bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Memory Search across the Visual Brain
Authors: Fedurco Milan
Published: July 2012

Signal transmission from the human retina to visual cortex and connectivity of visual brain areas are relatively well understood. How specific visual perceptions transform into corresponding long-term memories remains unknown. Here, I will review recent Blood Oxygenation Level-Dependent functional Magnetic Resonance Imaging (BOLD fMRI) in humans together with molecular biology studies (animal models) aiming to understand how the retinal image gets transformed into so-called visual (retinotropic) maps. The broken object paradigm has been chosen in order to illustrate the complexity of multisensory perception of simple objects subject to visual —rather than semantic— type of memory encoding. The author explores how amygdala projections to the visual cortex affect the memory formation and proposes the choice of experimental techniques needed to explain our massive visual memory capacity. Maintenance of the visual long-term memories is suggested to require recycling of GluR2-containingα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) andβ2-adrenoreceptors at the postsynaptic membrane, which critically depends on the catalytic activity of the N-ethylmaleimide-sensitive factor (NSF) and protein kinase PKMζ.
A Hamilton‐Poisson Model of the Chen‐Lee System
Authors: Pop Arieşanu Camelia
Published: July 2012

We will present some dynamical and geometrical properties
of Chen‐Lee system from the Poisson geometry point of view.
Diagnosis and Management of Peritoneal Metastases from Ovarian Cancer
Authors: Halkia Evgenia , Spiliotis John , Sugarbaker Paul
Published: July 2012

The management and the outcome of peritoneal metastases or recurrence from epithelial ovarian cancer are presented. The biology and the diagnostic tools of EOC peritoneal metastasis with a comprehensive approach and the most recent literatures data are discussed. The definition and the role of surgery and chemotherapy are presented in order to focuse on the controversial points. Finally, the paper discusses the new data about the introduction of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced epithelial ovarian cancer.
Tuberculous Lymphadenopathy Mimicking Pancreatic Neoplasm
Authors: Hoshino Kunikazu , Arakaki Shingo , Shibata Daisuke , Maeshiro Tatsuji , Hokama Akira , Kinjo Fukunori , Shiraishi Masayuki , Nishimaki Tadashi , Fujita Jiro
Published: July 2012

Abdominal tuberculosis (TB) is the sixth most common location of extrapulmonary TB involvement. Because its symptoms and signs are often nonspecific, laboratory and imaging findings mimic other diseases including carcinoma. Therefore, the diagnosis of abdominal TB is challenging. We herein report a case of 74-year-old woman who presented with abdominal pain, anorexia, and weight loss. She had been given a diagnosis of pancreatic head carcinoma. Laboratory data was unremarkable except for elevated erythrocyte sedimentation rate, CA125, and sIL-2R. CT scan revealed multiple enlarged peripancreatic lymph nodes and concentric thickening of the ileocecal wall. Colonoscopy demonstrated deformed ileocecal valve and erosions. Histological examination showed epithelioid granulomas. Laparoscopy revealed numerous white tubercles diffusely covering the parietal peritoneum. Histopathological images of peripancreatic lymph node revealed large multiple caseating granulomas surrounded by Langhans_giant cells and epithelioid cells. Polymerase chain reaction and culture of the specimens were positive forMycobacterium tuberculosis. Tuberculous lymphadenopathy, colitis, and peritonitis were finally diagnosed. She responded well to the antitubercular treatment.
Backward Bifurcation of an Epidemic Model with Infectious Force in Infected and Immune Period and Treatment
Authors: Xue Yakui , Wang Junfeng
Published: July 2012

An epidemic model with infectious force in infected and immune period and treatment rate of infectious individuals is proposed to understand the effect of the capacity for treatment of infective on the disease spread. It is assumed that treatment rate is proportional to the number of infective below the capacity and is constant when the number of infective is greater than the capacity. It is proved that the existence and stability of equilibria for the model is not only related to the basic reproduction number but also the capacity for treatment of infective. It is found that a backward bifurcation occurs if the capacity is small. It is also found that there exist bistable endemic equilibria if the capacity is low.
Impulsive Biological Pest Control Strategies of the Sugarcane Borer
Authors: Rafikov Marat , Lordelo Alfredo Del Sole , Rafikova Elvira
Published: July 2012

We propose an impulsive biological pest control of the sugarcane borer (Diatraea saccharalis) by its egg parasitoid Trichogramma galloi based on a mathematical model in which the sugarcane borer is represented by the egg and larval stages, and the parasitoid is considered in terms of the parasitized eggs. By using the Floquet theory and the small amplitude perturbation method, we show that there exists a globally asymptotically stable pest‐eradication periodic solution when some conditions hold. The numerical simulations show that the impulsive release of parasitoids provides reliable strategies of the biological pest control of the sugarcane borer.
Cellulosic Ethanol Production by Recombinant Cellulolytic Bacteria HarbouringpdcandadhII Genes ofZymomonas mobilis
Authors: Piriya P. Sobana , Vasan P. Thirumalai , Padma V. S. , Vidhyadevi U. , Archana K. , Vennison S. John
Published: July 2012

