bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual endothelin receptor antagonism prevents remodeling of resistance arteries in diabetesThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.
Authors: Sachidanandam Kamakshi , Portik-Dobos Vera , Kelly-Cobbs Aisha I. , Ergul Adviye 
Published: July 2010

Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/L) ratio, contributes to the development of microvascular complications in diabetes. We have previously shown in type 2 diabetic Goto–Kakizaki (GK) rats that selective ETAreceptor blockade prevents medial thickening of mesenteric arteries via regulation of matrix metalloproteases (MMP), whereas selective ETBreceptor blockade augments this thickening. The goal of this study was to determine the effect of combined ETAand ETBreceptor blockade on resistance vessel remodeling. Vessel structure, MMP activity, and extracellular matrix proteins were assessed in control Wistar and diabetic GK rats treated with vehicle or bosentan (100 mg/kg per day) for 4 weeks (n = 7–9 per group). Bosentan completely prevented the increase in M/L ratio and MMP-2 activity in diabetes but paradoxically increased M/L ratio and MMP activation in control animals. Collagenase (MMP-13) activity and protein levels were significantly decreased in diabetes. Accordingly, collagen deposition was augmented in GK rats. Dual ET receptor antagonism improved enzyme activity and normalized MMP-13 levels in diabetic animals but blunted MMP-13 activity in control animals. In summary, current findings suggest that diabetes-mediated remodeling of resistance arteries is prevented by dual blockade of ETAand ETBreceptors and that the relative role of ET receptors in the regulation of vascular structure differs in the control and disease states.
Activation of endothelin A receptors contributes to impaired responsiveness of renal mechanosensory nerves in congestive heart failureThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.
Authors: Kopp Ulla C. , Cicha Michael Z. , Jones Susan Y. 
Published: July 2010

Increasing renal pelvic pressure results in PGE2-mediated release of substance P, leading to increases in afferent renal nerve activity (ARNA) and natriuresis, that is, a renorenal reflex response. The renorenal reflexes are impaired in congestive heart failure (CHF). Impairment of the renorenal reflexes may contribute to the increased renal sympathetic nerve activity and sodium retention in CHF. Endothelin (ET)-1 contributes to the pathological changes in cardiac and renal function in CHF. Therefore, we examined whether the ETA receptor antagonist BQ123 altered the responsiveness of renal mechanosensory nerves in CHF. The ARNA responses to increasing renal pelvic pressure were suppressed in CHF but not in sham-CHF rats. In CHF, increasing renal pelvic pressure by 7.5 mm Hg before and during renal pelvic perfusion with BQ123 increased ARNA 12% ± 3% and 21% ± 3% (p < 0.05 vs. vehicle). In isolated renal pelvises from CHF rats, PGE2 increased substance P release from 5 ± 0 to 7 ± 1 pg/min without BQ123 and from 4 ± 1 to 9 ± 1 pg/min with BQ123 in the bath (p < 0.01 vs. vehicle). BQ123 had no effect on the ARNA responses or substance P release in sham-CHF. In conclusion, activation of ETA receptors contributes to the impaired responsiveness of renal mechanosensory nerves in CHF rats by a mechanism(s) at the renal sensory nerve endings.
Endothelins implicated in referred mechanical hyperalgesia associated with colitis induced by TNBS in miceThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.
Authors: Claudino Rafaela Franco , Marcon Rodrigo , Bento Allisson Freire , Chichorro Juliana Geremias , Rae Giles Alexander 
Published: July 2010

