bluuebunny/crossref_metadata_2025 huggingface dataset:
Air pollution and risk of urinary bladder cancer in a case-control study in Spain
Authors: Castaño-Vinyals Gemma , Cantor Kenneth P , Malats Núria , Tardon Adonina , Garcia-Closas Reina , Serra Consol , Carrato Alfredo , Rothman Nathaniel , Vermeulen Roel , Silverman Debra , Dosemeci Mustafa , Kogevinas Manolis
Published: July 2007

Objectives:

Air pollution has been associated with an increased risk for lung cancer. We examined whether long-term air pollution is associated with bladder cancer risk.

Methods:

Information from a case-control study in Spain that included 1219 incident cases and 1271 hospital controls was used. Information on residential history including several indicators of exposure to air pollution and other potential risk factors was collected in a face-to-face computerised personal interview. Odds ratios (OR) and 95% confidence intervals (95% CI) were adjusted for age, gender, region, smoking, occupation, water contaminants and diet.

Results:

Living more than 40 years in a city with a population of more than 100 000 was associated with an increased risk for bladder cancer overall (OR 1.30, 95% CI 1.04 to 1.63). Emissions of polycyclic aromatic hydrocarbons and diesel from industries near the residence, as evaluated by experts, were associated with an increased risk (OR 1.29, 95% CI 0.85 to 1.98), while lower or no excess risks were observed for other pollution-related variables. Odds ratios among never smokers tended to be higher than among smokers.

Conclusions:

The small to moderate positive associations found for several indices of air pollution and bladder cancer, while suggestive of excess risk, require further evaluation in other settings.
Increased cyclosporine bioavailability induced by experimental nephrotic syndrome in rats
Authors: Medeiros Mara , Pérez-Urizar José , Pedraza-Chaverri José , Muñoz-Arizpe Ricardo , Castañeda-Hernández Gilberto
Published: July 2007

Components of whole blood and plasma are highly altered during the presentation of nephrotic syndrome. The present study was aimed to explore the influence of nephrotic syndrome on the pharmacokinetics of cyclosporine (CsA) (10 mg/kg) administered i.v. to control or puromycin-induced nephrotic rats (P-NS). We found an increase in CsA bioavailability in the nephrotic group compared with controls. The area under the curve of blood CsA versus time (AUCiv) increased from 27.7 ± 5.3 to 60.6 ± 13.8 μg·h·mL–1in control and P-NS rats, respectively. The AUCivaugmentation was positively correlated with cholesterol levels. On the other hand, the total body clearance was significantly lower (0.38 ± 0.06 vs. 0.17 ± 0.03 L·(kg body mass)–1·h–1) and the volume of distribution at steady state (3.70 ± 0.52 vs. 2.85 ± 0.32 L/kg) was significantly smaller in nephrotic rats as compared with control. These pharmacokinetic changes lead to a longer terminal half-life of CsA in P-NS rats (11.8 ± 1.6 vs. 6.9 ± 0.91 h). We conclude that the physiopathologic changes induced by the nephrotic syndrome in P-NS animals result in a significant increase in CsA blood exposure by both the decrease in drug distribution and the reduction in elimination rate of CsA.
Comparative effectiveness of carvedilol and propranolol on glycemic control and insulin resistance associated withl-thyroxin-induced hyperthyroidism — an experimental study
Authors: Bhatt Parloop , Makwana Dharmesh , Santani Devdas , Goyal Ramesh
Published: July 2007

