bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-38: Evaluation of a PSA cleavable doxorubicin prodrug in the in vitro and in vivo LNCaP LN model
Authors: Elsadek Bakheet , Esser Norbert , Graeser Ralph , Warnecke André , Unger Clemens , Saleem Tahia , Kratz Felix
Published: February 2011

The goal of this work was to investigate the biological activity of a doxorubicin prodrug that is efficiently cleaved by prostate specific antigen (PSA) rapidly liberating doxorubicin as the final cleavage product. For this purpose we have developed an albumin-binding prodrug of doxorubicin, EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Leu-PABC-DOXO [EMC: ε-maleimidocaproyl; PABC: p-aminobenzyloxycarbonyl; DOXO: doxorubicin]. The incorporation of the PABC self-eliminating linker between the peptide sequence and doxorubicin enhanced the enzymatic cleavage rate and improved the cleavage profile. PSA cleavage produced the metabolite H-Ser-Leu-PABC-DOXO which was further degraded to release doxorubicin as a final cleavage product within a few hours in prostate tumor tissue homogenates as well as in PSA-positive LNCaP LN cell lysates. In the cell culture experiments, our prodrug exhibited antiproliferative activity in the low micromolar range with an IC50 value of ∼1 μM against a PSA-expressing prostate cancer cell line with a stably integrated Luciferase-Neomycin (LN) resistance fusion gene cassette (LNCaP LN). Moreover, H-Ser-Leu-PABC-DOXO showed comparable in vitro activity to doxorubicin (∼0.2 μM). Orientating toxicity studies in mice showed that the maximum tolerated dose of our novel prodrug was twice that of conventional doxorubicin. Consequently, the in vivo efficacy of the prodrug (6 mg/kg doxorubicin equivalents) is currently being compared to free doxorubicin (3 mg/kg) in a mouse model of human prostate cancer using luciferase transduced LNCaP cells orthotopically implanted in SCID mice.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-38.
Abstract LB-380: Apo2L/TRAIL reduces interstitial fluid pressure and enhances gemicitabine uptake in patient pancreatic tumor xenografts
Authors: Hylander Bonnie L. , Sen Arindam , Beachy Sarah , Gibbs John , Pitoniak Rose , Prey Joshua , Fetterly Gerald , Repasky Elizabeth A.
Published: February 2011

Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has promising anti-tumor therapeutic potential and is in clinical trials. It is known that microenvironmental factors such as elevated interstitial fluid pressure limits uptake and greatly inhibits anti-tumor efficacy of many therapeutics. We are investigating the role of interstitial fluid pressure in the anti-tumor effect of Apo2L/TRAIL alone and in combination with gemcitabine.

We first carried out a histological analysis of Colo205 tumors treated with a single 1000 g dose of Apo2L/TRAIL. Apoptosis (ck18+ cells) and infiltration of macrophages (F4/80+ cells) peaks by 8 hrs; by 24 and 48 hours, apoptotic debris has been cleared and the lumen of tumor vessels is clearly apparent. This is in sharp contrast to untreated tumors in which cells are densely packed and vessels with an open lumen are seldom seen. Correspondingly, measurements of tumor interstitial fluid pressure (IFP) taken 48 hrs after a single treatment of Apo2L/TRAIL revealed a significant reduction in IFP compared to tumors in the untreated mice (n=5; 0.3 cm H2O vs. 3.4 cm H2O, P= 0.002).

We have characterized the Apo2L/TRAIL sensitivity of a panel of patient pancreatic tumor xenografts and found a range of responses to Apo2L/TRAIL from actual regression (tumor growth inhibition, TGI, of 108%) to complete resistance (TGI of 0%). Histological analysis of a sensitive tumor showed that Apo2L/TRAIL induced both the physical changes seen in Colo205 as well as a similarly significant reduction in IFP (n=7; P= 0.003). Importantly, in these patient xenografts, combination therapy with Apo2L/TRAIL and chemotherapy has been shown to enhance the antitumor effect of gemcitabine. Therefore, we investigated the effect of Apo2L/TRAIL induced lowering of IFP on gemcitabine uptake. In these studies, a single dose of gemcitabine was administered 48 hrs after Apo2L/TRAIL administration. Pharmacological analysis reveals a 33% increase in gemcitabine uptake in tumors in the 6 hours following Apo2L/TRAIL administration; no such increase was observed in normal liver.

These results support the idea that pretreatment of a tumor with Apo2L/TRAIL leads to “decompression” of the tumor and will selectively improve tumor uptake of chemotherapeutics. We are currently investigating different schedules of administration in order to maximize the uptake of gemcitabine and optimize the anti-tumor efficacy of this combination therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-380.
Abstract LB-408: NAT2 polymorphisms, tobacco smoking, and breast cancer risk in the Breast and Prostate Cancer Cohort Consortium (BPC3)
Authors: Cox David G. , Dostal Lucie , Hunter David J. , Ziegler Regina G. , LeMarchand Loïc , Thun Michael J.
Published: February 2011