This study evaluated the contribution of endothelins to changes in sensitivity to mechanical stimulation of the lower abdomen and hind paw associated with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. The frequency of withdrawal responses to 10 consecutive applications of von Frey probes to the lower abdomen (0.07 g) or hind paw (0.4 g) was assessed in male BALB/c mice before and after intracolonic TNBS injection (0.5 mg in 100 µL of 35% ethanol). TNBS (0.5 mg) induced referred mechanical hyperalgesia in the abdomen (response frequencies at 24 h: saline 11.0% ± 3.1%, TNBS 48.0% ± 6.9%) and hind paw (frequencies at 24 h: saline 12.5% ± 4.7%, TNBS 47.1% ± 7.1%) lasting up to 72 and 48 h, respectively. Mice receiving 1.0 or 1.5 mg TNBS assumed hunch-backed postures and became immobile during abdominal mechanical stimulation, suggestive of excessive ongoing pain. Atrasentan (ETA receptor antagonist; 10 and 30 mg/kg, i.v.) given 24 h after TNBS abolished hind paw and abdominal mechanical hyperalgesia for 2–3 h. A-192621 (ETB receptor antagonist; 20 mg/kg, i.v.) attenuated abdominal mechanical hyperalgesia at the 3 h time point only. Thus, endothelins contribute importantly to abdominal and hind paw referred mechanical hyperalgesia during TNBS-induced colitis mainly through ETA receptor-signaled mechanisms.
Tumor Cells Secrete Galectin-1 to Enhance Endothelial Cell Activity
Authors: Thijssen Victor L. , Barkan Batya , Shoji Hiroki , Aries Ingrid M. , Mathieu Véronique , Deltour Louise , Hackeng Tilman M. , Kiss Robert , Kloog Yoel , Poirier Françoise , Griffioen Arjan W. 
Published: July 2010

Abstract
Tumor angiogenesis is a key event in cancer progression. Here, we report that tumors can stimulate tumor angiogenesis by secretion of galectin-1. Tumor growth and tumor angiogenesis of different tumor models are hampered in galectin-1–null (gal-1−/−) mice. However, tumor angiogenesis is less affected when tumor cells express and secrete high levels of galectin-1. Furthermore, tumor endothelial cells in gal-1−/− mice take up galectin-1 that is secreted by tumor cells. Uptake of galectin-1 by cultured endothelial cells specifically promotes H-Ras signaling to the Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (Erk) kinase (Mek)/Erk cascade and stimulates endothelial cell proliferation and migration. Moreover, the activation can be blocked by galectin-1 inhibition as evidenced by hampered membrane translocation of H-Ras.GTP and impaired Raf/Mek/Erk phosphorylation after treatment with the galectin-1–targeting angiogenesis inhibitor anginex. Altogether, these data identify galectin-1 as a proangiogenic factor. These findings have direct implications for current efforts on galectin-1–targeted cancer therapies. Cancer Res; 70(15); 6216–24. ©2010 AACR.
Akt3-Mediated Resistance to Apoptosis in B-RAF–Targeted Melanoma Cells
Authors: Shao Yongping , Aplin Andrew E. 
Published: July 2010

Abstract
Melanoma cells are highly resistant to anoikis, a form of apoptosis induced in nonadherent/inappropriate adhesion conditions. Depleting B-RAF or the prosurvival Bcl-2 family protein Mcl-1 renders mutant B-RAF melanoma cells susceptible to anoikis. In this study, we examined the effect of targeting B-RAF on the survival of primary stage melanoma cells cultured in three-dimensional type I collagen gels, which partially mimics the dermal microenvironment. Depletion/inhibition of B-RAF with small interfering RNA or the mutant B-RAF inhibitor, PLX4720, induced apoptosis of mutant B-RAF melanoma cells in three-dimensional collagen. Apoptosis was dependent on two upregulated BH3-only proteins, Bim-EL and Bmf, and was inhibited by ectopic Mcl-1 expression. Akt3 activation has been associated with the survival of melanoma cells. Mutant B-RAF melanoma cells ectopically expressing a constitutively activated form of Akt3 or endogenously expressing mutant Akt3 were protected from apoptosis induced by B-RAF knockdown or PLX4720 treatment. Furthermore, intrinsically resistant metastatic melanoma cells displayed elevated Akt phosphorylation in three-dimensional collagen and were rendered susceptible to PLX4720 by Akt3 knockdown. Importantly, myristylated Akt3 prevented B-RAF targeting–induced upregulation of Bim-EL and Bmf in three-dimensional collagen and partially protected Mcl-1–depleted cells from apoptosis. These findings delineate how mutant B-RAF protects melanoma cells from apoptosis and provide insight into possible resistance mechanisms to B-RAF inhibitors. Cancer Res; 70(16); 6670–81. ©2010 AACR.
Fructose Induces Transketolase Flux to Promote Pancreatic Cancer Growth
Authors: Liu Haibo , Huang Danshan , McArthur David L. , Boros Laszlo G. , Nissen Nicholas , Heaney Anthony P. 
Published: July 2010