The present study was undertaken to investigate the effectiveness of adrenergic antagonists carvedilol and propranolol on l-thyroxin-induced cardiovascular and metabolic disturbances in rats. Treatment with l-thyroxin sodium (75 mg/kg body mass, s.c., every alternate day for 3 weeks), produced a significant increase in food and water intake, body temperature, heart rate, systolic blood pressure, along with an increase in serum T3, T4, and triglyceride levels. Besides a significant reduction in body mass, serum levels of TSH and cholesterol were also reduced following l-thyroxin treatment. Carvedilol (10 mg/kg body mass, orally) and propranolol (10 mg/kg body mass, i.p.) administered daily in the third week to 2 separate groups of l-thyroxin-treated animals reversed thyroxin-induced loss in body mass and rise in body temperature, blood pressure, and heart rate. Propranolol treatment increased TSH levels and decreased T3and T4levels in hyperthyroid animals, whereas carvedilol did not produce any effect on thyroid hormones. Carvedilol treatment reversed thyroxin induced hypertriglyceridemia, whereas propranolol treatment had no effect. Both carvedilol and propranolol prevented decrease in cholesterol levels induced by thyroxine. Compared with normal animals, l-thyroxin-treated animals showed a state of hyperglycemia, hyperinsulinaemia, impaired glucose tolerance, and insulin resistance, as inferred from elevated fasting serum glucose and insulin levels, higher area under the curve over 120 min for glucose, and decreased insulin sensitivity index (KITT). Propranolol and carvedilol treatment significantly decreased fasting serum glucose levels. Treatment with propranolol did not alter serum insulin levels, area-under-the-curve glucose, or KITTvalues. However, treatment with carvedilol significantly reduced area-under-the-curve glucose, decreased fasting serum insulin levels and significantly increased KITTvalues. In conclusion, carvedilol appears to produce favorable effects on insulin sensitivity and glycemic control and can therefore be considered as more efficacious adjunctive treatment than propranolol in hyperthyroidism.
STUDY OF THREE GRID REFINEMENT METHODS IN THE LATTICE BOLTZMANN FRAMEWORK FOR REACTIVE-DIFFUSIVE PROCESSES
Authors: ALEMANI DAVIDE , BUFFLE JACQUES , CHOPARD BASTIEN , GALCERAN JOSEP
Published: July 2007

We consider a Reactive-Diffusive Lattice Boltzmann (RDLB) model for environmental applications, as for instance the computation of the flux of a metal ion M towards a consuming surface in presence of several ligands. In order to simulate such a environmental system, in which chemical rate constants may vary in a wide range of values, we need a multi-scale approach using grid refinement methods. In this paper we consider three different grid refinement techniques based on the conservation of lattice velocities, relaxation parameters and time steps respectively. We discuss the advantages and disadvantages of each way of refining the grid, in terms of computer speed and computational accuracy. Moreover, an application to a natural mixture of ligands of environmental interest is shown.
Burn injury decreases myocardial Na-K-ATPase activity: role of PKC inhibition
Authors: Horton Jureta W. , Tan Jing , White D. Jean , Maass David L.
Published: July 2007

Cardiomyocyte sodium accumulation after burn injury precedes the development of myocardial contractile dysfunction. The present study examined the effects of burn injury on Na-K-ATPase activity in adult rat hearts after major burn injury and explored the hypothesis that burn-related changes in myocardial Na-K-ATPase activity are PKC dependent. A third-degree burn injury (or sham burn) was given over 40% total body surface area, and rats received lactated Ringer solution (4 ml·kg−1·% burn−1). Subgroups of rats were killed 2, 4, or 24 h after burn ( n = 6 rats/time period), hearts were homogenized, and Na-K-ATPase activity was determined from ouabain-sensitive phosphate generation from ATP by cardiac sarcolemmal vesicles. Additional groups of rats were studied at several times after burn to determine the time course of myocyte sodium loading and the time course of myocardial dysfunction. Additional groups of sham burn-injured and burn-injured rats were given calphostin, an inhibitor of PKC, and Na-K-ATPase activity, cell Na+, and myocardial function were measured. Burn injury caused a progressive rise in cardiomyocyte Na+, and myocardial Na-K-ATPase activity progressively decreased after burn, while PKC activity progressively rose. Administration of calphostin to inhibit PKC activity prevented both the burn-related decrease in myocardial Na-K-ATPase and the rise in intracellular Na+and improved postburn myocardial contractile performance. We conclude that burn-related inhibition of Na-K-ATPase likely contributes to the cardiomyocyte accumulation of intracellular Na+. Since intracellular Na+is one determinant of electrical-mechanical recovery after insults such as burn injury, burn-related inhibition of Na-K-ATPase may be critical in postburn recovery of myocardial contractile function.
Effects of chronic spinal cord injury on body weight and body composition in rats fed a standard chow diet
Authors: Primeaux Stefany D. , Tong Melissa , Holmes Gregory M.
Published: July 2007