The ethanol fermenting genes such as pyruvate decarboxylase (pdc) and alcohol dehydrogenase II (adhII) were cloned fromZymomonas mobilisand transformed into three different cellulolytic bacteria, namelyEnterobacter cloacaeJV,Proteus mirabilisJV andErwinia chrysanthemiand their cellulosic ethanol production capability was studied. RecombinantE. cloacaeJV was found to produce 4.5% and 3.5% (v/v) ethanol, respectively, when CMC and 4% NaOH pretreated bagasse were used as substrates, whereas recombinantP. mirabilisandE. chrysanthemiwith the same substrates could only produce 4%, 3.5%, 1%, and 1.5 % of ethanol, respectively. The recombinantE. cloacaestrain produced twofold higher percentage of ethanol than the wild type. The recombinantE. cloacaestrain could be improved further by increasing its ethanol tolerance capability through media optimization and also by combining multigene cellulase expression for enhancing ethanol production from various types of lignocellulosic biomass so that it can be used for industrial level ethanol production.
HoneyComb: An Application-Driven Online Adaptive Reconfigurable Hardware Architecture
Authors: Thomas Alexander , Rückauer Michael , Becker Jürgen
Published: July 2012

Since the introduction of the first reconfigurable devices in 1985 the field of reconfigurable computing developed a broad variety of architectures from fine-grained to coarse-grained types. However, the main disadvantages of the reconfigurable approaches, the costs in area, and power consumption, are still present. This contribution presents a solution for application-driven adaptation of our reconfigurable architecture at register transfer level (RTL) to reduce the resource requirements and power consumption while keeping the flexibility and performance for a predefined set of applications. Furthermore, implemented runtime adaptive features like online routing and configuration sequencing will be presented and discussed. A presentation of the prototype chip of this architecture designed in 90 nm standard cell technology manufactured by TSMC will conclude this contribution.
Fine Spectra of Symmetric Toeplitz Operators
Authors: Altun Muhammed
Published: July 2012

The fine spectra of 2‐banded and 3‐banded infinite Toeplitz matrices were examined by several authors. The fine spectra of n‐banded triangular Toeplitz matrices and tridiagonal symmetric matrices were computed in the following papers: Altun, “On the fine spectra of triangular toeplitz operators” (2011) and Altun, “Fine spectra of tridiagonal symmetric matrices” (2011). Here, we generalize those results to the (2n + 1)‐banded symmetric Toeplitz matrix operators for arbitrary positive integer n.
A New Spectrophotometric Reagent for Fe(III): 2‐(2,3‐Dihydroxy‐4‐oxocyclobut‐2‐enylidene) Hydrozinecarbothiamide and Its Application in Real Samples
Authors: Saeidi Mahboubeh , Aboutalebi Reihaneh , Darehkordi Ali
Published: July 2012

A new reagent 2‐(2,3‐dihydroxy‐4‐oxocyclobut‐2‐enylidene) hydrozinecarbothiamide has been synthesized and used for developing a simple spectrophotometric method for the determination of Fe(III) which is based on a 2 : 1 complex formation between Fe(III) and new reagent in aqueous solution. The method is optimized in terms of the pH value, amount of reagent required, ionic strength, and stability of the complex, sensitivity, linearity, and tolerance limits of various foreign ions. The complex is a red‐brown chelate, with λmax = 465 nm at pH = 3 (ε = 1.95 × 103 L·mol−1·cm−1). The ionic strength was kept constant at 0.02 by adding appropriate amounts of NaCl solution. The calibration curve is linear in the concentration range from 0.27–33.50 μg·mL−1. The effects of foreign ions on the determination of Fe(III) were investigated in order to assess the selectivity of the method. The method was applied in determination of Fe(III) in tap water, cow milk, and human serum.
Hedgehog Signaling Regulates Bladder Cancer Growth and Tumorigenicity
Authors: Fei Dennis Liang , Sanchez-Mejias Avencia , Wang Zhiqiang , Flaveny Colin , Long Jun , Singh Samer , Rodriguez-Blanco Jezabel , Tokhunts Robert , Giambelli Camilla , Briegel Karoline J. , Schulz Wolfgang A. , Gandolfi A. Jay , Karagas Margaret , Zimmers Teresa A. , Jorda Merce , Bejarano Pablo , Capobianco Anthony J. , Robbins David J.
Published: July 2012

The role of Hedgehog (HH) signaling in bladder cancer remains controversial. The gene encoding the HH receptor and negative regulator PATCHED1 (PTCH1) resides on a region of chromosome 9q, one copy of which is frequently lost in bladder cancer. Inconsistent with PTCH1 functioning as a classic tumor suppressor gene, loss-of-function mutations in the remaining copy of PTCH1 are not commonly found. Here, we provide direct evidence for a critical role of HH signaling in bladder carcinogenesis. We show that transformed human urothelial cells and many urothelial carcinoma cell lines exhibit constitutive HH signaling, which is required for their growth and tumorigenic properties. Surprisingly, rather than originating from loss of PTCH1, the constitutive HH activity observed in urothelial carcinoma cell lines was HH ligand dependent. Consistent with this finding, increased levels of HH and the HH target gene product GLI1 were found in resected human primary bladder tumors. Furthermore, on the basis of the difference in intrinsic HH dependence of urothelial carcinoma cell lines, a gene expression signature was identified that correlated with bladder cancer progression. Our findings therefore indicate that therapeutic targeting of the HH signaling pathway may be beneficial in the clinical management of bladder cancer. Cancer Res; 72(17); 4449–58. ©2012 AACR.
Ectopic ATP Synthase Blockade Suppresses Lung Adenocarcinoma Growth by Activating the Unfolded Protein Response
Authors: Chang Hsin-Yi , Huang Hsuan-Cheng , Huang Tsui-Chin , Yang Pan-Chyr , Wang Yi-Ching , Juan Hsueh-Fen
Published: July 2012