Abstract
Carbohydrate metabolism via glycolysis and the tricarboxylic acid cycle is pivotal for cancer growth, and increased refined carbohydrate consumption adversely affects cancer survival. Traditionally, glucose and fructose have been considered as interchangeable monosaccharide substrates that are similarly metabolized, and little attention has been given to sugars other than glucose. However, fructose intake has increased dramatically in recent decades and cellular uptake of glucose and fructose uses distinct transporters. Here, we report that fructose provides an alternative substrate to induce pancreatic cancer cell proliferation. Importantly, fructose and glucose metabolism are quite different; in comparison with glucose, fructose induces thiamine-dependent transketolase flux and is preferentially metabolized via the nonoxidative pentose phosphate pathway to synthesize nucleic acids and increase uric acid production. These findings show that cancer cells can readily metabolize fructose to increase proliferation. They have major significance for cancer patients given dietary refined fructose consumption, and indicate that efforts to reduce refined fructose intake or inhibit fructose-mediated actions may disrupt cancer growth. Cancer Res; 70(15); 6368–76. ©2010 AACR.
Combinatorial Chemoprevention Reveals a Novel Smoothened-Independent Role of GLI1 in Esophageal Carcinogenesis
Authors: Ilyas Sumera I. , DeMars Cathrine J. , Comba Andrea , Gainullin Vladimir G. , Rizvi Zaheer , Almada Luciana L. , Wang Kenneth , Lomberk Gwen , Fernández-Zapico Martin E. , Buttar Navtej S. 
Published: July 2010

Abstract
Reflux-induced injury promotes esophageal adenocarcinoma, one of the most rapidly increasing, highly lethal cancers in Western countries. Here, we investigate the efficacy of a combinatorial chemoprevention strategy for esophageal adenocarcinoma and characterize the underlying molecular mechanisms. Specifically, our approach involves the use of ursodeoxycholic acid (Urso) due to its ability to decrease injury-inducing bile salts in combination with Aspirin to mitigate the consequences of injury. We find that Urso-Aspirin combination reduces the risk of adenocarcinoma in vivo in animals with reflux, decreases the proliferation of esophageal adenocarcinoma cells, and downregulates a key cell cycle regulator, CDK2. Mechanistically, using cell growth, luciferase reporter, expression, and chromatin immunoprecipitation assays, we identify GLI1, a Hedgehog-regulated transcription factor, as a novel target of Urso-Aspirin combination. We show that GLI1 is upregulated during esophageal carcinogenesis, and GLI1 can bind to the CDK2 promoter and activate its expression. Although the Urso-Aspirin combination downregulates GLI1, the GLI1 overexpression not only abrogates the effect of this combination on proliferation but it also restores CDK-2 expression. These findings support that the chemopreventive effect of the Urso-Aspirin combination occurs, at least in part, through a novel GLI1-CDK2–dependent mechanism. To further understand the regulation of CDK2 by GLI1, both pharmacologic and RNAi-mediated approaches show that GLI1 is a transcriptional activator of CDK2, and this regulation occurs independent of Smoothened, the central transducer of the Hedgehog canonical pathway. Collectively, these results identify a novel GLI1-to-CDK2 pathway in esophageal carcinogenesis, which is a bona fide target for effective combinatorial chemoprevention with Urso and Aspirin. Cancer Res; 70(17); 6787–96. ©2010 AACR.
A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk
Authors: Ratner Elena , Lu Lingeng , Boeke Marta , Barnett Rachel , Nallur Sunitha , Chin Lena J. , Pelletier Cory , Blitzblau Rachel , Tassi Renata , Paranjape Trupti , Hui Pei , Godwin Andrew K. , Yu Herbert , Risch Harvey , Rutherford Thomas , Schwartz Peter , Santin Alessandro , Matloff Ellen , Zelterman Daniel , Slack Frank J. , Weidhaas Joanne B. 
Published: July 2010