Aromatic and heterocyclic amines are carcinogens in tobacco smoke that cause mammary tumors in rodents. N-acetyltransferase 2 (NAT2) can detoxy aromatic amines and polymorphisms in the NAT2 gene result in slow, intermediate and rapid acetylation phenotypes. Slow NAT2 acetylation has been hypothesized to potentiate the risk of smoking for both breast and bladder cancer. Whereas this hypothesis is reasonably well-established for bladder cancer, the data for breast cancer are still being evaluated, most recently in a meta-analysis of up to 13 studies. In a subset of these studies including 4,264 cases, a ∼1.4 fold increase in risk of breast cancer was observed among women exposed to more than 20 pack-years of cigarette smoking. This increase in risk was confined to slow acetylators, and no statistically significant increase in risk was observed among rapid acetylators. We sought to replicate this finding in a consortium of six large prospective cohorts in the United States and Europe. We genotyped the three most common polymorphisms that define NAT2 acetylation phenotype in populations of European origin among approximately 7,750 breast cancer cases and 9,900 matched controls with prospectively collected information on tobacco smoking and established risk factors for breast cancer. Nested case-control analyses showed no association between NAT2 acetylation phenotype (rapid, intermediate, slow) and breast cancer risk. Furthermore, no interaction was observed between smoking status (specifically never, former or current) and NAT2 acetylation phenotype on breast cancer risk (likelihood ratio test p-interaction 0.58). Ongoing analyses are examining more detailed measures of cigarette smoking such as duration, intensity, pack years, and smoking during the potentially critical period between menarche and first full term pregnancy, as well as subsets of patients defined by menopausal or steroid hormone receptor status. These data contribute substantially to resolving the longstanding debate over whether smoking affects breast cancer risk particularly in women with limited capacity to acetylate tobacco carcinogens.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-408.
Abstract LB-412: Urinary polyphenols, GST copy number variation, and breast cancer risk: Results from the Shanghai Women's Health Study (SWHS)
Authors: Luo Jianfeng , Gao Yu-Tang , Chow Wong-Ho , Shu Xiao-ou , Li Honglan , Yang Gong , Cai Qiuyin , Li Guoliang , Rothman Nathaniel , Cai Hui , Shrubsole Martha J. , Franke Adrian A. , Zheng Wei , Dai Qi
Published: February 2011

Background: In vitro studies found that the flavanol epigallocatechin (EGC) and flavonols, but not the flavanol epicatechin (EC), activated glutathione s-transferases (GST), a family of phase II enzymes which detoxify reactive oxygen species, such as catechol estrogen metabolites. Objective: To investigate whether urinary excretion of tea polyphenols interacted with GST polymorphism in relation to breast cancer risk.

Design: We conducted a study of 353 incident breast cancer cases and 701 individually-matched controls nested within the Shanghai Women's Health Study cohort of women aged 40-70 years at baseline. Liquid chromatography tandem mass spectrometry was used to measure urinary excretion of flavanols and flavonols. Real-time multiplex PCR were used to quantify the copy number variation for the GSTM1 and GSTT1 genes.

Results: Urinary excretion of flavonols and flavanols, particularly, EGC(p=0.02), were significantly higher among those null for GSTM1 than those positive for GSTM1. Furthermore, urinary excretion of flavanol EGC significantly interacted with GSTM1 polymorphism (p=0.04), while flavonols, particularly kaempferol, may interact with both GSTM1 and GSTT1 genotype in relation to breast cancer. As a result, flavanols (primarily EGC) and flavonols significantly interacted with the joint genotypes of GSTM1 and GSTT1 in relation to breast cancer risk. Flavonols and flavanols (EGC in particular) were associated with a reduced risk of breast cancer among those null for GSTM1 and GSTT1, whereas flavonols, particularly kaempferol, were significantly associated with an increased risk of breast cancer for those possessing both GSTM1 and GSTT1.

Conclusion: These results, if confirmed, may provide a new avenue for the personalized prevention of breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-412.
Abstract LB-413: A multi-stage association study in breast cancer identifies a protective allele at NCOA7
Authors: Poland Kathryn S. , Breyer Joan P. , Bradley Kevin M. , Schuyler Peggy A. , Plummer W. Dale , Freudenthal Marcia G. , Trentham-Dietz Amy , Newcomb Polly A. , Titus-Ernstoff Linda T. , Garcia-Closas Montserrat , Sanders Melinda E. , Page David L. , Egan Kathleen M. , Dupont William D. , Smith Jeffrey R.
Published: February 2011