Ectopic expression of the mitochondrial F1F0-ATP synthase on the plasma membrane has been reported to occur in cancer, but whether it exerts a functional role in this setting remains unclear. Here we show that ectopic ATP synthase and the electron transfer chain exist on the plasma membrane in a punctuated distribution of lung adenocarcinoma cells, where it is critical to support cancer cell proliferation. Applying ATP synthase inhibitor citreoviridin induced cell cycle arrest and inhibited proliferation and anchorage-independent growth of lung cancer cells. Analysis of protein expression profiles after citreoviridin treatment suggested this compound induced the unfolded protein response (UPR) associated with phosphorylation the translation initiation factor 2α (eIF2α), triggering cell growth inhibition. Citreoviridin-enhanced eIF2α phosphorylation could be reversed by siRNA-mediated attenuation of the UPR kinase PKR-like endoplasmic reticulum kinase (PERK) combined with treatment with the antioxidant N-acetylcysteine, establishing that reactive oxygen species (ROS) boost UPR after citreoviridin treatment. Thus, a coordinate elevation of UPR and ROS initiates a positive feedback loop that convergently blocks cell proliferation. Our findings define a molecular function for ectopic ATP synthase at the plasma membrane in lung cancer cells and they prompt further study of its inhibition as a potential therapeutic approach. Cancer Res; 72(18); 4696–706. ©2012 AACR.
Oxidation-Mediated DNA Cross-Linking Contributes to the Toxicity of 6-Thioguanine in Human Cells
Authors: Brem Reto , Karran Peter
Published: July 2012

The thiopurines azathioprine and 6-mercaptopurine have been extensively prescribed as immunosuppressant and anticancer agents for several decades. A third member of the thiopurine family, 6-thioguanine (6-TG), has been used less widely. Although known to be partly dependent on DNA mismatch repair (MMR), the cytotoxicity of 6-TG remains incompletely understood. Here, we describe a novel MMR-independent pathway of 6-TG toxicity. Cell killing depended on two properties of 6-TG: its incorporation into DNA and its ability to act as a source of reactive oxygen species (ROS). ROS targeted DNA 6-TG to generate potentially lethal replication-arresting DNA lesions including interstrand cross-links. These triggered processing by the Fanconi anemia and homologous recombination DNA repair pathways. Allopurinol protected against 6-TG toxicity by acting as a ROS scavenger and preventing DNA damage. Together, our findings provide mechanistic evidence to support the proposed use of thiopurines to treat HR-defective tumors and for the coadministration of 6-TG and allopurinol as an immunomodulation strategy in inflammatory disorders. Cancer Res; 72(18); 4787–95. ©2012 AACR.
Abstract 1892: Folate intake and incident colorectal cancer by KRAS mutation status in a population-based cohort of older women
Authors: Razzak Anthony , Vierkant Robert A. , Wang Alice H. , Tillmans Lori S. , Lynch Charles F. , Anderson Kristin E. , Haile Robert W. , Harnack Lisa J. , Potter John D. , Slager Susan L. , Smyrk Thomas C. , Thibodeau Stephen N. , Cerhan James R. , Limburg Paul J.
Published: July 2012

Background: Folate intake (FI) appears to affect colorectal cancer (CRC) risk, but the molecular mechanism(s) involved are incompletely defined. In this study, we analyzed associations between FI and incident CRC, overall and by KRAS mutation status, in the population-based Iowa Women's Health Study (IWHS).

Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). FI and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were recently collected from 732 representative CRC cases diagnosed through 12/31/2002. FI (including supplements) was categorized by quartiles. KRAS mutation status (wildtype [wt] vs. mutated [mut]) was determined by direct sequence analysis of codons 12 and 13 (exon 2). Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).

Results: Of the 732 available CRC cases, 470 (64%) had complete FI and KRAS data. FI was not associated with incident CRC overall (for quartile 4 vs. quartile 1, RR = 1.03; 95% CI = 0.82-1.28; p trend = 0.90), or with the KRAS-wt or KRAS-mut subtypes (see Table).

Conclusions: These data do not support an association between FI and incident CRC, overall or by KRAS-defined subtypes, among older, predominately white, non-Hispanic women.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1892. doi:10.1158/1538-7445.AM2011-1892
Abstract 1904: B vitamin intake and incidence of colorectal cancer by tumor site and stage: Results from the Women's Health Initiative cohort
Authors: Zschäbitz Stefanie , Cheng Ting-Yuan D. , Neuhouser Marian L. , Zheng Yingye , Ray Roberta M. , Miller Joshua W. , Song Xiaoling , Bailey Lynn B. , Maneval David R. , Beresford Shirley AA , Ulrich Cornelia M.
Published: July 2012

Introduction: The role of one-carbon metabolism related nutrients (folate, riboflavin (B2), B6, and B12) in colorectal carcinogenesis is still not fully understood. Folate and other B vitamins are essential for DNA methylation and repair and higher levels have been associated with a decreased risk for colorectal cancer (CRC) in some studies; however, non-linear relationships have been observed. We investigated the dietary intake of one-carbon nutrients and CRC risk in the WHI Observational Study, a large cohort of postmenopausal women.