The inability to maintain body weight within prescribed ranges occurs in a significant portion of the human spinal cord injury (SCI) population. Using a rodent model of long-term high thoracic (spinal level T3) spinal cord transection (TX), we aimed to identify derangements in body weight, body composition, plasma insulin, glucose tolerance, and metabolic function, as measured by uncoupling protein 1 (UCP1) expression in interscapular brown adipose tissue (IBAT). Sixteen weeks after SCI, body weights of injured female rats stabilized and were significantly lower than surgical control animals. At the same time point, SCI rats had a significantly lower whole body fat:lean tissue mass ratio than controls, as measured indirectly by NMR. Despite lower body weight and fat mass, the cumulative consumption of standard laboratory chow (4.0 kcal/g) and mean energy intake (kcal·day−1·100 g body wt−1) of chronic SCI rats was significantly more than controls. Glucose tolerance tests indicated a significant enhancement in glucose handling in 16-wk SCI rats, which were coupled with lower serum insulin levels. The post mortem weight of gonadal and retroperitoneal fat pads was significantly reduced after SCI and IBAT displayed significantly lower real-time PCR expression of UCP1 mRNA. The reduced fat mass and IBAT UCP1 mRNA expression are contraindicative of the cumulative caloric intake by the SCI rats. The prolonged postinjury loss of body weight, including fat mass, is not due to hypophagia but possibly to permanent changes in gastrointestinal transit and absorption, as well as whole body homeostatic mechanisms.
Seizures and Reduced Life Span in Mice Lacking the Potassium Channel Subunit Kv1.2, but Hypoexcitability and Enlarged Kv1 Currents in Auditory Neurons
Authors: Brew Helen M. , Gittelman Joshua X. , Silverstein Robert S. , Hanks Timothy D. , Demas Vas P. , Robinson Linda C. , Robbins Carol A. , McKee-Johnson Jennifer , Chiu Shing Yan , Messing Albee , Tempel Bruce L.
Published: July 2007

Genes Kcna1 and Kcna2 code for the voltage-dependent potassium channel subunits Kv1.1 and Kv1.2, which are coexpressed in large axons and commonly present within the same tetramers. Both contribute to the low-voltage–activated potassium current IKv1, which powerfully limits excitability and facilitates temporally precise transmission of information, e.g., in auditory neurons of the medial nucleus of the trapezoid body (MNTB). Kcna1-null mice lacking Kv1.1 exhibited seizure susceptibility and hyperexcitability in axons and MNTB neurons, which also had reduced IKv1. To explore whether a lack of Kv1.2 would cause a similar phenotype, we created and characterized Kcna2-null mice (−/−). The −/− mice exhibited increased seizure susceptibility compared with their +/+ and +/− littermates, as early as P14. The mRNA for Kv1.1 and Kv1.2 increased strongly in +/+ brain stems between P7 and P14, suggesting the increasing importance of these subunits for limiting excitability. Surprisingly, MNTB neurons in brain stem slices from −/− and +/− mice were hypoexcitable despite their Kcna2 deficit, and voltage-clamped −/− MNTB neurons had enlarged IKv1. This contrasts strikingly with the Kcna1-null MNTB phenotype. Toxin block experiments on MNTB neurons suggested Kv1.2 was present in every +/+ Kv1 channel, about 60% of +/− Kv1 channels, and no −/− Kv1 channels. Kv1 channels lacking Kv1.2 activated at abnormally negative potentials, which may explain why MNTB neurons with larger proportions of such channels had larger IKv1. If channel voltage dependence is determined by how many Kv1.2 subunits each contains, neurons might be able to fine-tune their excitability by adjusting the Kv1.1:Kv1.2 balance rather than altering Kv1 channel density.
WNT Signaling Pathway and Stem Cell Signaling Network
Authors: Katoh Masuko , Katoh Masaru
Published: July 2007