Estrogen metabolism and growth factor signaling pathway genes play a potential role in breast cancer predisposition. We evaluated pathway genes in a nested case-control investigation of women within the Nashville Breast Cohort, using germline DNA obtained from archival benign breast biopsies (formalin-fixed paraffin embedded). We applied methods enabling large-scale candidate gene investigation in the archival DNA (2 to 6 decades old). The study included 447 women who progressed to breast cancer (cases), and 838 women who did not (controls, matched on age and year of biopsy to cases in a ∼ 2:1 ratio). Single allele- and haplotype-based tests of association were explored among 115 tagged pathway genes, and results were compared to those of the CGEMS GWAS (1,145 cases, 1,142 controls). Findings across the two study populations were concordant in 8 genes. Further replication of results was sought in the Collaborative Breast Cancer Study (1,552 cases, 1,185 controls). FGFR2 and NCOA7 associations were concordant across all three studies. FGFR2 carries known susceptibility variants confirmed in prior GWAS, whereas the association at NCOA7 on 6q22.32 is novel. NCOA7 encodes a nuclear receptor co-activator that directly interacts with estrogen receptor to modulate its activity. A haplotype of NCOA7 had a significant inverse association with breast cancer in each of the three studies (odds ratios of 0.67, 0.77, and 0.78 (respectively) for haplotype carriers relative to non-carriers), with a combined odds ratio of 0.77 (95% CI 0.65-0.89), P = 5.1 × 10-4. These observations provide credible evidence that this NCOA7 variant has a protective effect on breast cancer risk.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-413.
Abstract LB-415: Polymorphisms in nucleotide excision repair genes and endometrial cancer risk
Authors: Doherty Jennifer A. , Weiss Noel S. , Fish Sherianne , Loomis Melissa M. , Rossing Mary A. , Chen Chu
Published: February 2011

The increased risk of endometrial cancer associated with unopposed exogenous estrogens and high levels of endogenous estrogens (as are present in obesity) has been hypothesized to result, at least in part, via two possible mechanisms: 1) increased cellular proliferation, and 2) through the production of estrogen metabolites, which can result in DNA damage by directly binding to DNA and forming bulky DNA adducts, and/or indirectly through the production of reactive oxygen species. Thus, interindividual variation in the ability to repair such damage might influence a woman's risk of endometrial cancer. To test this hypothesis, we examined whether the presence of the minor alleles in 64 tag SNPs in the nucleotide excision repair genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, LIG1, XPA, and XPC was associated with risk of endometrial cancer in a population-based case-control study in Washington State, with 726 cases ages 50-74 years diagnosed between 1994-2005, and 736 controls frequency-matched to the cases by age. The analyses were restricted to non-Hispanic white women. Most of the genotypes that we investigated were not associated with endometrial cancer risk. However, the presence of the rs4150386 C allele (ERCC5), the rs3730865 C allele (LIG1), and the rs3731127 T allele (XPC) was associated with risk, with respective age-adjusted per-allele odds ratios (ORs) and 95% confidence intervals (CIs) of 0.68 (0.53-0.87), 1.50 (1.05-2.14) and 1.52 (1.10-2.10). The association between rs4150386 and endometrial cancer risk was considerably stronger among obese women (body mass index (BMI)≥30 kg/m2: per-C-allele OR=0.40, 95% CI 0.24-0.65) compared to women with BMI<30 kg/m2 (per-C-allele OR=0.86, 95% CI 0.64-1.14), while the association with rs3730865 was stronger among lighter versus heavier weight women (per-C-allele ORs and 95% CIs were: 1.69, 95% CI 1.12-2.56 for BMI<30 kg/m2, and 1.15, 95% CI 0.55-2.42 for BMI≥30 kg/m2). The association with rs3731127 did not vary by BMI, and the altered risk associated with the minor alleles of the three SNPs did not vary by use of long-term unopposed estrogens. Because of the multiple redundancies in DNA repair pathways and the large number of possible associations examined, there is the potential for false positive findings, both overall and in BMI subgroups. Any conclusions regarding the influence of NER genotypes on risk of endometrial cancer await the results of additional studies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-415.
Abstract LB-425: Design of ß-cyclodextrin-curcumin self-assembly: A new approach for enhanced curcumin delivery and therapeutic efficacy in prostate cancer cells
Authors: Yallapu Murali M. , Jaggi Meena , Chauhan Subhash C.
Published: February 2011

Curcumin (CUR), a hydrophobic polyphenolic compound derived from the rhizome of the herb Curcuma longa, has shown a wide range of biological applications including cancer prevention and treatment. However, low water solubility, poor pharmacokinetics and suboptimal tumor uptake, greatly hamper its anti-cancer efficacy. This study was designed to develop a novel ß-cyclodextrin-curcumin (CD-CUR) self-assembly approach for sustained release and improved curcumin delivery in prostate cancer cells. Cyclodextrin-curcumin self-assemblies were prepared by solvent evaporation technique. The formation of self-assemblies was evaluated by Fourier Transform Infra-red (FTIR), Differential Scanning Calorimetry (DSC), Thermo-gravimetric Analysis (TGA), Scanning and Transmission Electron Microscopic (SEM/TEM) analyses. Intracellular uptake of these self-assemblies was evaluated by Flow cytometry and immunofluorescence microscopy analyses. Therapeutic efficacy of these self-assemblies was determined by cell proliferation and colony formation assays using C4-2, DU145, LNCaP and PC3 prostate cancer cells. The effect of CD-CUR formulation on apoptosis related proteins was determined by immunoblotting. Physico-chemical characterization analyses confirm the formation of CD-CUR self-assemblies, which demonstrated excellent stability and solubility in physiological solutions and showed enhanced intracellular uptake in cells. Additionally, CD-CUR formulation has exhibited an improved therapeutic efficacy and enhanced PARP cleavage in prostate cancer cells compared to free curcumin. In conclusion, CD-CUR self-assemblies enhance intracellular delivery of active curcumin in prostate cancer cells and improved its therapeutic efficacy. This study suggests that CD-CUR self-assembly may be a useful nanoscale formulation for improved curcumin delivery in prostate cancer cells. Tumor specific antibody targeted CD-CUR formulation can further improve the in vivo delivery of curcumin in prostate tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-425.
Abstract LB-68: Comparative analysis of the miRNome in tumors and plasma from colorectal cancer patients
Authors: Nielsen Søren J. , Jacobsen Nana , Fog Jacob U. , Willenbrock Hanni , Baker Adam , Ørntoft Torben F. , Nielsen Hans J. , Andersen Claus L. , Møller Søren
Published: February 2011