Abstract
Ovarian cancer (OC) is the single most deadly form of women's cancer, typically presenting as an advanced disease at diagnosis in part due to a lack of known risk factors or genetic markers of risk. The KRAS oncogene and altered levels of the microRNA (miRNA) let-7 are associated with an increased risk of developing solid tumors. In this study, we investigated a hypothesized association between an increased risk of OC and a variant allele of KRAS at rs61764370, referred to as the KRAS-variant, which disrupts a let-7 miRNA binding site in this oncogene. Specimens obtained were tested for the presence of the KRAS-variant from nonselected OC patients in three independent cohorts, two independent ovarian case-control studies, and OC patients with hereditary breast and ovarian cancer syndrome (HBOC) as well as their family members. Our results indicate that the KRAS-variant is associated with more than 25% of nonselected OC cases. Further, we found that it is a marker for a significant increased risk of developing OC, as confirmed by two independent case-control analyses. Lastly, we determined that the KRAS-variant was present in 61% of HBOC patients without BRCA1 or BRCA2 mutations, previously considered uninformative, as well as in their family members with cancer. Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing OC, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for HBOC families without other known genetic abnormalities. Cancer Res; 70(16); 6509–15. ©2010 AACR.
The Combination of Multiple Receptor Tyrosine Kinase Inhibitor and Mammalian Target of Rapamycin Inhibitor Overcomes Erlotinib Resistance in Lung Cancer Cell Lines through c-Met Inhibition
Authors: Nakachi Ichiro , Naoki Katsuhiko , Soejima Kenzo , Kawada Ichiro , Watanabe Hideo , Yasuda Hiroyuki , Nakayama Sohei , Yoda Satoshi , Satomi Ryosuke , Ikemura Shinnosuke , Terai Hideki , Sato Takashi , Ishizaka Akitoshi 
Published: July 2010

Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) show antitumor activity in a subset of non–small cell lung cancer (NSCLC) patients. However, the initial tumor response is followed by recurrence. Several studies have suggested the importance of other receptor tyrosine kinases (RTK) and downstream kinases as potential targets in the treatment of NSCLC. We used the multiple-RTK inhibitor AEE788, which inhibits EGFR, vascular endothelial growth factor receptor, and human epidermal growth factor receptor 2, with and without the downstream kinase inhibitor RAD001 (an inhibitor of mammalian target of rapamycin). AEE788 inhibited cell growth more effectively than did erlotinib in three NSCLC cell lines examined (A549, H1650, and H1975). However, in the EGFR-TKI–resistant cell line H1975 harboring T790M resistance mutation, cell growth inhibition by AEE788 was only mild, and the phosphorylation of its leading targets such as EGFR and vascular endothelial growth factor receptor 2 was not inhibited. In H1975, AEE788 induced significantly greater cell growth inhibition when combined with RAD001 than when used alone. This cooperative effect was not seen with the combination of erlotinib and RAD001. We found that c-Met was highly phosphorylated in this cell line, and the phosphorylated c-Met was inhibited effectively by AEE788. Using a phospho-RTK array, the phosphorylation of c-Met and insulin-like growth factor-I receptor was inhibited by AEE788. These results suggest that upstream RTK inhibitor overcomes the acquired resistance to EGFR-TKI when combined with downstream kinase inhibitor. Thus, the combined inhibition of upstream and downstream RTKs is a promising strategy for the treatment of NSCLC. Mol Cancer Res; 8(8); 1142–51. ©2010 AACR.
BAD, a Proapoptotic Member of the BCL2 Family, Is a Potential Therapeutic Target in Hepatocellular Carcinoma
Authors: Galmiche Antoine , Ezzoukhry Zakaria , François Catherine , Louandre Christophe , Sabbagh Charles , Nguyen-Khac Eric , Descamps Véronique , Trouillet Nathalie , Godin Corinne , Regimbeau Jean-Marc , Joly Jean-Paul , Barbare Jean-Claude , Duverlie Gilles , Mazière Jean-Claude , Chatelain Denis 
Published: July 2010

