bluuebunny/crossref_metadata_2025 huggingface dataset:
Upper airway loading induces growth retardation and change in local chondrocyte IGF-I expression is reversed by stimulation of GH release in juvenile rats
Authors: Segev Yael , Berdugo-Boura Nilly , Porati Orit , Tarasiuk Ariel
Published: September 2008

Chronic resistive airway loading (CAL) impairs growth in juvenile rats. The effects of CAL on epiphyseal growth plate (EGP) structure and insulin-like growth factor (IGF)-I gene expression have not been explored. Little is known about whether stimulants of endogenous growth hormone (GH) secretion can normalize this growth impairment. This study explored the effect of CAL on circulating and EGP GH/IGF-I pathway GH and the effect of ritanserin (endogenous GH stimulant) on somatic growth and the GH/IGF-I axis. We hypothesized that CAL would lead to a decrease in body temperature (Tb) and alterations of GH/IGF-I pathways, consequently leading to growth retardation. The tracheae of 22-day-old male rats were obstructed by tracheal banding (38 sham-operated control, 42 CAL). Tibial EGP morphometry, liver and EGP IGF mRNA, and serum GH and IGF-I levels were analyzed with quantitative real-time PCR and ELISA. Tband locomotion activity (MA) were measured with telemetric transmitters inserted into the abdominal cavity. CAL animals had lower Tband MA despite preserved food consumption. CAL impaired both tibial and tail length gains. Tail and tibial length gains inversely correlated with tracheal resistance. Circulating GH and IGF-I, liver and EGP IGF-I mRNA, and EGP width were decreased in the CAL group. Ritanserin administration to CAL animals normalized circulating and local EGP GH and IGF-I levels and minimized the longitudinal growth impairment. We conclude that CAL causes growth delay associated with alterations in the GH/IGF-I axis. Stimulation of GH release by ritanserin restored both global and local GH/IGF-I pathways, yet growth parameters were only partially restored.
Discovery of a novel class of AKT pleckstrin homology domain inhibitors
Authors: Mahadevan Daruka , Powis Garth , Mash Eugene A. , George Benjamin , Gokhale Vijay M. , Zhang Shuxing , Shakalya Kishore , Du-Cuny Lei , Berggren Margareta , Ali M. Ahad , Jana Umasish , Ihle Nathan , Moses Sylvestor , Franklin Chloe , Narayan Satya , Shirahatti Nikhil , Meuillet Emmanuelle J.
Published: September 2008

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non–lipid-based compounds that bind selectively to the PH domain of AKT, with “in silico” calculated KD values ranging from 0.8 to 3.0 μmol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide–dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro KDs for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 μmol/L. Some of the compounds exhibited PH domain–binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide–dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT. [Mol Cancer Ther 2008;7(9):2621–32]
Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-κB-dependent mechanism
Authors: Rettig Matthew B. , Heber David , An Jiabin , Seeram Navindra P. , Rao Jian Y. , Liu Huiren , Klatte Tobias , Belldegrun Arie , Moro Aune , Henning Susanne M. , Mo Deqiong , Aronson William J. , Pantuck Allan
Published: September 2008

Constitutive nuclear factor-κB (NF-κB) activation is observed in androgen-independent prostate cancer and represents a predictor for biochemical recurrence after radical prostatectomy. Dietary agents such as pomegranate extract (PE) have received increasing attention as potential agents to prevent the onset or progression of many malignancies, including prostate cancer. Here, we show that PE inhibited NF-κB and cell viability of prostate cancer cell lines in a dose-dependent fashion in vitro. Importantly, maximal PE-induced apoptosis was dependent on PE-mediated NF-κB blockade. In the LAPC4 xenograft model, PE delayed the emergence of LAPC4 androgen-independent xenografts in castrated mice through an inhibition of proliferation and induction of apoptosis. Moreover, the observed increase in NF-κB activity during the transition from androgen dependence to androgen independence in the LAPC4 xenograft model was abrogated by PE. Our study represents the first description of PE as a promising dietary agent for the prevention of the emergence of androgen independence that is driven in part by heightened NF-κB activity. [Mol Cancer Ther 2008;7(9):2662–71]
Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901
Authors: Leyton Julius , Smith Graham , Lees Mark , Perumal Meg , Nguyen Quang-de , Aigbirhio Franklin I. , Golovko Oksana , He Quimin , Workman Paul , Aboagye Eric O.
Published: September 2008