MicroRNAs (miRNAs) constitute a recently discovered class of small cellular RNAs (typically 21-23 nt) that function as post-transcriptional regulators of gene expression through binding of miRNA target sequences in mRNA 3′ untranslated regions (UTRs). Current estimates indicate that at least one third of the cellular transcriptome is regulated by miRNAs, and that each miRNA has the potential to regulate hundreds of different mRNAs. As a consequence, miRNAs have been proposed to be master regulators of cellular state. This hypothesis has been borne out by a large number of studies demonstrating a causal link between miRNA dys-regulation and numerous disease states, including a diverse array of human cancers. Furthermore, the high relative stability of miRNA in common clinical source materials (e.g. FFPE blocks, plasma, urine, saliva, etc.) and the ability of miRNA expression profiles to accurately classify discrete tissue types and disease states have positioned miRNA quantification as a promising new tool for a wide range of diagnostic applications.

To facilitate discovery and clinical transfer of miRNA-based diagnostic markers, we developed a genome-wide LNA™-based miRNA q-rt-PCR platform with unparalleled sensitivity and robustness. The platform uses a universal RT system and thus allows high-throughput profiling of miRNAs from important clinical sources without the need for pre-amplification. Using this system, we profiled samples relevant to colorectal cancer: tumor samples from colorectal cancer patients, normal adjacent tissue (NAT) from the same patients, plasma from the same patients from blood drawn on the day before surgery, and plasma from matched healthy volunteers. Both principal component analysis and unsupervised hierarchical clustering of the most variable miRNAs accurately classified tumor samples away from the set of NAT samples, suggesting that the single most important distinguishing factor between the two sets of samples is related to neoplastic transformation. We also define miRNAs that are differentially expressed in the plasma of healthy volunteers versus colorectal cancer patients and we will present an analysis of the overlap between differentially expressed miRNAs in plasma and tissue.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-68.
Abstract LB-70: In vitro anti-cancer activity of PF-04691502, a potent dual inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) in a panel of human breast cancer cell lines
Authors: Britten Carolyn D. , Chow Lucy , Conklin Dylan , Kalous Ondrej , Desai Amrita , Ginther Charles , Dering Judy , Christensen James , Milham Robert , Slamon Dennis J. , Finn Richard S.
Published: February 2011

Introduction: Activating mutations in the PIK3CA gene (encoding for the P110 catalytic subunit of PI3K) are found in more than 25% of human breast cancers [Saal LH Cancer Res 2005]. PF-04691502 is a potent orally-available ATP-competitive and reversible dual inhibitor of PI3K and mTOR. This study evaluates the anti-proliferative and cytotoxic activity of PF-04691502 across a large panel of breast cancer cell lines that recapitulate the clinical spectrum of the disease.

Methods: Over 40 human breast cancer cell lines were exposed in vitro to PF-0469102 over 9 concentrations to generate dose-response curves. These assays were performed over a 6-day incubation period using direct cell counts. The ability of PF-04691502 to inhibit proliferation and induce cell death was calculated using IC50 and LD50 values, respectively. PI3K mutation status was available from public databases. In addition, baseline gene expression profiles were generated using the Agilent platform. A subset of breast cancer cell lines with varying levels of sensitivity to the compound were incubated with PF-04691502 concentrations ranging from 10 to 1000 nM, and processed for Western blotting.

Results: Twenty-two cell lines had IC50 values < 100 nM, with a trend towards increased sensitivity to PF-04691502 in breast cancer cell lines harboring PIK3CA mutations, and in those belonging to the luminal subtype. Lethality (LD50 < 1 M) was observed in 10 out of 12 breast cancer cell lines harboring PI3KCA mutations, and was prevalent in cell lines of luminal subtype. Inhibition of the downstream target pAKT was observed.