Methods: Dietary intake of folate and other B vitamins was determined via a Food Frequency Questionnaire and supplement inventory in 88,045 healthy women (aged 50 – 79 years, recruited between 1994 – 1998). Multivariate Cox proportional hazards regression models was used to estimate associations between nutrient intake and CRC risk and to evaluate differences in the associations by tumor site and stage. Hazard ratios (HR) for the 4th vs. 1st quartile were estimated.

Results: In age-adjusted analyses significantly reduced risks for CRC were observed for the total (supplemental plus dietary) intake of folate (HR=0.82, 95%CI=0.68-0.97), vitamin B12 (HR=0.82, 0.69-0.99), vitamin B6 (HR=0.77, 0.65-0.92), and riboflavin (HR=0.75, 0.63-0.90). After multivariate adjustment (age, BMI, race, prior colonoscopy, smoking, physical activity, postmenopausal HT use) only the total intake of riboflavin (HR=0.80, 0.66-0.96) remained associated with a reduced risk for CRC. For the intake of vitamin B6 a borderline significance was observed (p=0.06, HR=0.85, 0.70-1.02). A site-specific observation was notable for supplemental and total riboflavin intake with a reduced risk for cancer of the distal colon (HRsupp=0.56, 0.33-0.96; HRtotal=0.69, 0.46-1.04) but not in proximal and rectal cancer. In regards to tumor stage, no significant difference was detected for localized and distant disease; the inverse association between the supplemental and total intake of riboflavin and vitamin B6 was limited to regionally spread disease (HRB2;supp=0.66, 0.45-0.96; HRB2;total=0.73, 0.54-0.99; HRB6;supp=0.69, 0.49-0.98; HRB6;total=0.72, 0.53-0.97).

Conclusion: Higher riboflavin and vitamin B6 intake was linked to decreased risk for colorectal cancer in a large cohort of postmenopausal women, with some suggestion for stage- and site-specific associations. Our study provides limited support for an association of other B vitamins with CRC risk. (NIH R01 CA120523, N01WH22110)

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1904. doi:10.1158/1538-7445.AM2011-1904
Abstract 1905: The association between coffee and green tea intake and upper aerodigestive tract cancer in Japanese population
Authors: Oze Isao , Matsuo Keitaro , Hosono Satoyo , Ito Hidemi , Watanabe Miki , Tajima Kazuo , Tanaka Hideo
Published: July 2012

[Background] Coffee and tea are the most common beverages worldwide. Specifically, green tea is the most common tea in Japan. Coffee and green tea are potentially thought to have anticancer effect because of the antioxidative components such as chlorogenic acids in coffee and catechins in tea. On the other hand, coffee and green tea are often consumed with high temperature. Hot foods and beverages are considered as risk factor for esophageal cancer (e.g. yarba mate in Latin America). Thus, coffee and green tea might be carcinogenic. Then, we conducted a case-control study to elucidate the association between UAT cancer and coffee and green tea consumption.

[Method] Cases were 961 patients with histologically diagnosed as UAT cancer (head and neck cancer in 527 and esophageal cancer in 434) between January 2001 and December 2005 at Aichi Cancer Center Hospital. Controls were 2883 first-visit outpatients who were confirmed to have no cancer during the same period. Cases and Controls were matched by age and sex. Information on coffee and green tea consumption and other lifestyle factors were obtained via self-administered questionnaire. Associations between coffee and green tea consumption and UAT cancer were assessed by odds ratios (ORs) and 95% confidence intervals (CIs) by using conditional logistic regression models.

[Result] Both coffee and green tea consumption had significant association with UAT cancer overall (trend p=0.011 and 0.007, respectively). Those who had three or more cups of coffee a day showed significantly lower OR for UAT cancer (OR 0.71, 95% CI 0.55-0.93) than those with non-daily consumers. In contrast, three or more cups of green tea consumption had significant positive association with UAT cancer (OR 1.28, 95% CI 1.06-1.56). These trends were not clear for esophageal cancer. The inverse association between coffee consumption and UAT cancer was evident among current drinkers, while the positive association between green tea and UAT cancer was evident among never drinkers. Similar trends were observed in other categories.