The mitogenic extracellular kinase 1/2 (MEK1/2) inhibitor, PD0325901, has potent activity in a number of cancer cell types in vitro. In SKMEL-28 human melanoma cells (BRAF mutant), the drug rapidly decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein levels. We investigated if 3′-deoxy-3′-[18F]fluorothymidine-positron emission tomography ([18F]FLT-PET) could be used to image changes in cell proliferation following MEK1/2 inhibition in vivo. Mice bearing SKMEL-28 and human colon cancer HCT116 (K-RAS mutant) xenografts were treated daily with PD0325901 at 25 mg/kg and imaged by dynamic [18F]FLT-PET after 1 and 10 days of initiating treatment. The drug decreased tumor [18F]FLT uptake after 1 and 10 days of treatment compared with control animals. The normalized (maximal) [18F]FLT uptake in SKMEL-28 xenografts (at 60 minutes; NUVmax) after 1 day of vehicle or PD0325901 therapy was 1.81 ± 0.18 versus 1.23 ± 0.10, respectively (P = 0.03). In this model, NUVmax after 10 days was 2.07 ± 0.40 versus 1.08 ± 0.14, respectively (P = 0.03). The corresponding values for HCT116 tumors were 2.30 ± 0.84 versus 1.88 ± 0.36 (P = 0.045) after 1 day, and 1.97 ± 0.13 versus 1.00 ± 0.03 (P = 0.03) after 10 days. Similar changes were found for other [18F]FLT retention variables. The drug decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein. Tumor [18F]FLT-PET variables correlated with proliferation as measured by Ki67 labeling index (r ≥ 0.6; P ≥ 0.003). In summary, [18F]FLT-PET is a sensitive imaging biomarker for detecting the antiproliferative effect of MEK1/2 inhibition by PD0325901. [Mol Cancer Ther 2008;7(9):3112–21]
16-kDa fragment of pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development
Authors: Ducès Aurélie , Karaky Racha , Martel-Renoir Dominique , Mir Lluis , Hamma-Kourbali Yamina , Biéche Ivan , Opolon Paule , Delbé Jean , Courty José , Perricaudet Michel , Griscelli Frank
Published: September 2008

Pleiotrophin (PTN) is a 136-amino acid secreted heparin-binding protein that is considered as a rate-limiting growth and an angiogenic factor in the onset, invasion, and metastatic process of many tumors. Its mitogenic and tumorigenic activities are mediated by the COOH-terminal residues 111 to 136 of PTN, allowing it to bind to cell surface tyrosine kinase-linked receptors. We investigated a new strategy consisting in evaluating the antitumor effect of a truncated PTN, lacking the COOH-terminal 111 to 136 portion of the molecule (PTNΔ111-136), which may act as a dominant-negative effector for its mitogenic, angiogenic, and tumorigenic activities by heterodimerizing with the wild-type protein. In vitro studies showed that PTNΔ111-136 selectively inhibited a PTN-dependent MDA-MB-231 breast tumor and endothelial cell proliferation and that, in MDA-MB-231 cells expressing PTNΔ111-136, the vascular endothelial growth factor-A and hypoxia-inducible factor-1α mRNA levels were significantly decreased by 59% and 71%, respectively, compared with levels in wild-type cells. In vivo, intramuscular electrotransfer of a plasmid encoding a secretable form of PTNΔ111-136 was shown to inhibit MDA-MB-231 tumor growth by 81%. This antitumor effect was associated with the detection of the PTNΔ111-136 molecule in the muscle and tumor extracts, the suppression of neovascularization within the tumors, and a decline in the Ki-67 proliferative index. Because PTN is rarely found in normal tissue, our data show that targeted PTN may represent an attractive and new therapeutic approach to the fight against cancer. [Mol Cancer Ther 2008;7(9):2817–27]
A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells
Authors: Kim Byung Hak , Yin Chang-Hong , Guo Qianxu , Bach Erika A. , Lee Haeryun , Sandoval Claudio , Jayabose Somasundaram , Ulaczyk-Lesanko Agnieszka , Hall Dennis G. , Baeg Gyeong-Hun
Published: September 2008

Inappropriate activation of JAK/STAT signaling occurs with high frequency in human cancers and is associated with cancer cell survival and proliferation. Therefore, the development of pharmacologic STAT signaling inhibitors has therapeutic potential in the treatment of human cancers. Here, we report 2-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-1-(4-nitro-phenylamino)-6-phenyl-1,2,4a,7a-tetrahydro-pyrrolo[3,4-b]-pyridine-5,7-dione (AUH-6-96) as a novel small-molecule inhibitor of JAK/STAT signaling that we initially identified through a cell-based high-throughput screening using cultured Drosophila cells. Treatment of Drosophila cells with AUH-6-96 resulted in a reduction of Unpaired-induced transcriptional activity and tyrosine phosphorylation of STAT92E, the sole Drosophila STAT homologue. In human cancer cell lines, AUH-6-96 inhibited both constitutive and interleukin-6-induced STAT3 phosphorylation. Specifically, in Hodgkin lymphoma L540 cells, treatment with AUH-6-96 resulted in reduced levels of tyrosine phosphorylated STAT3 and of the STAT3 downstream target gene SOCS3 in a dose- and time-dependent manner. In addition, AUH-6-96-treated L540 cells showed decreased expression of persistently activated JAK3, suggesting that AUH-6-96 inhibits the JAK/STAT pathway signaling in L540 cells by affecting JAK3 activity and subsequently blocking STAT3 signaling. Importantly, AUH-6-96 selectively affected cell viability only of cancer cells harboring aberrant JAK/STAT signaling. In support of the specificity of AUH-6-96 for inhibition of JAK/STAT signaling, treatment with AUH-6-96 decreased cancer cell survival by inducing programmed cell death by down-regulating the expression of STAT3 downstream target antiapoptotic genes, such as Bcl-xL. In summary, this study shows that AUH-6-96 is a novel small-molecule inhibitor of JAK/STAT signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK/STAT signaling. [Mol Cancer Ther 2008;7(9):2672–80]
Fas-mediated killing of primary prostate cancer cells is increased by mitoxantrone and docetaxel
Authors: Symes Juliane C. , Kurin Michael , Fleshner Neil E. , Medin Jeffrey A.
Published: September 2008