WNT signals are transduced to the canonical pathway for cell fate determination, and to the noncanonical pathway for control of cell movement and tissue polarity. Canonical WNT signals are transduced through Frizzled family receptors and LRP5/LRP6 coreceptor to the β-catenin signaling cascade. Microtubule affinity–regulating kinase (PAR-1) family kinases, casein kinase Iε (CKIε), and FRAT are positive regulators of the canonical WNT pathway, whereas APC, AXIN1, AXIN2, CKIα, NKD1, NKD2, βTRCP1, βTRCP2, ANKRD6, Nemo-like kinase (NLK), and peroxisome proliferator–activated receptor γ (PPARγ) are negative regulators. Nuclear complex, consisting of T-cell factor/lymphoid enhancer factor, β-catenin, BCL9/BCL9L, and PYGO, activates transcription of canonical WNT target genes such as FGF20, DKK1, WISP1, MYC, CCND1, and Glucagon (GCG). Noncanonical WNT signals are transduced through Frizzled family receptors and ROR2/RYK coreceptors to the Dishevelled-dependent (Rho family GTPases and c-jun NH2-terminal kinase) or the Ca2+-dependent (NLK and nuclear factor of activated T cells) signaling cascades. WNT signals are context-dependently transduced to both pathways based on the expression profile of WNT, SFRP, WIF, DKK, Frizzled receptors, coreceptors, and the activity of intracellular WNT signaling regulators. Epigenetic silencing and loss-of-function mutation of negative regulators of the canonical WNT pathway occur in a variety of human cancer. WNT, fibroblast growth factor (FGF), Notch, Hedgehog, and transforming growth factor β/bone morphogenetic protein signaling network are implicated in the maintenance of tissue homeostasis by regulating self-renewal of normal stem cells as well as proliferation or differentiation of progenitor (transit-amplifying) cells. Breakage of the stem cell signaling network leads to carcinogenesis. Nonsteroidal anti-inflammatory drugs and PPARγ agonists with the potential to inhibit the canonical WNT signaling pathway are candidate agents for chemoprevention. ZTM000990 and PKF118-310 are lead compounds targeted to the canonical WNT signaling cascade. Anti-WNT1 and anti-WNT2 monoclonal antibodies show in vitro effects in cancer treatment. After the optimization, derivatives of small-molecule compound and human monoclonal antibody targeted to the WNT signaling pathway could be used in cancer medicine.
Vascular Endothelial Growth Factor Trap Blocks Tumor Growth, Metastasis Formation, and Vascular Leakage in an Orthotopic Murine Renal Cell Cancer Model
Authors: Verheul Henk M.W. , Hammers Hans , van Erp Karen , Wei Yonfeng , Sanni Tolib , Salumbides Brenda , Qian David Z. , Yancopoulos George D. , Pili Roberto
Published: July 2007

Purpose: Angiogenesis inhibitors have shown clinical benefit in patients with advanced renal cell cancer, but further therapeutic improvement is needed. Vascular endothelial growth factor (VEGF) Trap is a newly developed VEGF-blocking agent with stronger affinity and broader activity than the anti-VEGF antibody bevacizumab. In this study, we tested the activity of VEGF Trap in an orthotopic murine model of renal cancer with spontaneous lung metastases.

Experimental Design: Murine syngeneic renal cell carcinoma cells (RENCA) transfected with a luciferase-expressing vector were injected into the renal capsule of BALB/c mice. I.p. treatment with VEGF Trap or control protein (10 or 25 mg/kg twice weekly) was started shortly after tumor injection to prevent tumor development (prevention model) or after established tumors were formed to inhibit tumor growth and metastasis formation (intervention model).

Results: In the prevention model, VEGF Trap inhibited tumor growth by 87 ± 14% compared with control (P = 0.007) and significantly prolonged survival. In the intervention model, VEGF Trap inhibited tumor growth by 74 ± 9% (P < 0.001) and the formation of lung metastases was inhibited by 98% (P < 0.004). Microvascular density was reduced by 66% due to VEGF Trap treatment (P < 0.001). In addition, VEGF Trap prevented fibrinogen leakage into the tumor microenvironment representative for reduced vascular leaking as shown by immunohistochemical staining.

