard models were used to identify relationships between gene expression and recurrence.
Results: TOP2A expression exhibited the strongest association with increased recurrence risk (P = 0.01), and was significantly associated with recurrence (P = 0.008) in a multivariate analysis adjusted for clinicopathologic features. Elevated TOP2A expression above the median was associated with a 2.6-fold increase (95% confidence interval, 1.3-5.2; P = 0.008) in risk of recurrence if the RS was &lt;18, and a 2.0-fold increase (95% confidence interval, 1.2-3.2, P = 0.003) if there was an intermediate RS of 18 to 30.
Conclusions: In patients with HR-positive, HER2-normal breast cancer, a population known to have a low incidence of TOP2A gene alterations thought to be predictive of anthracycline benefit, there is a range of TOP2A RNA expression that is strongly associated with recurrence after adjuvant anthracyclines, which provides information complementary to RS, indicating that it merits further evaluation as a prognostic and predictive marker. (Clin Cancer Res 2009;15(24):7693–700)
Clinical Benefit of Allogeneic Melanoma Cell Lysate–Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients
Authors: Toh Han Chong , Wang Who-Whong , Chia Whay Kuang , Kvistborg Pia , Sun Li , Teo Kelly , Phoon Yee Peng , Soe Yatanar , Tan Sze Huey , Hee Siew Wan , Foo Kian Fong , Ong Simon , Koo Wen Hsin , Zocca Mai-Britt , Claesson Mogens H. 
Published: December 2009

AbstractPurpose: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)–pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate.Experimental Design: DCs were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83- and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 × 106 cells per dose) at biweekly intervals.Results: Twenty patients received a total of 161 vaccinations. Treatment was well tolerated and quality of life measurements did not vary much across time. One patient experienced partial response [5%; 95% confidence interval (CI), 1-24%] and seven achieved stable disease (35%; 95% CI, 18-57%), one of whom also achieved late tumor regression, yielding a clinical benefit response rate of 40% (95% CI, 22-61%). Although overall median progression-free survival was 2.4 months (95% CI, 1.9-4.1 months), five patients (25%) experienced prolonged progression-free survival (&gt;6 months), two of whom (10%) remain progression-free for &gt;27 and &gt;37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding patients that may correlate with vaccine activity and report a prevaccination protein signature distinguishing responders from nonresponders.Conclusion: This phase II vaccine study using mature, MCL-pulsed DCs has shown promising results and warrants further evaluation in a prospective randomized setting. (Clin Cancer Res 2009;15(24):7726–36)
Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases
Authors: Amaravadi Ravi K. , Schuchter Lynn M. , McDermott David F. , Kramer Amy , Giles Lydia , Gramlich Kristi , Carberry Mary , Troxel Andrea B. , Letrero Richard , Nathanson Katherine L. , Atkins Michael B. , O'Dwyer Peter J. , Flaherty Keith T. 
Published: December 2009

Abstract
Purpose: The combination of the oral alkylating agent temozolomide and the oral multikinase inhibitor sorafenib was evaluated in advanced melanoma patients.
Experimental Design: Patients with metastatic melanoma (n = 167) were treated on four arms. All patients received sorafenib at 400 mg p.o. twice daily without interruption. Patients without brain metastases or prior temozolomide were randomized between arm A: extended dosing of temozolomide (75 mg/m2 temozolomide daily for 6 of every 8 weeks) and arm B: standard dosing (150 mg/m2 temozolomide daily for 5 of every 28 days). Patients previously treated with temozolomide were enrolled on arm C: extended dosing of temozolomide. Patients with brain metastases and no prior temozolomide were assigned to arm D: standard dosing. The primary end point was 6-month progression-free survival (PFS) rate. Secondary end points included response rate, toxicity rates, and the rates of BRAF or NRAS mutations.
Results: The 6-month PFS rate for arms A, B, C, and D were 50%, 40%, 11%, and 23%. The median PFS for patients on arm A, B, C, and D was 5.9, 4.2, 2.2, and 3.5 months, respectively. No significant differences were observed between arms A and B in 6-month PFS rate, median PFS, or response rates. Treatment was well tolerated in all arms. No significant differences in toxicity were observed between arms A and B except for more grade 3 to 4 lymphopenia in arm A.
Conclusion: Temozolomide plus sorafenib was well tolerated and showed activity in melanoma patients without prior history of temozolomide. The activity of this combination regimen warrants further investigation. (Clin Cancer Res 2009;15(24):7711–8)
In vivo activation of the hypoxia-targeted cytotoxin AQ4N in human tumor xenografts
Authors: Williams Kaye J. , Albertella Mark R. , Fitzpatrick Brian , Loadman Paul M. , Shnyder Steven D. , Chinje Edwin C. , Telfer Brian A. , Dunk Chris R. , Harris Peter A. , Stratford Ian J. 
Published: December 2009