Therapies for prostate cancer based on Fas (CD95) modulation have been under active development at the preclinical stage using immortalized cell lines. To address clinical applicability, the potential of 11 cultures of primary prostate cancer cells to be killed by Fas-mediated apoptosis was investigated. In addition, the effect of the chemotherapeutic agents mitoxantrone and docetaxel on this killing was determined. Apoptosis was induced in patient-derived, primary prostate cancer cells using effector cells engineered by recombinant lentivirus infection to express Fas ligand (FasL) and measured by 51Cr release assays. All cultured prostate cells were found to undergo Fas-mediated killing; cytotoxicity ranged from 12% to 87% after 6 h. These cells were significantly more sensitive to FasL-mediated killing than PC-3 cells. The basal expression of Fas or the expression of five inhibitors of apoptosis (c-FLIP, survivin, cellular inhibitors of apoptosis protein 1 and 2, and bcl-2) was not found to correlate with susceptibility to Fas-mediated killing. Both mitoxantrone and docetaxel were able to induce Fas receptor expression on primary prostate cancer cells, which translated into a 1.5- to 3-fold enhancement of apoptosis mediated by FasL. Whereas mitoxantrone increased the Fas-induced apoptotic response of all cultured prostate cells tested, docetaxel pretreatment was found to preferentially enhance the killing of bcl-2-expressing cells. These findings show that cultured primary prostate cancer cells are sensitive to Fas-mediated apoptosis. Furthermore, the incidence of apoptosis was found to be improved by combining Fas-mediated therapy with standard chemotherapeutic agents. These findings may have significant implications for prostate cancer therapy. [Mol Cancer Ther 2008;7(9):3018–28]
17α-Hydroxylase/17,20 lyase inhibitor VN/124-1 inhibits growth of androgen-independent prostate cancer cells via induction of the endoplasmic reticulum stress response
Authors: Bruno Robert D. , Gover Tony D. , Burger Angelika M. , Brodie Angela M. , Njar Vincent C.O.
Published: September 2008

Inhibitors of the enzyme 17α-hydroxylase/17,20 lyase are a new class of anti–prostate cancer agents currently undergoing preclinical and clinical development. We have previously reported the superior anticancer activity of our novel 17α-hydroxylase/17,20 lyase inhibitor, VN/124-1, against androgen-dependent cancer models. Here, we examined the effect of VN/124-1 on the growth of the androgen-independent cell lines PC-3 and DU-145 and found that the compound inhibits their growth in a dose-dependent manner in vitro (GI50, 7.82 μmol/L and 7.55 μmol/L, respectively). We explored the mechanism of action of VN/124-1 in PC-3 cells through microarray analysis and found that VN/124-1 up-regulated genes involved in stress response and protein metabolism, as well as down-regulated genes involved in cell cycle progression. Follow-up real-time PCR and Western blot analyses revealed that VN/124-1 induces the endoplasmic reticulum stress response resulting in down-regulation of cyclin D1 protein expression and cyclin E2 mRNA. Cell cycle analysis confirmed G1-G0 phase arrest. Measurements of intracellular calcium levels ([Ca2+]i) showed that 20 μmol/L VN/124-1 caused a release of Ca2+ from endoplasmic reticulum stores resulting in a sustained increase in [Ca2+]i. Finally, cotreatment of PC-3 cells with 5, 10, and 20 μmol/L VN/124-1 with 10 nmol/L thapsigargin revealed a synergistic relationship between the compounds in inhibiting PC-3 cell growth. Taken together, these findings show VN/124-1 is endowed with multiple anticancer properties that may contribute to its utility as a prostate cancer therapeutic. [Mol Cancer Ther 2008;7(9):2828–36]
AAV-HGFK1 and Ad-p53 cocktail therapy prolongs survival of mice with colon cancer
Authors: Nie Biao , Shen Zan , Wen Jun-Bao , Wong Oscar Gee-Wan , Hsueh Wayne D. , Huo Long-Fei , Kung Hsiang-Fu , Jiang Bo , Lin Marie C.M.
Published: September 2008