Conclusions: VEGF Trap is a potent inhibitor of RENCA tumor growth and metastasis formation and blocks the biological function of VEGF in vivo. These results support further clinical development of VEGF Trap for renal cell cancer and other cancer types.
Effect of Tibolone on Breast Cancer Cell Proliferation in Postmenopausal ER+ Patients: Results from STEM Trial
Authors: Kubista Ernst , Planellas Gomez Juan V.M. , Dowsett Mitch , Foidart Jean-Michel , Pohlodek Kamil , Serreyn Rudolphe , Nechushkin Michail , Manikhas Alexey G. , Semiglazov Victor F. , Hageluken Cornelius C.M. , Singer Christian F.
Published: July 2007

Purpose: Tibolone is a selective tissue estrogenic activity regulator, approved for the treatment of vasomotor symptoms in postmenopausal women. We have done an exploratory, double-blind, randomized, placebo-controlled pilot trial to investigate the tissue-specific effects of 2.5 mg tibolone on breast cancer in postmenopausal women, in particular on tissue proliferation (STEM, Study of Tibolone Effects on Mamma carcinoma tissue).

Experimental Design: Postmenopausal women with initially stage I/II, estrogen receptor–positive (ER+) primary breast cancer, were randomly assigned to 14 days of placebo or 2.5 mg/d tibolone. Core biopsies of the primary tumor were obtained before and after treatment. Ki-67 and apoptosis index were analyzed in baseline and corresponding posttreatment specimen.

Results: Of 102 enrolled patients, 95 had evaluable data. Baseline characteristics were comparable between both treatment groups. Breast cancer cases are mainly invasive (99%), stage I or II (42% and 50% respectively), and ER+ (99%). Median intratumoral Ki-67 expression at baseline was 13.0% in the tibolone group and 17.8% in the placebo group, and decreased to 12.0% after 14 days of tibolone while increasing to 19.0% in the placebo group. This change from baseline was not significantly different between tibolone and placebo (Wilcoxon test; P = 0.17). A significant difference was observed between the treatment groups when the median change from baseline apoptosis index was compared between the treatment groups (tibolone, 0.0%; placebo, +0.3%; Wilcoxon test; P = 0.031). The incidence of adverse effects was comparable.

Conclusions: In ER+ breast tumors, 2.5 mg/d tibolone given for 14 days has no significant effect on tumor cell proliferation.
Loss of IFNγ Receptor Is an Independent Prognostic Factor in Ovarian Cancer
Authors: Duncan Timothy J. , Rolland Phil , Deen Suha , Scott Ian V. , Liu David T.Y. , Spendlove Ian , Durrant Lindy G.
Published: July 2007

Purpose: There is evidence that IFNγ plays an important role in ovarian cancer development. IFNγ produces numerous antitumor effects and it may be evasion of these effects which allows tumor progression. We postulate that genetic instability in tumor cells may lead to modulation of expression of the IFNγ receptor, thus leading to altered tumor biology and patient prognosis. This hypothesis would support the theory of immunoediting in ovarian cancer.

Experimental Design: Using tissue microarray technology of 339 primary ovarian cancers, the expression of IFNγ receptor was assessed immunohistochemically. Coupled to a comprehensive database of clinicopathologic variables, its effect on these factors was studied.

Results: Tumors expressing high levels of IFNγ receptor had significantly improved survival (P = 0.017) compared with tumors expressing low levels of the receptor; this was also seen with complete receptor loss (P = 0.014). Factors shown to predict prognosis independently of each other were the following: age, International Federation of Gynecologists and Obstetricians stage, and the absence of macroscopic disease after surgery. The level of IFNγ receptor expression and complete receptor loss were independently predictive of prognosis on multivariate analysis. There was no correlation between receptor status and any of the standard clinicopathologic variables.

Conclusions: Loss of IFNγ receptor independently predicts poor prognosis in ovarian cancer. Loss of receptor expression may be responsible for the limited success in the therapeutic use of IFNγ in ovarian cancer trials and highlights a subgroup of high expressing IFNγ receptor tumors which are more likely to be susceptible to such treatments.
Doxorubicin Directs the Accumulation of Interleukin-12–Induced IFNγ into Tumors for Enhancing STAT1–Dependent Antitumor Effect
Authors: Zhu Shiguo , Waguespack Marian , Barker Steven A. , Li Shulin
Published: July 2007

Purpose: To examine the mechanism by which doxorubicin plus interleukin-12 (IL-12) gene transfer induces enhanced therapeutic efficacy against tumors.