Conclusions: PF-04691502 has anti-cancer activity across a spectrum of breast cancer cell lines, and demonstrates lethality against a subset of cell lines. A first-in-human phase I trial of PF-04691502 is ongoing.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-70.
Abstract LB-93: The epigenetic basis of the tumorigenic action of retinoic acid
Authors: Rossetti Stefano , Ren MingQiang , Somenzi Giulia , Tagliavacca Luigina , Sacchi Nicoletta
Published: February 2011

Preformed vitamin A, or Retinol, is found in animal foods, such as liver and whole milk, and in some fortified food products. Carotenoids, such as beta-carotene from fruit and vegetables, are also efficiently converted into Retinol. Retinol, once converted into its bioactive form, retinoic acid (RA), plays a major role in cell division, cell death, and cell differentiation. We found that RA can exert a double-edged action: it can either inhibit, or promote, tumorigenesis according to the functional status of one of its receptors, the RA receptor alpha (RARA). Further, we found that RA, through RARA, controls a network of tumor suppressor genes governing cell death, cell proliferation, cell differentiation, migration, and invasion. Finally, we observed that concomitant with epigenetic silencing of the tumor suppressor gene network, due to loss/functional inhibition of RARA, RA exerts a clear tumor-promoting action, raising the question as to whether dietary sources of RA, or RA precursors, can also promote tumorigenesis in cells with an impaired RARA. Using an isogenic breast cancer cell model (T47D), comprising two clonal cell lines, one with a functional RARA-regulated gene network (T47DLXC5) and one without functional RARA (T47DDNC8) (Ren et al., MCB, 2006), we generated subcutaneous xenograft tumors in athymic female nude mice. A 6-week diet with either RA (5 or 10 mg/kg) or Retinol (50 mg/kg) induced an opposite effect on xenograft tumor growth. T47DDNC8 xenograft tumors were stimulated to grow and metastasize to distant sites by RA/Retinol, while T47DLXC5 xenograft tumors were growth-inhibited by RA/Retinol, and did not invade.

In breast cancer RARA function is often impaired due to a variety of upstream causes, including faulty RA transport by CRABP2 onto RARA and/or loss of Estrogen Receptor alpha (ERA), a pivotal RARA transcriptional regulator. Early detection of epigenetic silencing of tumor suppressor genes of the RARA network can be used to prevent tumorigenic effects of dietary sources of RA on breast tumorigenesis.

This work was funded by R01 CA127614 (NS), PRIN 2007 (LT, SR).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-93.
Cardiac Progenitor Cell Commitment Is Inhibited by Nuclear Akt Expression
Authors: Fischer Kimberlee M. , Din Shabana , Gude Natalie , Konstandin Mathias H. , Wu Weitao , Quijada Pearl , Sussman Mark A.
Published: February 2011

Rationale:

Stem cell therapies to regenerate damaged cardiac tissue represent a novel approach to treat heart disease. However, the majority of adoptively transferred stem cells delivered to damaged myocardium do not survive long enough to impart protective benefits, resulting in modest functional improvements. Strategies to improve survival and proliferation of stem cells show promise for significantly enhancing cardiac function and regeneration.

Objective:

To determine whether injected cardiac progenitor cells (CPCs) genetically modified to overexpress nuclear Akt (CPCeA) increase structural and functional benefits to infarcted myocardium relative to control CPCs.

Methods and Results:

CPCeA exhibit significantly increased proliferation and secretion of paracrine factors compared with CPCs. However, CPCeA exhibit impaired capacity for lineage commitment in vitro. Infarcted hearts receiving intramyocardial injection of CPCeA have increased recruitment of endogenous c-kit cells compared with CPCs, but neither population provides long-term functional and structural improvements compared with saline-injected controls. Pharmacological inhibition of Akt alleviated blockade of lineage commitment in CPCeA.

Conclusions:

Although overexpression of nuclear Akt promotes rapid proliferation and secretion of protective paracrine factors, the inability of CPCeA to undergo lineage commitment hinders their capacity to provide functional or structural benefits to infarcted hearts. Despite enhanced recruitment of endogenous CPCs, lack of functional improvement in CPCeA-treated hearts demonstrates CPC lineage commitment is essential to the regenerative response. Effective stem cell therapies must promote cellular survival and proliferation without inhibiting lineage commitment. Because CPCeA exhibit remarkable proliferative potential, an inducible system mediating nuclear Akt expression could be useful to augment cell therapy approaches.
Sunnybrook and House‐Brackmann Systems in 5397 Facial Gradings
Authors: Kanerva Mervi , Jonsson Lars , Berg Thomas , Axelsson Sara , Stjernquist‐Desatnik Anna , Engström Mats , Pitkäranta Anne
Published: February 2011

Objectives

To study the correlation between Sunnybrook and House‐Brackmann facial grading systems at different time points during the course of peripheral facial palsy.

Study Design

Prospective multicenter trial.

Setting

Seventeen otorhinolaryngological centers.

Subjects and Methods

Data are part of the Scandinavian Bell’s palsy study. The facial function of 1920 patients with peripheral facial palsy was assessed 5397 times with both Sunnybrook and House‐Brackmann (H‐B) facial grading systems. Grading was done at initial visit, at days 11 to 17 of palsy onset, and at 1 month, 2 months, 3 months, 6 months, and 12 months. Statistical evaluation was by Spearman correlation coefficient and box plot analysis.

Results

Spearman correlation coefficient varied from −0.81 to −0.96, with the weakest correlation found at initial visit. Box plot analysis for all assessments revealed that Sunnybrook scores were widely spread over different H‐B grades. With 50% of the results closest to the median, Sunnybrook composite scores varied in H‐B grades as follows: H‐B I, 100; H‐B II, 71 to 90; H‐B III, 43 to 62; H‐B IV, 26 to 43; H‐B V, 13 to 25; and H‐B VI, 5 to 14.