This study tried to evaluate the application of a novel cancer gene therapy using recombinant adeno-associated virus (AAV) carrying the kringle 1 domain of human hepatocyte growth factor (AAV-HGFK1) in combination with recombinant adenovirus carrying p53 gene (Ad-p53). BALB/c and nude mice models of colon cancer were established and the mice were treated with AAV-HGFK1 alone or in combination with Ad-p53. Combination of AAV-HGFK1 and Ad-p53 significantly prolonged the survival of the mice and also significantly inhibited primary and secondary tumor growth. Histochemical examination of the tumors revealed that AAV-HGFK1+Ad-p53 combinatorial treatment not only induced necrosis and apoptosis in the tumors but also suppressed tumor angiogenesis. The antiangiogenesis effect could likely be attributed to the ability of AAV-HGFK1+Ad-p53 viral cocktail to inhibit endothelial cell migration and proliferation. AAV-HGFK1+Ad-p53 also inhibited tumor cell growth in vitro by inhibiting epidermal growth factor receptor phosphorylation. Therefore, AAV-HGFK1+Ad-p53 cocktail therapy has a significantly higher therapeutic effect than AAV-HGFK1 or Ad-p53 alone and is a novel promising gene therapy for colon cancer. [Mol Cancer Ther 2008;7(9):2855–65]
Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway
Authors: Lioni Mercedes , Noma Kazuhiro , Snyder Andrew , Klein-Szanto Andres , Diehl J. Alan , Rustgi Anil K. , Herlyn Meenhard , Smalley Keiran S.M.
Published: September 2008

Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate <5%. From an initial drug screen, we identified bortezomib as having robust activity in ESCC lines. Mechanistically, bortezomib induced a G2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens. [Mol Cancer Ther 2008;7(9):2866–75]
Polyethylene glycol-mediated colorectal cancer chemoprevention: roles of epidermal growth factor receptor and Snail
Authors: Wali Ramesh K. , Kunte Dhananjay P. , Koetsier Jennifer L. , Bissonnette Marc , Roy Hemant K.
Published: September 2008

Polyethylene glycol (PEG) is a clinically widely used agent with profound chemopreventive properties in experimental colon carcinogenesis. We reported previously that Snail/β-catenin signaling may mediate the suppression of epithelial proliferation by PEG, although the upstream events remain unclear. We report herein the role of epidermal growth factor receptor (EGFR), a known mediator of Snail and overepressed in ∼80% of human colorectal cancers, on PEG-mediated antiproliferative and hence antineoplastic effects in azoxymethane (AOM) rats and HT-29 colon cancer cells. AOM rats were randomized to either standard diet or one with 10% PEG-3350 and euthanized 8 weeks later. The colonic samples were subjected to immunohistochemical or Western blot analyses. PEG decreased mucosal EGFR by 60% (P < 0.001). Similar PEG effects were obtained in HT-29 cells. PEG suppressed EGFR protein via lysosmal degradation with no change in mRNA levels. To show that EGFR antagonism per se was responsible for the antiproliferative effect, we inhibited EGFR by either pretreating cells with gefitinib or stably transfecting with EGFR-short hairpin RNA and measured the effect of PEG on proliferation. In either case, PEG effect was blunted, suggesting a vital role of EGFR. Flow cytometric analysis revealed that EGFR-short hairpin RNA cells, besides having reduced membrane EGFR, also expressed low Snail levels (40%), corroborating a strong association. Furthermore, in EGFR silenced cells, PEG effect on EGFR or Snail was muted, similar to that on proliferation. In conclusion, we show that EGFR is the proximate membrane signaling molecule through which PEG initiates antiproliferative activity with Snail/β-catenin pathway playing the central intermediary function. [Mol Cancer Ther 2008;7(9):3103–11]
AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies
Authors: Zabludoff Sonya D. , Deng Chun , Grondine Michael R. , Sheehy Adam M. , Ashwell Susan , Caleb Benjamin L. , Green Stephen , Haye Heather R. , Horn Candice L. , Janetka James W. , Liu Dongfang , Mouchet Elizabeth , Ready Shannon , Rosenthal Judith L. , Queva Christophe , Schwartz Gary K. , Taylor Karen J. , Tse Archie N. , Walker Graeme E. , White Anne M.
Published: September 2008

Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings. [Mol Cancer Ther 2008;7(9):2955–66]
Antitumor activity of a membrane lytic peptide cyclized with a linker sensitive to membrane type 1-matrix metalloproteinase
Authors: Zhong Jieying , Chau Ying
Published: September 2008

Membrane lytic peptides are a novel class of anticancer agents that have the potential to overcome drug resistance. The limited selectivity against cancer cells, however, presents a major hurdle for the application. We aim to exploit the proteolytic activity of tumor-associated matrix metalloproteinases (MMP) to mediate the cytotoxicity of these peptides. We designed a membrane lytic peptide cyclized with a linker cleavable by membrane type 1-MMP (MT1-MMP). We showed that the cyclic peptide could be restored to the linear state on MT1-MMP digestion, and it preferentially killed MMP-overexpressing cells above a threshold concentration. Circular dichroism indicated that cyclization resulted in a more rigid structure, making it more difficult for the lytic peptide to transit from random coil to α-helix in a membrane-mimicking environment. Selective membrane activity of the cyclic peptide was shown by comparing cytotoxicity results on RBC and two human breast cancer cell lines of different malignancy and MT1-MMP expression: highly invasive MDA-MB-435 and noninvasive MCF-7. Above a concentration of 5 μmol/L, suppressed activity to MCF-7 and RBC was observed, whereas the toxicity against MDA-MB-435 was maintained. MMP inhibition experiments further showed that the membrane-lysing activity was enzyme dependent. [Mol Cancer Ther 2008;7(9):2933–40]
Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters
Authors: Okabe Mitsunori , Szakács Gergely , Reimers Mark A. , Suzuki Toshihiro , Hall Matthew D. , Abe Takaaki , Weinstein John N. , Gottesman Michael M.
Published: September 2008