Experimental Design: Tumor-bearing mice were treated with doxorubicin, IL-12–encoding plasmid DNA, doxorubicin plus IL-12–encoding plasmid DNA, or plasmid DNA control. Doxorubicin was systemically given via i.p. injection, and IL-12 was systemically expressed via i.m. injection. To show that doxorubicin enhances the accumulation of IL-12–induced IFNγ into tumors and the signal transducer and activator of transcription 1 (Stat1)–dependent antitumor efficacy, the distribution of IFNγ and the therapeutic end points, such as T-cell infiltration, inhibition of tumor vessel density, tumor growth inhibition, and inhibition of spontaneous tumor metastasis in wild-type and Stat1−/− host and tumors were determined after the treatment at the indicated time points.

Results: In this study, a novel mechanism was unveiled. We discovered that doxorubicin enhances the accumulation of IL-12–induced IFNγ in tumors. The doxorubicin-mediated accumulation of IFNγ in tumors is caused by an increased accumulation of IFNγ-secreting immune cells and not by a direct translocation of IFNγ protein into tumors. Depletion of immune cells reverses the doxorubicin-mediated accumulation of IFNγ into tumors and reverses the inhibition of tumor vessel density induced by coadministration of doxorubicin and IL-12 DNA. Knocking out IFNγ signaling in the tumor host reverses the significant inhibition of tumor growth by coadministration of doxorubicin and IL-12.

Conclusions: The enhanced antitumor efficacy by coadministration of doxorubicin and IL-12 is dependent on the accumulation of IFNγ in tumors. This discovery provides a possible strategy to reduce side effects caused by IL-12.
Pilot Study of a Heptavalent Vaccine-Keyhole Limpet Hemocyanin Conjugate plus QS21 in Patients with Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer
Authors: Sabbatini Paul J. , Ragupathi Govind , Hood Chandra , Aghajanian Carol A. , Juretzka Margrit , Iasonos Alexia , Hensley Martee L. , Spassova Maria K. , Ouerfelli Ouathek , Spriggs David R. , Tew William P. , Konner Jason , Clausen Henrik , Abu Rustum Nadeem , Dansihefsky Samuel J. , Livingston Philip O.
Published: July 2007

Purpose: To characterize the safety and immunogenicity of a heptavalent antigen-keyhole limpet hemocyanin (KLH) plus QS21 vaccine construct in patients with epithelial ovarian, fallopian tube, or peritoneal cancer in second or greater complete clinical remission.

Experimental Design: Eleven patients in this pilot trial received a heptavalent vaccine s.c. containing GM2 (10 μg), Globo-H (10 μg), Lewis Y (10 μg), Tn(c) (3 μg), STn(c) (3 μg), TF(c) (3 μg), and Tn-MUC1 (3 μg) individually conjugated to KLH and mixed with adjuvant QS21(100 μg). Vaccinations were administered at weeks 1, 2, 3, 7, and 15. Periodic blood and urine samples were obtained to monitor safety (complete blood count, comprehensive panel, amylase, thyroid-stimulating hormone, and urinalysis) and antibody production (ELISA, fluorescence-activated cell sorting, and complement-dependent cytotoxicity).

Results: Eleven patients were included in the safety analysis; 9 of 11 patients remained on study for at least 2 weeks past fourth vaccination and were included in the immunologic analysis (two withdrew, disease progression). The vaccine was well tolerated. Self-limited and mild fatigue (maximum grade 2 in two patients), fever, myalgia, and localized injection site reactions were most frequent. No clinically relevant hematologic abnormalities were noted. No clinical or laboratory evidence of autoimmunity was seen. Serologic responses by ELISA were largely IgM against each antigen with the exception of Tn-MUC1 where both IgM and IgG responses were induced. Antibody responses were generally undetectable before immunization. After immunization, median IgM titers were as follows: Tn-MUC1, 1:640 (IgG 1:80); Tn, 1:160; TF, 1:640; Globo-H, 1:40; and STn, 1:80. Only one response was seen against Lewis Y; two were against GM2. Eight of nine patients developed responses against at least three antigens. Antibody titers peaked at weeks 4 to 8 in all patients. Fluorescence-activated cell sorting and complement-dependent cytotoxicity analysis showed substantially increased reactivity against MCF7 cells in seven of nine patients, with some increase seen in all patients.