[Conclusion] UAT cancer was inversely associated with coffee consumption, and positively associated with green tea consumption. Further epidemiologic studies are warranted.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1905. doi:10.1158/1538-7445.AM2011-1905
Abstract 1907: Pancreatic cancer risk update: Associations with meat-derived carcinogen intake in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort
Authors: Anderson Kristin E. , Mongin Steven J. , Sinha Rashmi , Stolzenberg-Solomon Rachael , Gross Myron D. , Ziegler Regina G. , Mabie Jerome E. , Risch Adam , Kazin Sally S. , Church Timothy R.
Published: July 2012

Epidemiological studies report positive associations between high-temperature cooked meat intake and pancreatic cancer. We assessed the association between dietary intake of heterocyclic amines (HCAs) and benzo(a)pyrene (BaP)_mutagens formed in meat cooked at high temperatures_and incident exocrine pancreatic cancer in a prospective cohort. Methods: The 62,581 subjects randomized to screening in the multi-center Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO) who completed a dietary survey at study entry, which assessed meat intake, cooking methods, and doneness preferences defined the cohort. Subjects were surveyed annually for incident cancers through 2007; information was also obtained from physicians, next-of-kin, state registries, and national mortality data. A National Cancer Institute research database (CHARRED) was used to estimate intake of HCA, BaP, and mutagenic activity (Mutagenic Activity Index) from the dietary survey data. The proportional hazard ratios (HRs) for risk of pancreatic cancer were estimated from multivariate-adjusted survival analyses. Results: During follow-up (median: 10 yrs), 248 cases of exocrine pancreatic cancer were confirmed. Intake of well- and very-well done meat was generally associated with increased risks. For example, intake of very well done steak yielded an HR (95% confidence interval) of 1.43 (0.80, 2.56). Using estimated mutagen intake, significant elevations in the risk of pancreatic cancer were found in the upper quintiles of the Mutagenic Activity Index, with HRs of 1.81 (1.16, 2.83) and 1.87 (1.16, 3.02) for quintiles 4 and 5, respectively, relative to the lowest quintile. Significantly increased risks were also associated with exposure high levels of two specific mutagens: 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx). The HRs for DiMeIQx for quintiles 4 and 5 were 1.31 (0.86, 1.98) and 1.81 (1.20, 2.74), respectively, while those for MeIQx were 1.34 (0.87, 2.06) and 1.75 (1.11, 2.76). All three of these exposures exhibited significant positive trends in risk as their intake increased (P for linear trend: 0.01-0.03). Conclusion: Additional follow-up of this cohort has provided stronger evidence that consumption of well-done meat with elevated mutagen levels from high temperature cooking confers an increased risk of pancreatic cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1907. doi:10.1158/1538-7445.AM2011-1907
Abstract 2002: Prevention of gastric cancers induced by Helicobacter pylori infection with a DNA demethylating reagent, 5-aza-2′-deoxycytidine
Authors: Niwa Tohru , Toyoda Takeshi , Tsukamoto Tetsuya , Mori Akiko , Tatematsu Masae , Ushijima Toshikazu
Published: July 2012

Aberrant DNA methylation is deeply involved in carcinogenesis, and Helicobacter pylori infection, a Group-I carcinogen according to IARC classification, is known to induce aberrant methylation in gastric epithelial cells. Therefore, it is likely that methylation induction is the major mechanism by which H. pylori infection induces gastric cancers. In this study, using a Mongolian gerbil model, we aimed to clarify whether a DNA demethylating reagent, 5-aza-2′-deoxycytidine (5-aza-dC), can prevent H. pylori-induced gastric cancers. Administration of N-methyl-N-nitrosourea (20 p.p.m. by drinking water from 5 to 25 weeks of age) and H. pylori infection (∼108 CFU, at 5 weeks of age) induced gastric cancers in 55.2% of the gerbils at 55 weeks of age. By intraperitoneal infection of 5-aza-dC (0.125 mg/kg body weight, twice a week from 5 to 55 weeks of age), the incidence decreased significantly to 23.3% (P<0.05). Methylation levels of two CpG islands in gastric epithelial cells decreased to 46-69% of those of the infected gerbils without 5-aza-dC treatment (P<0.05). Also, the global methylation level decreased from 83.0% to 80.3% by 5-aza-dC as measured by luminometric methylation assay (P<0.05). At the same time, 5-aza-dC treatment tended to reduce expression of inflammation-related genes (Il1b and Nos2) in the stomach, suggesting that 5-aza-dC treatment can also modulate inflammatory responses. These results showed that H. pylori infection-induced gastric cancers could be suppressed by 5-aza-dC, and suggested that inhibition of methylation induction and/or immunomodulation by 5-aza-dC were the mechanisms of the suppression. Suppression of epigenetic alterations is a promising target for cancer prevention.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2002. doi:10.1158/1538-7445.AM2011-2002
Abstract 2028: HOX genes in oral cancer: Expression profile and functional characterization
Authors: Coletta Ricardo D. , Bitu Carolina C. , Pereira Manoela , Lopes Marcio A. , Graner Edgard
Published: July 2012