Molecular and pharmacologic profiling of the NCI-60 cell panel offers the possibility of identifying pathways involved in drug resistance or sensitivity. Of these, decreased uptake of anticancer drugs mediated by efflux transporters represents one of the best studied mechanisms. Previous studies have also shown that uptake transporters can influence cytotoxicity by altering the cellular uptake of anticancer drugs. Using quantitative real-time PCR, we measured the mRNA expression of two solute carrier (SLC) families, the organic cation/zwitterion transporters (SLC22 family) and the organic anion transporters (SLCO family), totaling 23 genes in normal tissues and the NCI-60 cell panel. By correlating the mRNA expression pattern of the SLCO and SLC22 family member gene products with the growth-inhibitory profiles of 1,429 anticancer drugs and drug candidate compounds tested on the NCI-60 cell lines, we identified SLC proteins that are likely to play a dominant role in drug sensitivity. To substantiate some of the SLC-drug pairs for which the SLC member was predicted to be sensitizing, follow-up experiments were performed using engineered and characterized cell lines overexpressing SLC22A4 (OCTN1). As predicted by the statistical correlations, expression of SLC22A4 resulted in increased cellular uptake and heightened sensitivity to mitoxantrone and doxorubicin. Our results indicate that the gene expression database can be used to identify SLCO and SLC22 family members that confer sensitivity to cancer cells. [Mol Cancer Ther 2008;7(9):3081–91]
Effect of chemotherapeutic stress on induction of vascular endothelial growth factor family members and receptors in human colorectal cancer cells
Authors: Fan Fan , Gray Michael J. , Dallas Nikolaos A. , Yang Anthony D. , Van Buren George , Camp E. Ramsay , Ellis Lee M.
Published: September 2008

Vascular endothelial growth factor (VEGF) is induced by stress. We determined whether chemotherapy (genotoxic stress) could induce expression of VEGF and VEGF receptors (VEGFR) in human colorectal cancer cells. The colorectal cancer cell lines HT29, RKO, and HCT116 were acutely exposed to increasing doses of oxaliplatin or 5-fluorouracil for 2, 6, and 24 h in vitro. Expression of VEGF ligand family members, VEGFRs, and signaling intermediates was determined by reverse transcription-PCR and Northern and Western blotting. The effect of oxaliplatin on VEGF-A transcriptional activity was determined by promoter assays. Acute exposure of human colorectal cancer cells to oxaliplatin led to a marked induction of VEGF-A mRNA and protein, whereas 5-fluorouracil alone or when added to oxaliplatin did not cause a further increase in VEGF levels. VEGF-A promoter activity was induced by oxaliplatin exposure. Expression of VEGF-C, placental growth factor, VEGFR-1, and neuropilin-1 levels were also increased when cells were treated with oxaliplatin. Oxaliplatin led to an increase in Akt and Src activation in HT29 cells. In contrast, Akt activation did not change in RKO cells whereas phospho-Src and phospho-p44/42 mitogen-activated protein kinase was dramatic increased by oxaliplatin. Inhibition of Akt or Src activation with wortmannin or PP2 blocked induction of VEGF-A by oxaliplatin in HT29 or RKO cells, respectively. VEGFRs may reflect the adaptive stress responses by which tumor cells attempt to protect themselves from genotoxic stress. Neutralization of prosurvival responses with anti-VEGF therapy might explain, in part, some of the beneficial effects of anti-VEGF therapy when added to chemotherapy. [Mol Cancer Ther 2008;7(9):3064–70]
Comparative Effects of Home- and Group-Based Exercise on Balance Confidence and Balance Ability in Older Adults: Cluster Randomized Trial
Authors: Cyarto Elizabeth V. , Brown Wendy J. , Marshall Alison L. , Trost Stewart G.
Published: September 2008