Conclusion

Gradings correlated better in follow‐up assessments than at initial visit. As shown by the wide overlap of the grading results, subjective grading systems are only approximate. However, a conversion table for Sunnybrook and H‐B gradings was obtained and is included in the article. It can be used for further development of facial grading systems.
Thyroid Alar Cartilage Graft Laryngotracheal Reconstruction in Adults
Authors: Cui Pengcheng , Gao Pengfei , Luo Jiasheng , Ruan Yanyan
Published: February 2011

Objective

To assess the outcomes of laryngotracheal reconstruction using thyroid alar cartilage grafting in adult patients with laryngotracheal stenosis.

Study Design

Case series with chart review.

Setting

Tertiary university hospital.

Subjects and Methods

Twelve adults who underwent thyroid alar cartilage graft laryngotracheal reconstruction from April 1997 to April 2009 for laryngotracheal stenosis were analyzed. The mean age of the study population was 29 years. Using the Myer‐Cotton grading system, 3 patients had grade II stenosis, 7 had grade III, and 2 had grade IV. Seven of the 12 patients had subglottic stenosis, 3 had tracheal stenosis, and 2 had subglottic and upper tracheal stenosis.

Results

Nine of 12 (75%) patients were decannulated. Of the patients in whom laryngotracheal reconstruction failed, 2 had grade IV stenosis and 1 had severe grade III stenosis with a long segment of stenotic tissue. The postoperative complications were hematoma of the left laryngeal ventricle at the donor site in 1 patient, granulation tissues in the supraglottic and suprastomal region and at the graft site in 4 patients, and neck wound infection in 1 patient. Ossification of the thyroid alar cartilage was observed in 2 patients. A T‐tube remained in situ for 6 to 18 months.

Conclusion

Laryngotracheal reconstruction with thyroid alar cartilage graft could be a viable alternative for the treatment of laryngotracheal stenosis in adults. However, it should be used only in cases of limited and minor subglottic or tracheal stenosis.
Politically Relevant Ethnic Groups across Space and Time: Introducing the GeoEPR Dataset
Authors: Wucherpfennig Julian , Weidmann Nils B. , Girardin Luc , Cederman Lars-Erik , Wimmer Andreas
Published: February 2011

This article introduces GeoEPR, a geocoded version of the Ethnic Power Relations (EPR) dataset that charts politically relevant ethnic groups across space and time. We describe the dataset in detail, discuss its advantages and limitations, and use it in a replication of Cederman, Wimmer and Min’s (2010) study on the causes of ethno-nationalist conflict. We show that territorial conflicts are more likely to involve groups that settle far away from the capital city and close to the border, while these spatial variables have no effect for governmental conflicts.
Cerebral Air Emboli With Atrial-Esophageal Fistula Following Atrial Fibrillation Ablation
Authors: French K. F. , Garcia C. , Wold J. J. , Hoesch R. E. , Ledyard H. K.
Published: February 2011

Background: Atrial-esophageal fistula (AEF) is a rare and early complication of radiofrequency ablation for medically refractory atrial fibrillation, but has devastating consequences when the diagnosis is delayed or difficult to make. Methods: Single case in a neurosciences critical care center. Results: A 69-year-old man with significant cardiac and neurologic medical history who underwent atrial fibrillation ablation 50 days prior to admission to the neurocritical care unit presented with acute left-sided weakness and gram-positive bacterial sepsis. This is an exceptional case discussing the need for early detection of AEF presenting with sepsis, neurologic deficit along with complicated decision-making in the neurocritical care setting. His hospital course was complicated by acute stroke, left ventricular (LV) aneurysm with thrombus, gastrointestinal (GI) bleed discovered to be from left atrial esophageal fistula, and subsequent cerebral air emboli leading to death. Conclusions: This is the most delayed presentation of AEF following atrial fibrillation ablation reported in the literature to date. We emphasize the need for awareness of this complication even after such an unexpected time-frame postprocedure as well as the unintended complications of cerebral air emboli following upper endoscopy.
Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium
Authors: Pidala Joseph , Kurland Brenda , Chai Xiaoyu , Majhail Navneet , Weisdorf Daniel J. , Pavletic Steven , Cutler Corey , Jacobsohn David , Palmer Jeanne , Arai Sally , Jagasia Madan , Lee Stephanie J.
Published: February 2011

Quality of life (QOL) after hematopoietic cell transplantation (HCT) is compromised by chronic GVHD. In a prospectively assembled multicenter cohort of adults with chronic GVHD (n = 298), we examined the relationship between chronic GVHD severity defined by National Institutes of Health (NIH) criteria and QOL as measured by the SF-36 and FACT-BMT instruments at time of enrollment. Chronic GVHD severity was independently associated with QOL, adjusting for age. Compared with population normative data, SF-36 scores were more than a SD (10 points) lower on average for the summary physical component score (PCS) and role-physical subscale, and significantly lower (with magnitude 4-10 points) for several other subscales. Patients with moderate and severe cGVHD had PCS scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, and greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease. Moderate to severe cGVHD as defined by NIH criteria is associated with significant compromise in multiple QOL domains, with PCS scores in the range of other systemic autoimmune diseases. Compromised QOL provides a functional assessment of the effects of chronic GVHD, and may be measured in cGVHD clinical studies using either the SF-36 or the FACT-BMT.
Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation
Authors: Jo Stephanie Y. , Granowicz Eric M. , Maillard Ivan , Thomas Dafydd , Hess Jay L.
Published: February 2011