Abstract
AQ4N (banoxantrone) is a prodrug that, under hypoxic conditions, is enzymatically converted to a cytotoxic DNA-binding agent, AQ4. Incorporation of AQ4N into conventional chemoradiation protocols therefore targets both oxygenated and hypoxic regions of tumors, and potentially will increase the effectiveness of therapy. This current pharmacodynamic and efficacy study was designed to quantify tumor exposure to AQ4 following treatment with AQ4N, and to relate exposure to outcome of treatment. A single dose of 60 mg/kg AQ4N enhanced the response of RT112 (bladder) and Calu-6 (lung) xenografts to treatment with cisplatin and radiation therapy. AQ4N was also given to separate cohorts of tumor-bearing mice 24 hours before tumor excision for subsequent analysis of metabolite levels. AQ4 was detected by high performance liquid chromatography/mass spectrometry in all treated samples of RT112 and Calu-6 tumors at mean concentrations of 0.23 and 1.07 μg/g, respectively. These concentrations are comparable with those shown to be cytotoxic in vitro. AQ4-related nuclear fluorescence was observed in all treated tumors by confocal microscopy, which correlated with the high performance liquid chromatography/mass spectrometry data. The presence of the hypoxic marker Glut-1 was shown by immunohistochemistry in both Calu-6 tumors and RT112 tumors, and colocalization of AQ4 fluorescence and Glut-1 staining strongly suggested that AQ4N was activated in these putatively hypoxic areas. This is the first demonstration that AQ4N will increase the efficacy of chemoradiotherapy in preclinical models; the intratumoral levels of AQ4 found in this study are comparable with tumor AQ4 levels found in a recent phase I clinical study, which suggests that these levels could be potentially therapeutic. [Mol Cancer Ther 2009;8(12):3266–75]
BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR
Authors: Carboni Joan M. , Wittman Mark , Yang Zheng , Lee Francis , Greer Ann , Hurlburt Warren , Hillerman Stephen , Cao Carolyn , Cantor Glenn H. , Dell-John Janet , Chen Cliff , Discenza Lorell , Menard Krista , Li Aixin , Trainor George , Vyas Dolatrai , Kramer Robert , Attar Ricardo M. , Gottardis Marco M. 
Published: December 2009

AbstractBMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, &lt;2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5–365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, &lt;1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family–targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents. [Mol Cancer Ther 2009;8(12):3341–9]
Sulindac sulfide selectively inhibits growth and induces apoptosis of human breast tumor cells by phosphodiesterase 5 inhibition, elevation of cyclic GMP, and activation of protein kinase G
Authors: Tinsley Heather N. , Gary Bernard D. , Keeton Adam B. , Zhang Wei , Abadi Ashraf H. , Reynolds Robert C. , Piazza Gary A. 
Published: December 2009

AbstractSulindac displays promising antineoplastic activity, but toxicities from cyclooxygenase inhibition limit its use for chemoprevention. Previous reports suggest that its anticancer properties may be attributed to a cyclooxygenase-independent mechanism, although alternative targets have not been well defined. Here, we show that sulindac sulfide (SS) induces apoptosis and inhibits the growth of human breast tumor cells with IC50 values of 60 to 85 μmol/L. Within the same concentration range, SS inhibited cyclic GMP (cGMP) hydrolysis in tumor cell lysates but did not affect cyclic AMP hydrolysis. SS did not induce apoptosis of normal human mammary epithelial cells (HMEC) nor did it inhibit phosphodiesterase (PDE) activity in HMEC lysates. SS increased intracellular cGMP levels and activated protein kinase G in breast tumor cells but not HMEC. The guanylyl cyclase (GC) activator, NOR-3, and cGMP PDE inhibitors, trequinsin and MY5445, displayed similar growth-inhibitory activity as SS, but the adenylyl cyclase activator, forskolin, and other PDE inhibitors had no effect. Moreover, GC activation increased the sensitivity of tumor cells to SS, whereas GC inhibition reduced sensitivity. By comparing PDE isozyme profiles in breast tumor cells with HMEC and determining the sensitivity of recombinant PDE isozymes to SS, PDE5 was found to be overexpressed in breast tumor cells and selectively inhibited by SS. The mechanism of SS binding to the catalytic domain of PDE5 was revealed by molecular modeling. These data suggest that PDE5 inhibition is responsible for the breast tumor cell growth–inhibitory and apoptosis-inducing activity of SS and may contribute to the chemopreventive properties of sulindac. [Mol Cancer Ther 2009;8(12):3331–40]
RanBPM Has Proapoptotic Activities That Regulate Cell Death Pathways in Response to DNA Damage
Authors: Atabakhsh Elnaz , Bryce Dawn M. , Lefebvre Karen J. , Schild-Poulter Caroline 
Published: December 2009

Abstract
Ran-binding protein M (RanBPM) is a nucleocytoplasmic protein previously implicated in various signaling pathways, but whose function remains enigmatic. Here, we provide evidence that RanBPM functions as an activator of apoptotic pathways induced by DNA damage. First, transient expression of RanBPM in HeLa cells induced cell death through caspase activation, and in the long-term, forced expression of RanBPM impaired cell viability. RanBPM COOH-terminal domain stimulated the ability of RanBPM to induce caspase activation, whereas this activity was negatively regulated by the central SPRY domain. Second, small interfering RNA–directed knockdown of RanBPM prevented DNA damage–induced apoptosis, as evidenced by the marked reduction in caspase-3 and caspase-2 activation. This correlated with a magnitude fold increase in the survival of RanBPM-depleted cells. Following ionizing radiation treatment, we observed a progressive relocalization of RanBPM from the nucleus to the cytoplasm, suggesting that the activation of apoptotic pathways by RanBPM in response to ionizing radiation may be regulated by nucleocytoplasmic trafficking. Finally, RanBPM downregulation was associated with a marked decrease of mitochondria-associated Bax, whereas Bcl-2 overall levels were dramatically upregulated. Overall, our results reveal a novel proapoptotic function for RanBPM in DNA damage–induced apoptosis through the regulation of factors involved in the mitochondrial apoptotic pathway. (Mol Cancer Res 2009;7(12):1962–72)