Background: Exercise can modify fall risk factors such as balance and mobility impairments. However, can exercise improve balance confidence? In one strength-training study, researchers reported that a change in balance confidence was not uniformly associated with changes in objective measures of fall risk or physical performance. In fact, some participants’ balance confidence decreased while their physical abilities increased and vice versa. Objective: The aim of this study was to compare changes in balance confidence and balance ability resulting from three exercise interventions (home-based resistance and balance training (RBT), group-based RBT and group-based walking), and the concomitant relationships between change in balance confidence and change in ability. It was hypothesized that participants in the group-based RBT program would improve their balance confidence and performance more than those in the home-based or walking programs. Methods: In a cluster-randomized design, nine retirement villages were assigned to one of the three exercise groups. One hundred and sixty-seven independent-living residents (aged 65–96 years) participated. Each group exercised twice weekly for 20 weeks. Objective balance ability was measured using timed tandem and one-leg stands (static balance), and the 8-foot (2.5 m) up-and-go test (dynamic balance/agility). Balance confidence was assessed using the self-report Activities-specific Balance Confidence (ABC) Scale. Results: Participants in the group-based RBT program improved their static balance scores more than those in the home-based program; however, improvements in balance confidence were greater among participants in the home-based program (all p < 0.05). Discordance between static balance and balance confidence change scores was evident for up to 20% of participants. Change in ABC score was weakly correlated with a change in the up-and-go test score. Conclusions: Exercise training can improve balance confidence and balance ability in retirement village residents. However, as has been shown previously, this study found that exercise interventions may improve balance ability without associated increases in balance confidence and vice versa. Whether the ABC score and balance ability can be enhanced by providing a tailored intervention to improve balance confidence in combination with a RBT program requires further study.
Utility of Portable Electromyography for Quantifying Muscle Activity during Daily Use
Authors: Jakobi Jennifer M. , Edwards Darl L. , Connelly Denise M.
Published: September 2008

Background: Mobility has been studied using performance, questionnaire, pedometer and accelerometer measures, but these tools do not provide information about muscle activity. To better understand mechanisms associated with movement impairment as they relate to function, it is valuable to quantify muscle activity during everyday activities. Objective: This report presents electromyography (EMG) during daily activities from the affected and unaffected limbs of a 74-year-old man who survived a stroke 12 years ago, compared to 7 older healthy men who had not experienced a stroke. Methods: The biceps brachii, triceps brachii, quadriceps and hamstring muscles were recorded continuously for one 8-hour session in the unaffected limbs of the stroke survivor and control subjects. On a second day, EMG from these same muscles of the affected side was recorded for 4 h. Bursts (amplitude >2% maximum effort, duration >0.1 s) and gaps (amplitude <1% maximum effort, duration >0.1 s) of EMG were quantified for the number of times they occurred, mean event duration (seconds), mean peak amplitude (percent maximum voluntary efforts) and rate of activity (event activity/second). Results: Burst and gap patterns of the unaffected limb muscles were similar between the stroke survivor and controls. Increased numbers of bursts (approx. 40%) and gaps (approx. 44%) were seen in the subject’s lower limb muscles of his affected versus unaffected side. Biceps brachii burst activity of the affected limb was increased, whereas triceps brachii burst activity was decreased. These muscle activity changes in the affected limb suggest that the triceps brachii was relatively inactive and the biceps brachii and lower limb muscles were active in an ‘on’ and ‘off’ pattern. Conclusion: Muscle activity in the unaffected limb of the stroke survivor was similar compared to control subjects, but the affected limb differed from the unaffected after stroke. Portable EMG to monitor muscle activity for prolonged periods was not reported to be an impediment by the case or control subjects. Using this technology, EMG bursts and gaps can be recorded and used to describe muscle activity. Future work may consider the feasibility of this technique to monitor rehabilitation progression or long-term plasticity of muscle activity.
C-Reactive Protein Isoforms Differ in Their Effects on Thrombus Growth
Authors: Molins Blanca , Peña Esther , Vilahur Gemma , Mendieta Carlos , Slevin Mark , Badimon Lina
Published: September 2008

Objective—

We studied the impact of native (natCRP) and modified CRP (mCRP) isoforms on platelet adhesion and thrombus growth under arterial flow.

Methods and Results—

Blood was perfused over type I collagen at a wall shear rate of 1500 s
−1
, and platelet deposition and thrombus growth were evaluated by confocal microscopy. natCRP and mCRP were either incubated with blood before perfusion experiments or immobilized in the collagen surface and exposed to flowing blood. mCRP significantly increased platelet adhesion and thrombus growth when directly incubated with blood and when immobilized on a collagen surface (
P
<0.05). In contrast, natCRP did not exert any effect. Confocal immunohistochemistry revealed the presence of CRP on the surface of adhered platelets and within the thrombus and showed an upregulation of P-selectin and CD36 in effluent platelets preincubated with mCRP (
P
<0.05). Flow cytometry analysis of agonist-induced platelet activation demonstrated that mCRP, but not natCRP, significantly increased platelet surface P-selectin (
P
<0.05) without modifying CD63 and PAC-1.