Homeobox genes, specifically the HOX family, play an important role in the development by controlling cellular proliferation, differentiation and apoptosis. In the present study it was investigated whether genes of the HOX family play a role in oral cancer. Our results demonstrated that the expression of HOXA4, A5, A7, A10, B7, C4, C5, C6, C8, C9, C10, C11, D9, D10, D11 and D13 was statistically higher in oral squamous cell carcinoma (OSCC) samples when compared with those from normal oral mucosa. We further demonstrated that HOXA1 and HOXB7 overexpression in HaCAT human epithelial cell line promotes proliferation, whereas downregulation of HOXB7 endogenous levels in human oral carcinoma cells (SCC9 cells) decreases it. In OSCCs, expression of HOXB7 and Ki67, a marker of proliferation, correlate strongly with each other (rs=0.79, p<0.006). High immunohistochemical expression of HOXB7 was correlated with T stage (p=0.06), N stage (p=0.07), disease stage (p=0.09) and Ki67 expression (p=0.01), and patients with tumors showing high number of HOXB7-positive cells had shorter overall survival (p<0.08) and shorter disease-free survival after treatment (p<0.10) compared with patients with tumors exhibiting low amount of HOXB7-positive cells. No correlation between HOXA1 and clinicopathological parameters was observed. Our data suggest that HOXA1 and HOXB7 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and imply that HOXB7 may be an important determinant of OSCC patient's prognosis. Thus, dysregulated expression of specific members of the HOX family of homeobox genes is related to the tumorigenesis of oral cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2028. doi:10.1158/1538-7445.AM2011-2028
Abstract 2031: A functional nuclear epidermal growth factor receptor, Src and Stat3 heteromeric complex in pancreatic cancer cells
Authors: Paladino David , Jaganathan Soumya , Yue Peibin , Bogdanovic Jelena , Huo Qun , Turkson James
Published: July 2012

Pancreatic cancer is an extremely lethal malignancy whose prognosis has not improved appreciably in the last decade. The disease is usually diagnosed only after it has reached an advanced or metastatic state but even local, surgically resectable, tumors have a fairly poor prognosis. This is further complicated by the fact that little is known about the underlying mechanisms of pancreatic cancer, as evidenced by a lack of any efficacious targeted therapies. While hyperactive epidermal growth factor receptor (EGFR), Src tyrosine kinase and Signal Transducer and Activator of Transcription (Stat)3 have been detected in pancreatic cancer and implicated in the disease, the exact mechanisms by which they promote the disease phenotype are not well understood. We present evidence of a functional heteromeric complex of EGFR, c-Src and Stat3 that is detected at the plasma membrane and cytoplasm, and inside the nucleus of pancreatic cancer cells. The inhibition of c-Src, but not EGFR kinase, reduced the level of nuclear EGFR levels. Furthermore, the inhibition of Src or EGFR kinase alone decreased nuclear Stat3 levels, while the greatest decrease occurred upon the combined inhibition of EGFR and Src kinase activities. Significantly, evidence shows that the nuclear EGFR, Src and Stat3 complex functions as a transcriptional complex. Thus, the siRNA knockdown of EGFR or Src, or the pharmacological inhibition of aberrant Stat3 activity only moderately decreased c-Myc, iNOS, and VEGF expression. By contrast, the knockdown of EGFR or Src together with the inhibition of Stat3 activity strongly suppressed c-Myc expression in Panc-1 and Colo-357 cells. Chromatin immunoprecipitation (ChIP) studies further validated these findings and showed that the nuclear EGFR, Src, and Stat3 complex is bound to the c-Myc promoter. Taken together, these data identify a novel and functional heteromeric EGFR, Src, and Stat3 complex that promotes the induction of c-Myc in pancreatic cancer cells. Our study provides additional insight into the mechanisms by which hyperactive EGFR, Src and Stat3 pathway promotes the pancreatic cancer phenotype.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2031. doi:10.1158/1538-7445.AM2011-2031
Abstract 2049: Role of hypoxia-induced upregulation of caveolin-1 in hepatocellular carcinoma cell migration and invasion
Authors: Wong Sivia Yuen Sze , Tse Edith Yuk Ting , Yam Judy Wai Ping
Published: July 2012

Intratumoral hypoxia occurs when cells in the inner core of solid tumor mass become deprived of oxygen. It correlates with an increased risk to develop metastasis. However, the molecular basis about the adaptation and survival of tumor cells in hypoxic environment remains obscure. Our recent data revealed that Cav1, a component of focal adhesion, is dramatically increased in metastatic hepatocellular carcinoma (HCC) cell lines and tissues, suggesting a role of Cav1 in HCC metastasis. In this study, we further investigated the potential role of Cav1 in HCC metastasis under hypoxia. Our data revealed that Cav1 mRNA and protein expressions were enhanced in various HCC cells lines when placed in hypoxic chamber or treated with hypoxic mimetic drug. Such upregulation of Cav1 was abolished with the addition of HIF1α inhibitor or depletion of HIF1α by siRNA. This suggests that hypoxia-induced Cav1 expression is HIF1α-dependent. Our findings also showed that HCC cells possessed enhanced motility under hypoxia. However, knockdown of Cav1 in HCC cells attenuated the capacity of cells to migrate and invade. Collectively, our study suggests that the increased motility of HCC cells conferred by the hypoxia-induced Cav1 expression is an adaptive mechanism of cells to survive under hypoxic stress.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2049. doi:10.1158/1538-7445.AM2011-2049
Abstract 2051: Hypoxia-induced triple suicide gene TK/CD/UPRT expression enhances cytotoxicity to GCV and 5-FC and radiosensitization in human colorectal cancer cells
Authors: Hsiao Hung-Tsung , Xing Ligang , Deng Xuelong , Sun Xiaorong , He Fuqiu , Ling C. Clifton , Li Gloria C.
Published: July 2012