Abstract
Proteins of the BCL2 family are key regulators of apoptosis. Their expression levels are frequently altered in cancers, enabling tumor cells to survive. To gain insight into the pathogenesis of hepatocellular carcinoma (HCC), we performed a comprehensive survey of the expression of the members of the BCL2 family in samples obtained from surgically resected HCCs. Here, we report the occurrence of a new molecular anomaly, consisting of a strong reduction in the expression of the proapoptotic protein BAD in HCC compared with surrounding nontumoral tissue. We investigate the function of BAD in a panel of HCC cell lines. Using gene overexpression and RNA interference, we show that BAD is involved in the cytotoxic effects of sorafenib, a multikinase blocker, which is currently the sole therapeutic drug effective for the treatment of HCC. Finally, we report that ABT-737, a compound that interacts with proteins of the BCL2 family and exhibits a BAD-like reactivity, sensitizes HCC cells toward sorafenib-induced apoptosis. Collectively, our findings indicate that BAD is a key regulator of apoptosis in HCC and an important determinant of HCC cell response to sorafenib. Mol Cancer Res; 8(8); 1116–25. ©2010 AACR.
Factors Affecting the Decision of Breast Cancer Patients to Undergo Contralateral Prophylactic Mastectomy
Authors: Yi Min , Hunt Kelly K. , Arun Banu K. , Bedrosian Isabelle , Barrera Angelica Gutierrez , Do Kim-Anh , Kuerer Henry M. , Babiera Gildy V. , Mittendorf Elizabeth A. , Ready Kaylene , Litton Jennifer , Meric-Bernstam Funda 
Published: July 2010

Abstract
Increasing numbers of women with breast cancer are electing for contralateral prophylactic mastectomy (CPM) to reduce the risk of developing contralateral breast cancer. The objective of this study was to identify factors that may affect a patient's decision to undergo CPM. We identified 2,504 women with stage 0 to III unilateral primary breast cancer who underwent breast surgery at our institution from January 2000 to August 2006 from a prospectively maintained database. We did logistic regression analyses to determine which factors were associated with undergoing CPM. Of 2,504 breast cancer patients, 1,223 (48.8%) underwent total mastectomy. Of the 1,223 patients who underwent mastectomy, 284 (23.2%) underwent immediate or delayed CPM. There were 33 patients (1.3%) who had genetic testing before the surgery, with the use of testing increasing in the latter years of the study (0.1% in 2000-2002 versus 2.0% in 2003-2006; P &lt; 0.0001). Multivariable analysis revealed several factors that were associated with a patient undergoing CPM: age younger than 50 years, white ethnicity, family history of breast cancer, BRCA1/2 mutation testing, invasive lobular histology, clinical stage, and use of reconstruction. We identified specific patient and tumor characteristics associated with the use of CPM. Although genetic testing is increasing, most women undergoing CPM did not have a known genetic predisposition to breast cancer. Evidence-driven models are needed to better inform women of their absolute risk of contralateral breast cancer as well as their competing risk of recurrence from the primary breast cancer to empower them in their active decision making. Cancer Prev Res; 3(8); 1026–34. ©2010 AACR.
Oral Selenium Supplementation Has No Effect on Prostate-Specific Antigen Velocity in Men Undergoing Active Surveillance for Localized Prostate Cancer
Authors: Stratton M. Suzanne , Algotar Amit M. , Ranger-Moore James , Stratton Steven P. , Slate Elizabeth H. , Hsu Chiu-Hsieh , Thompson Patricia A. , Clark Larry C. , Ahmann Frederick R. 
Published: July 2010