Conclusions—

Our data indicate that whereas serum natCRP may not affect thrombus growth, mCRP displays a prothrombotic phenotype enhancing not only platelet deposition, but also thrombus growth under arterial flow conditions.
Subseasonal SST Variability in the Tropical Eastern North Pacific during Boreal Summer
Authors: Maloney Eric D. , Chelton Dudley B. , Esbensen Steven K.
Published: September 2008

Boreal summer intraseasonal (30–90-day time scale) sea surface temperature (SST) variability in the east Pacific warm pool is examined using Tropical Rainfall Measuring Mission (TRMM) Microwave Imager (TMI) sea surface temperatures during 1998–2005. Intraseasonal SST variance maximizes at two locations in the warm pool: in the vicinity of 9°N, 92°W near the Costa Rica Dome and near the northern edge of the warm pool in the vicinity of 19°N, 108°W. Both locations exhibit a significant spectral peak at 50–60-day periods, time scales characteristic of the Madden–Julian oscillation (MJO). Complex empirical orthogonal function (CEOF) and spectra coherence analyses are used to show that boreal summer intraseasonal SST anomalies are coherent with precipitation anomalies across the east Pacific warm pool. Spatial variations of phase are modest across the warm pool, although evidence exists for the northward progression of intraseasonal SST and precipitation anomalies. Intraseasonal SSTs at the north edge of the warm pool lag those in the vicinity of the Costa Rica Dome by about 1 week.

The MJO explains 30%–40% of the variance of intraseasonal SST anomalies in the east Pacific warm pool during boreal summer. Peak-to-peak SST variations of 0.8°–1.0°C occur during MJO events. SST is approximately in quadrature with MJO precipitation, with suppressed (enhanced) MJO precipitation anomalies leading positive (negative) SST anomalies by 7–10 days. Consistent with the CEOF and coherence analyses, MJO-related SST and precipitation anomalies near the Costa Rica Dome lead those at the northern edge of the warm pool by about 1 week.
Turbulent Condensation of Droplets: Direct Simulation and a Stochastic Model
Authors: Paoli Roberto , Shariff Karim
Published: September 2008

The effect of turbulent mixing on droplet condensation is studied via direct numerical simulations of a population of droplets in a periodic box of homogeneous isotropic turbulence. Each droplet is tracked as a fluid particle whose radius grows by condensation of water vapor. Forcing of the small wavenumbers is used to sustain velocity, vapor, and temperature fluctuations. Temperature and vapor fluctuations lead to supersaturation fluctuations, which are responsible for broadening the droplet size distribution in qualitative agreement with in situ measurements. A model for the condensation of a population of cloud droplets in a homogeneous turbulent flow is presented. The model consists of a set of Langevin (stochastic) equations for the droplet area, supersaturation, and temperature surrounding the droplets. These equations yield corresponding ordinary differential equations for various moments and correlations. The statistics predicted by the model, for instance, the droplet area–supersaturation correlation, reproduce the simulations well.
The Vertical Structure of Mesoscale Convective Vortices
Authors: Davis Christopher A. , Galarneau Thomas J.
Published: September 2008

Simulations of two cases of developing mesoscale convective vortices (MCVs) are examined to determine the dynamics governing the origin and vertical structure of these features. Although one case evolves in strong vertical wind shear and the other evolves in modest shear, the evolutions are remarkably similar. In addition to the well-known mesoscale convergence that spins up vorticity in the midtroposphere, the generation of vorticity in the lower troposphere occurs along the convergent outflow boundary of the parent mesoscale convective system (MCS). Lateral transport of this vorticity from the convective region back beneath the midtropospheric vorticity center is important for obtaining a deep column of cyclonic vorticity. However, this behavior would be only transient without a secondary phase of vorticity growth in the lower troposphere that results from a radical change in the divergence profile favoring lower-tropospheric convergence. Following the decay of the nocturnal MCS, subsequent convection occurs in a condition of greater relative humidity through the lower troposphere and small conditional instability. Vorticity and potential vorticity are efficiently produced near the top of the boundary layer and a cyclonic circulation appears at the surface.
A New Look at Stratospheric Sudden Warmings. Part III: Polar Vortex Evolution and Vertical Structure
Authors: Matthewman N. J. , Esler J. G. , Charlton-Perez A. J. , Polvani L. M.
Published: September 2008

The evolution of the Arctic polar vortex during observed major midwinter stratospheric sudden warmings (SSWs) is investigated for the period 1957–2002, using 40-yr European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-40) Ertel’s potential vorticity (PV) and temperature fields. Time-lag composites of vertically weighted PV, calculated relative to the SSW onset time, are derived for both vortex-displacement SSWs and vortex-splitting SSWs, by averaging over the 15 recorded displacement and 13 splitting events. The evolving vertical structure of the polar vortex during a typical SSW of each type is clearly illustrated by plotting an isosurface of the composite PV field, and is shown to be very close to that observed during representative individual events. Results are verified by comparison with an elliptical diagnostic vortex moment technique.