The hypoxic microenvironment, an important feature of human solid tumors but absent in normal tissues, may provide an opportunity for cancer-specific gene theapy. We constructed two vectors, both under the control of nine copies of hypoxia responsive element (HRE): (1) a herpes simplex virus type 1 thymidine kinase (TK) and enhanced green fluorescent protein (eGFP) fusion gene, and (2) a triple-fusion-gene, cytosine deaminase (CD), uracil phosphoribosyltransferase (UPRT) and monomeric DsRed (mDsRed). Human colorectal cancer cells (HCT8) were transfected with these plasmids, singly or in combination. Stable HCT8-HRE cells were established that contained and expressed the hypoxia-inducible vectors (i.e. HRE-TK/eGFP, HRE-CD/UPRT/mDsRed, or both HRE-TK/eGFP and HRE-CD/UPRT/mDsRed), as assessed by RT-PCR, Western blots and fluorescence microscopy analysis. In in vitro studies, we showed that hypoxia-induced TK/eGFP and CD/UPRT/mDsRed expression not only increased cytotoxicity to GCV and 5-FC, but also led to significant radiosensitization. In HCT8-HRE tumors transplanted in athymic mice, the distribution of TK/eGFP and CD/UPRT/mDsRed co-localized with that of the hypoxia marker pimonidazole. In addition, the administration of GCV and 5-FC in combination with local irradiation resulted in significant tumor regression, greater than that observed with drug or radiation treatment alone. Our data suggest that the hypoxia-inducible TK/GCV+CDUPRT/5-FC triple gene therapy has the ability to specifically target hypoxic cancer cells and significantly improve tumor control in combination with radiotherapy. This novel model is a valuable tool for studying tumor hypoxia and hypoxia-targeted radio-gene therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2051. doi:10.1158/1538-7445.AM2011-2051
Abstract 2057: Hypoxia stimulates the epithelial-mesenchymal transition of gastric cancer cells via TGF-β/ TGF-β receptor signaling
Authors: Matsuoka Junko , Y Masakazu , Kashiwagi Shinichiro , Kato Yukihiro , Fuyuhiro Yuhiko , Kubo Naoshi , Tanaka Hiroaki , Muguruma Kazuya , Yamada Nobuya , Maeda Kiyoshi , Ohira Masaichi , Ishikawa Tetsuro , Hirakawa Kosei
Published: July 2012

Introduction: Epithelial mesenchymal transition (EMT) is a cellular process during which epithelial cells acquire mesenchymal properties while losing cell-cell interactions and apicobasal polarity. EMT is considered to be correlated with malignancy of cancer cells and to be responsible for cancer invasion and metastasis. Patients with gastric cancer show a poor prognosis because of frequent metastasis. We previously reported that hypoxia was associated with distant metastasis and poor prognosis in gastric cancer. Therefore, we investigated the effect of hypoxic condition on EMT of gastric cancer cells.

Materials and Methods:Three gastric cancer cell lines, OCUM-2MD3, OCUM-2M, and OCUM-12 derived from gastric cancer were used. Cells were cultured in normoxia (21% O2) or hypoxia (1% O2). EMT rate was evaluated as the percentage of spindle-shaped cells of total cells. The expression level of TGF-β and TGF-β receptor was evaluated by real time RT-PCR. Effect of TGF-β or TGF-βR inhibitor, SB431542, on the EMT was evaluated by cell morphology.

Results: Hypoxia stimulated EMT of OCUM-2MD3 and OCUM-12 cells, but not that of OCUM-2M cells. The level of TGF-β expression was increased significantly (p<0.001) under hypoxia in comparison with normoxia in all of three cell lines. The level of TGF-β receptor expression was increased in OCUM-2MD3 and OCUM-12 cells, but not OCUM-2M cells. TGF-βR inhibitor, SB431542, significantly suppressed EMT of OCUM-2MD3 (p=0.03) and OCUM-12 (p<0.01).

Conclusion: Hypoxia stimulates the EMT of gastric cancer cells via TGF-β/ TGF-β receptor signaling. TGF-β receptor inhibitor might be promising for the treatment of gastric cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2057. doi:10.1158/1538-7445.AM2011-2057
Abstract 2064: Regulation of the VHL tumor suppressor protein in hypoxia and through the cell cycle
Authors: Gnarra James R. , Brown Julie , Liu Weijun
Published: July 2012