Disruptor of telomeric silencing 1-like (Dot1l) is a histone 3 lysine 79 methyltransferase. Studies of constitutive Dot1l knockout mice show that Dot1l is essential for embryonic development and prenatal hematopoiesis. DOT1L also interacts with translocation partners of Mixed Lineage Leukemia (MLL) gene, which is commonly translocated in human leukemia. However, the requirement of Dot1l in postnatal hematopoiesis and leukemogenesis of MLL translocation proteins has not been conclusively shown. With a conditional Dot1l knockout mouse model, we examined the consequences of Dot1l loss in postnatal hematopoiesis and MLL translocation leukemia. Deletion of Dot1l led to pancytopenia and failure of hematopoietic homeostasis, and Dot1l-deficient cells minimally reconstituted recipient bone marrow in competitive transplantation experiments. In addition, MLL-AF9 cells required Dot1l for oncogenic transformation, whereas cells with other leukemic oncogenes, such as Hoxa9/Meis1 and E2A-HLF, did not. These findings illustrate a crucial role of Dot1l in normal hematopoiesis and leukemogenesis of specific oncogenes.
Expression profile analysis of the inflammatory response regulated by hepatocyte nuclear factor 4α
Authors: Wang Zhongyan , Bishop Eric P , Burke Peter A
Published: February 2011

Background

Hepatocyte nuclear factor 4α (HNF4α), a liver-specific transcription factor, plays a significant role in liver-specific functions. However, its functions are poorly understood in the regulation of the inflammatory response. In order to obtain a genomic view of HNF4α in this context, microarray analysis was used to probe the expression profile of an inflammatory response induced by cytokine stimulation in a model of HNF4α knock-down in HepG2 cells.

Results

The expression of over five thousand genes in HepG2 cells is significantly changed with the dramatic reduction of HNF4α concentration compared to the cells with native levels of HNF4α. Over two thirds (71%) of genes that exhibit differential expression in response to cytokine treatment also reveal differential expression in response to HNF4α knock-down. In addition, we found that a number of HNF4α target genes may be indirectly mediated by an ETS-domain transcription factor ELK1, a nuclear target of mitogen-activated protein kinase (MAPK).

Conclusion

The results indicate that HNF4α has an extensive impact on the regulation of a large number of the liver-specific genes. HNF4α may play a role in regulating the cytokine-induced inflammatory response. This study presents a novel function for HNF4α, acting not only as a global player in many cellular processes, but also as one of the components of inflammatory response in the liver.
Discovery of barley miRNAs through deep sequencing of short reads
Authors: Schreiber Andreas W , Shi Bu-Jun , Huang Chun-Yuan , Langridge Peter , Baumann Ute
Published: February 2011

Background

MicroRNAs are important components of the regulatory network of biological systems and thousands have been discovered in both animals and plants. Systematic investigations performed in species with sequenced genomes such as Arabidopsis, rice, poplar and Brachypodium have provided insights into the evolutionary relationships of this class of small RNAs among plants. However, miRNAs from barley, one of the most important cereal crops, remain unknown.

Results

We performed a large scale study of barley miRNAs through deep sequencing of small RNAs extracted from leaves of two barley cultivars. By using the presence of miRNA precursor sequences in related genomes as one of a number of supporting criteria, we identified up to 100 miRNAs in barley. Of these only 56 have orthologs in wheat, rice or Brachypodium that are known to be expressed, while up to 44 appear to be specifically expressed in barley.

Conclusions

Our study, the first large scale investigation of small RNAs in barley, has identified up to 100 miRNAs. We demonstrate that reliable identification of miRNAs via deep sequencing in a species whose genome has not been sequenced requires a more careful analysis of sequencing errors than is commonly performed. We devised a read filtering procedure for dealing with errors. In addition, we found that the use of a large dataset of almost 35 million reads permits the use of read abundance distributions along putative precursor sequences as a practical tool for isolating miRNAs in a large background of reads originating from other non-coding and coding RNAs. This study therefore provides a generic approach for discovering novel miRNAs where no genome sequence is available.
FGFR4 Gly388Arg polymorphism contributes to prostate cancer development and progression: A meta-analysis of 2618 cases and 2305 controls
Authors: Xu Bin , Tong Na , Chen Shu Q , Hua Li X , Wang Zeng J , Zhang Zheng D , Chen Ming
Published: February 2011

Background

Fibroblast growth factor receptor 4 (FGFR4) displays multiple biological activities, including mitogenic and angiogenic activity, and plays important roles in the etiology and progression of prostate cancer. Gly388Arg polymorphism in FGFR4 gene has been reported to be involved in prostate cancer incidence and aggressiveness in several studies. To derive a more precise estimation of the relationship, a meta-analysis was performed.