For both types of SSW, little variation is found between individual events in the orientation of the developing vortex relative to the underlying topography; that is, the location of the vortex during SSWs of each type is largely fixed in relation to the earth’s surface. During each type of SSW, the vortex is found to have a distinctive vertical structure. Vortex-splitting events are typically barotropic, with the vortex split occurring near simultaneously over a large altitude range (20–40 km). In the majority of cases, of the two daughter vortices formed, it is the “Siberian” vortex that dominates over its “Canadian” counterpart. In contrast, displacement events are characterized by a very clear baroclinic structure; the vortex tilts significantly westward with height, so that the top and bottom of the vortex are separated by nearly 180° longitude before the upper vortex is sheared away and destroyed.
The Global Zonally Integrated Ocean Circulation, 1992–2006: Seasonal and Decadal Variability
Authors: Wunsch Carl , Heimbach Patrick
Published: September 2008

The zonally integrated meridional and vertical velocities as well as the enthalpy transports and fluxes in a least squares adjusted general circulation model are used to estimate the top-to-bottom oceanic meridional overturning circulation (MOC) and its variability from 1992 to 2006. A variety of simple theories all produce time scales suggesting that the mid- and high-latitude oceans should respond to atmospheric driving only over several decades. In practice, little change is seen in the MOC and associated heat transport except very close to the sea surface, at depth near the equator, and in parts of the Southern Ocean. Variability in meridional transports in both volume and enthalpy is dominated by the annual cycle and secondarily by the semiannual cycle, particularly in the Southern Ocean. On time scales longer than a year, the solution exhibits small trends with complicated global spatial patterns. Apart from a net uptake of heat from the atmosphere (forced by the NCEP–NCAR reanalysis, which produces net ocean heating), the origins of the meridional transport trends are not distinguishable and are likely a combination of model disequilibrium, shifts in the observing system, other trends (real or artificial) in the meteorological fields, and/or true oceanic secularities. None of the results, however, supports an inference of oceanic circulation shifts taking the system out of the range in which changes are more than small perturbations. That the oceanic observations do not conflict with an apparent excess heat uptake from the atmosphere implies a continued undersampling of the global ocean, even in the upper layers.
In Situ Data Biases and Recent Ocean Heat Content Variability*
Authors: Willis Josh K. , Lyman John M. , Johnson Gregory C. , Gilson John
Published: September 2008

Two significant instrument biases have been identified in the in situ profile data used to estimate globally integrated upper-ocean heat content. A large cold bias was discovered in a small fraction of Argo floats along with a smaller but more prevalent warm bias in expendable bathythermograph (XBT) data. These biases appear to have caused the bulk of the upper-ocean cooling signal reported by Lyman et al. between 2003 and 2005. These systematic data errors are significantly larger than sampling errors in recent years and are the dominant sources of error in recent estimates of globally integrated upper-ocean heat content variability. The bias in the XBT data is found to be consistent with errors in the fall-rate equations, suggesting a physical explanation for that bias. With biased profiles discarded, no significant warming or cooling is observed in upper-ocean heat content between 2003 and 2006.
An Objective Model for Identifying Secondary Eyewall Formation in Hurricanes
Authors: Kossin James P. , Sitkowski Matthew
Published: September 2008

Hurricanes, and particularly major hurricanes, will often organize a secondary eyewall at some distance around the primary eyewall. These events have been associated with marked changes in the intensity and structure of the inner core, such as large and rapid deviations of the maximum wind and significant broadening of the surface wind field. While the consequences of rapidly fluctuating peak wind speeds are of great importance, the broadening of the overall wind field also has particularly dangerous consequences in terms of increased storm surge and wind damage extent during landfall events. Despite the importance of secondary eyewall formation in hurricane forecasting, there is presently no objective guidance to diagnose or forecast these events. Here a new empirical model is introduced that will provide forecasters with a probability of imminent secondary eyewall formation. The model is based on environmental and geostationary satellite features applied to a naïve Bayes probabilistic model and classification scheme. In independent testing, the algorithm performs skillfully against a defined climatology.
Evaluation of Probabilistic Medium-Range Temperature Forecasts from the North American Ensemble Forecast System
Authors: McCollor Doug , Stull Roland
Published: September 2008

Ensemble temperature forecasts from the North American Ensemble Forecast System were assessed for quality against observations for 10 cities in western North America, for a 7-month period beginning in February 2007. Medium-range probabilistic temperature forecasts can provide information for those economic sectors exposed to temperature-related business risk, such as agriculture, energy, transportation, and retail sales.

The raw ensemble forecasts were postprocessed, incorporating a 14-day moving-average forecast–observation difference, for each ensemble member. This postprocessing reduced the mean error in the sample to 0.6°C or less. It is important to note that the North American Ensemble Forecast System available to the public provides bias-corrected maximum and minimum temperature forecasts.

Root-mean-square-error and Pearson correlation skill scores, applied to the ensemble average forecast, indicate positive, but diminishing, forecast skill (compared to climatology) from 1 to 9 days into the future. The probabilistic forecasts were evaluated using the continuous ranked probability skill score, the relative operating characteristics skill score, and a value assessment incorporating cost–loss determination. The full suite of ensemble members provided skillful forecasts 10–12 days into the future.

A rank histogram analysis was performed to test ensemble spread relative to the observations. Forecasts are underdispersive early in the forecast period, for forecast days 1 and 2. Dispersion improves rapidly but remains somewhat underdispersive through forecast day 6. The forecasts show little or no dispersion beyond forecast day 6. A new skill versus spread diagram is presented that shows the trade-off between higher skill but low spread early in the forecast period and lower skill but better spread later in the forecast period.