The von Hippel-Lindau (VHL) gene is a classical tumor suppressor and is inactivated in patients with von Hippel-Lindau disease, as well as the majority of patients with sporadic clear cell renal carcinoma (RCC). The VHL protein (pVHL) is an E3 ubiquitin ligase with many functions, including regulating the hypoxia response as well as microtubule stability. While the involvement of pVHL in targeting of HIF alpha subunits for ubiquitin-mediated degradation is well documented, less is understood about regulation of pVHL itself. We determined pVHL levels under normoxic (room air, 21% oxygen) and hypoxic (1% oxygen) conditions and found that pVHL levels decreased in hypoxia. VHL protein half-life was similar in cells cultured in normoxia or hypoxia, suggesting that pVHL expression is regulated through a post-transcriptional mechanism. Down regulation of pVHL in hypoxia suggests a novel and complementary mechanism to account for stabilization of HIF alpha subunits. While pVHL-negative RCC cells progress through the cell cycle when cultured in hypoxia, isogenic pVHL-expressing RCC exhibited hypoxia-induced arrest in G1 phase of the cell cycle. We also determined pVHL levels during cell cycle progression and found that pVHL levels were decreased levels during mitosis and G1. The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that is active during late M phase and G1 through the association with the activators, Cdh1 and Cdc20. Cdh1 and Cdc20 bind to APC/C target proteins through recognition of Destruction box consensus sequences. Such sequences are found in pVHL, suggesting that pVHL may be a target for APC/C ubiquitylation. We found that pVHL physically bound to Cdh1, that Cdh1 knockdown was associated with increased pVHL levels, that Cdh1 overexpression was associated with decreased pVHL levels and increased polyubiquitylation pVHL, and that these activities were dependent on pVHL Destruction box sequences. Our results indicate that pVHL is a novel substrate of APC/C-Cdh1.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2064. doi:10.1158/1538-7445.AM2011-2064
Abstract 2087: Estrogen receptor beta sensitizes breast cancer cells to endoplasmic reticulum stress-regulated apoptosis
Authors: Rajapaksa Gayani K. , Nikolos Fotis , Thomas Christoforos G. , Gustafsson Jan-Ake
Published: July 2012

Estrogen receptor beta (ERβ) as estrogen-regulated transcription factor is involved in the development of the normal mammary gland and affects the progression and the anti-estrogen resistance of breast cancer. Recent data connect this resistance with the activation of survival mechanisms including the unfolded protein response (UPR). The UPR assists the cells to cope with the stress induced upon accumulation of unfolded proteins in the endoplasmic reticulum (ER) named ER stress. Although estrogen receptor alpha (ERα) has been shown to alter the resistance of breast cancer cells to anti-estrogens by modulating the levels of ER stress, the role of ERβ in the regulation of the UPR has not been elucidated. Here we show that ERβ decreases the resistance of breast cancer cells to chemically-induced ER stress by altering the inositol-requiring enzyme-1 (IRE-1) pathway of the UPR. In particular, we found that induction in the expression of ERβ enhances apoptosis and upregulates the ER stress-regulated pro-apoptotic CHOP/GADD153 in MDA-MB-231 breast cancer cells in response to treatment with the ER stressor thapsigargin. ERβ induces apoptosis under ER stress by inhibiting the unconventional mRNA splicing of X-box binding protein-1 (XBP-1), and thus, attenuating the upregulation of the active transcription factor which reduces the load of unfolded proteins in the ER. These results suggest ERβ as a potential modulator of the resistance of breast cancer cells to ER stressors through regulating the UPR.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2087. doi:10.1158/1538-7445.AM2011-2087
Abstract 2099: Tid1 regulates galectin-7 mediated tumorigenesis of oral squamous cell carcinoma
Authors: Wu Yi-Chen , Huang Lu-Ying , Lo Jeng-Fan
Published: July 2012

Background: We previously identified Tid1, a DnaJ cochaperon protein, functions as a tumour suppressor in oral squamous cell carcinoma (OSCC) tumourigenesis (J Pathol 2009;219:347-55). To further understand the molecular mechanisms mediated by Tid1 on oral tumorigenesis, we applied affinity chromatography and systemic proteomics analysis to identify galectin-7, which specifically interacted with Tid1. Others have shown that Galectin-7 plays a number of important roles in tumor development. However, the role of Galectin-7 in OSCC tumourigenesis remains unclear. Herein, we elucidated the mechanism mediated by Tid1 on regulating galectin-7 mediated cellular signaling and tumorigenesis in OSCC.

Methods: First, through HA-tag affinity chromatography and mass spectrometry we identified substrate proteins that specifically interact with Tid1. Secondly, co-immunoprecipitation analysis and confocal microscope was performed to confirm the protein-protein interaction between galectin-7 and Tid1. In vitro tumorigenic properties of OSCC overexpressing galectin-7 were determined. Subsequently, the tumorigenic properties of OSCC after co-overexpression of galectin-7 and Tid1 were investigated. Finally, immunoprecipitation analysis was performed to recognize the Tid1 induced deregulation of galectin-7 by enhancing ubiquitination.

Results: We found out that Tid1 interacted with galectin-7. Furthermore, overexpression galectin-7 expression resulted in up-regulation migration, invasion and soft agar colony formation abilities in OSCC. Importantly, co-overexpression of Tid1 decreased the galectin-7 expression and impaired galectin-7-mediated migration, invasion and soft agar colony formation ability of OSCC. Finally, we found galectin-7 ubiquitination as revealed by antiubiquitin immunoblot analysis in immunoprecipitates.

Conclusion: Our studies first pointed out that galectin-7 played pivotal roles in OSCC tumorigenesis. Notably, we identified galectin-7 that specifically interacted with Tid1. We hypothesized that Tid1/ Hsp70 may regulate galectin-7 stability by ubiquitinylation. The molecular mechanism by which Tid1 negatively modulates the galectin-7 warrants further investigation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2099. doi:10.1158/1538-7445.AM2011-2099