Methods

Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association.

Results

The Arg388 allele increased prostate cancer risk compared with Gly388 allele (OR = 1.17, 95% CI = 1.07-1.29). When stratified by race, there was a significantly increased prostate cancer risk in Asian and Caucasian populations. Moreover, prostate cancer patients with Arg/Arg genotype had a 1.34-fold increased risk of advanced prostate cancer (95% CI: 1.03-1.74) compared with those with Gly/Gly+Gly/Arg genotype.

Conclusion

This meta-analysis showed the evidence that FGFR4 Gly388Arg polymorphism was associated with an increased risk of prostate cancer development and progression, suggesting that FGFR4 Gly388Arg polymorphism could be a marker for prostate cancer development and progression.
Multi-omics approach to study the growth efficiency and amino acid metabolism in Lactococcus lactis at various specific growth rates
Authors: Lahtvee Petri-Jaan , Adamberg Kaarel , Arike Liisa , Nahku Ranno , Aller Kadri , Vilu Raivo
Published: February 2011

Background

Lactococcus lactisis recognised as a safe (GRAS) microorganism and has hence gained interest in numerous biotechnological approaches. As it is fastidious for several amino acids, optimization of processes which involve this organism requires a thorough understanding of its metabolic regulations during multisubstrate growth.

Results

Using glucose limited continuous cultivations, specific growth rate dependent metabolism ofL. lactisincluding utilization of amino acids was studied based on extracellular metabolome, global transcriptome and proteome analysis. A new growth medium was designed with reduced amino acid concentrations to increase precision of measurements of consumption of amino acids. Consumption patterns were calculated for all 20 amino acids and measured carbon balance showed good fit of the data at all growth rates studied. It was observed that metabolism ofL. lactisbecame more efficient with rising specific growth rate in the range 0.10 - 0.60 h-1, indicated by 30% increase in biomass yield based on glucose consumption, 50% increase in efficiency of nitrogen use for biomass synthesis, and 40% reduction in energy spilling. The latter was realized by decrease in the overall product formation and higher efficiency of incorporation of amino acids into biomass.L. lactisglobal transcriptome and proteome profiles showed good correlation supporting the general idea of transcription level control of bacterial metabolism, but the data indicated that substrate transport systems together with lower part of glycolysis inL. lactiswere presumably under allosteric control.

Conclusions

The current study demonstrates advantages of the usage of strictly controlled continuous cultivation methods combined with multi-omics approach for quantitative understanding of amino acid and energy metabolism ofL. lactiswhich is a valuable new knowledge for development of balanced growth media, gene manipulations for desired product formation etc. Moreover, collected dataset is an excellent input for developing metabolic models.
Studying the local character of Raman features of single-walled carbon nanotubes along a bundle using TERS
Authors: Peica Niculina , Thomsen Christian , Maultzsch Janina
Published: February 2011

Here, we show that the Raman intensity of the G-mode in tip-enhanced Raman spectroscopy (TERS) is strongly dependent on the height of the bundle. Moreover, using TERS we are able to position different single-walled carbon nanotubes along a bundle, by correlating the observed radial breathing mode (RBM) with the AFM topography at the measuring point. The frequency of the G- mode behaves differently in TERS as compared to far-field Raman. Using the RBM frequency, the diameters of the tubes were calculated and a very good agreement with the G--mode frequency was observed.
Enhanced specific immune responses by CpG DNA in mice immunized with recombinant hepatitis B surface antigen and HB vaccine
Authors: Zhang Xiancheng , He Peng , Hu Zhongyu , Wang Xingtai , Liang Zhenglun
Published: February 2011

Background

Hepatitis B vaccine adjuvant, alum, is generally used for vaccination although it does not stimulate Th1 immunity and 10% of the population has low or no antibody response. Efforts have been continued to find more efficient vaccine adjuvants for better antibody response as well as stimulation of Th1 immunity.

Methods

CpG DNA was used as an adjuvant for recombinant HBsAg to immunize 6- to 8-week-old female BALB/c mice with or without alum for different dosages. The production of HBsAb, CD80 and CD86 from dendritic cells, and cytokines IL-10, IL12, etc., were analyzed and compared for the performance of immunization.

Results

5-20 μg CpG DNA had the best co-stimulation effect of HBsAb serum conversion for mice vaccinated with recombinant expressed HBsAg. The mice vaccinated with recombinant 20 μg CpG DNA and regular vaccine (containing alum adjuvant) had the highest concentration of antibody production. IL-12b, IL-12a and IL10 mRNA reached to the peak level between 3 and 6 hours after the CpG DNA induction in splenocytes. The expression levels of CD80 and CD86 leucocyte surface molecules were increased with 20 μg CpG DNA alone or with 20 μg CpG DNA and 4 μg HBsAg.

Conclusions

Our results confirmed the adjuvant effect of CpG DNA for HBsAg in the mouse model. The increase of IL10 and IL12 production suggested the involvement of Th1 cell activation. The activation of CD80 and CD86 molecules by CpG-ODN might be part of the mechanism of T/B cells coordination and the enhancement of recombinant HBsAg induced immune response.