Abstract
The Nutritional Prevention of Cancer trial showed a 52% lower incidence of prostate cancer in men supplemented with selenium. As a result, our study was designed to assess whether selenium supplementation attenuates the progression of prostate cancer. A phase 2 randomized, double-blind, placebo-controlled clinical trial was conducted in men with localized nonmetastatic prostate cancer who had elected to forgo active treatment and be followed by active surveillance. A total of 140 men were randomized to placebo (n = 46), 200 μg/d (n = 47), or 800 μg/d (n = 47) selenium p.o. (as selenized yeast) and followed every 3 months for up to 5 years. Prostate-specific antigen (PSA) velocity was used as a marker of prostate cancer progression and was estimated using mixed-effects regression. Adjusting for age, body mass index, baseline selenium, smoking, baseline PSA, race, PSA method, and Gleason score, PSA velocities for the 200 μg/d and 800 μg/d treatment groups were not statistically significantly different from placebo (P = 0.32 and P = 0.61, respectively). In the highest quartile of baseline selenium, men supplemented with 800 μg selenium showed statistically significantly higher PSA velocity as compared with placebo (P = 0.018). Selenium supplementation did not show a protective effect on PSA velocity in subjects with localized prostate cancer. On the contrary, supplementation with high-dose selenium was observed to be a risk factor for increased PSA velocity in men with high baseline plasma selenium concentrations. Cancer Prev Res; 3(8); 1035–43. ©2010 AACR.
TRA-418, a thromboxane A2 receptor antagonist and prostacyclin receptor agonist, inhibits platelet-leukocyte interaction in human whole blood
Authors: Ohno Michihiro , Yamada Naohiro , Ohtake Atsushi , Matsushita Teruo , Miyamoto Mitsuko 
Published: July 2010

SummaryTRA-418, a compound with both thromboxane A2 receptor (TP receptor) antagonistic and prostacyclin receptor (IP receptor) agonistic activities, was synthesised in our laboratory as a new antithrombotic agent. In this study, we examined the effects of TRA-418 on platelet-leukocyte interactions in human whole blood. Platelet-leukocyte interactions were induced by U-46619 in the presence of epinephrine (U-46619 + epinephrine) or with thrombin receptor agonist peptide 1–6 (TRAP). Platelet-leukocyte interactions were assessed by flow cytometry, with examination of both platelet-neutrophil and platelet-monocyte complexes. In a control experiment, the TP receptor antagonist SQ-29548 significantly inhibited the induction of platelet-leukocyte complexes by the combination of U-46619 and epinephrine, but not TRAP-induced formation of platelet-leukocyte complexes. Conversely, the IP receptor agonist beraprost sodium inhibited platelet-leukocyte complex formation induced by both methods, although the IC50 values of beraprost sodium for U-46619 + epinephrine were at least 10-fold greater than for TRAP. Under such conditions, TRA-418 inhibited both U-46619 + epinephrine-induced and TRAP-induced platelet-leukocyte complex formation in a concentration-dependent manner, in a similar range. These results suggest that TRA-418 exerts its inhibitory effects on platelet-leukocyte interactions by acting as a TP receptor antagonist as well as an IP receptor agonist in an additive or synergistic manner. These inhibitory effects of TRA-418 on formation of platelet-leukocyte complexes suggest the compound is beneficial effects as an antithrombotic agent.