Conclusions: This heptavalent-KLH conjugate plus QS21 vaccine safely induced antibody responses against five of seven antigens. Investigation in an adequately powered efficacy trial is warranted.
Abrogation of Signal Transducer and Activator of Transcription 3 Reactivation after Src Kinase Inhibition Results in Synergistic Antitumor Effects
Authors: Johnson Faye M. , Saigal Babita , Tran Hai , Donato Nicholas J.
Published: July 2007

Purpose: The Src family of kinases (SFKs) regulate multiple signal transduction cascades and influence proliferation, motility, survival, and angiogenesis. Dasatinib inhibits SFKs, which leads to cytotoxicity, cell cycle arrest, apoptosis, and decreased invasion of cancer cells. Signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor that regulates survival and proliferation. Dasatinib results in rapid and durable inhibition of c-Src, whereas STAT3 undergoes only transient inactivation. We hypothesized that the reactivation of STAT3 after dasatinib treatment represents the engagement of a compensatory signal for cell survival that blocks the antitumor effects of SFK inhibition.

Experimental Design: The effects of upstream inhibitors on STAT3 activation were assessed with western blotting and a quantitative bioplex phosphoprotein assay. We used the 3–(4,5-dimethylthiazol–2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to determine the cytotoxicity and propidium iodine/annexin V staining with flourescence-activated cell sorting (FACS) analysis to evaluate cell cycle change and apoptosis. The combination index was calculated by the Chou-Talalay equation. Cytokines were quantitated using a multiplexed, particle-based FACS analysis.

Results: C-Src and several downstream molecules were rapidly and durably inhibited by dasatinib. However, STAT3 was reactivated by 24 h. The addition of JAK inhibitors during dasatinib incubation resulted in sustained inhibition of STAT3, although JAK activation by dasatinib was not shown. Combined SFK and JAK inhibition resulted in synergistic cytotoxicity due to increased apoptosis.

Conclusions: The reactivation of STAT3 during dasatinib treatment is caused by the engagement of a compensatory pathway that suppresses the antitumor effects of SFK inhibition and allows cancer cell survival. Abrogation of this pathway resulted in synergistic cytotoxicity. Given that STAT3 reactivation occurred in 14 of 15 solid tumor cell lines, dasatinib combined with Janus-activated kinase inhibitors may have widespread application in cancer treatment.
Epigenetic Inactivation Implies Independent Functions for Insulin-like Growth Factor Binding Protein (IGFBP)-Related Protein 1 and the Related IGFBPL1 in Inhibiting Breast Cancer Phenotypes
Authors: Smith Paul , Nicholson Linda J. , Syed Nelofer , Payne Annette , Hiller Louise , Garrone Ornella , Occelli Marcella , Gasco Milena , Crook Tim
Published: July 2007

Purpose: To analyze epigenetic regulation of two related genes, insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) and IGFBPL1, and its significance as a determinant of clinical phenotypes in human breast cancer.

Experimental Design: We have investigated the expression and epigenetic regulation of IGFBP-rP1 and IGFBPL1 in human breast cancer cell lines and primary and metastatic carcinomas.

Results: Expression of IGFBP-rP1 and IGFBPL1 is down-regulated in breast cancer cell lines. Aberrant methylation in the CpG islands of each gene correlates well with loss of expression at the mRNA level. Analysis of methylation in DNA isolated from human primary breast tumors showed that methylation in either gene was associated with a worse overall survival (OS; P = 0.008) and disease-free survival (DFS) following surgery (P = 0.04) and worse DFS following adjuvant chemotherapy (P = 0.01). Methylation of IGFBP-rP1 alone was associated with a trend toward decreased OS (P = 0.10) and decreased DFS (P = 0.25). Methylation in IGFBPL1 was clearly associated with worse OS (P = 0.001) and DFS (P < 0.0001). Methylation in either IGFBP-rP1 or IGFBPL1 was significantly associated with nodal disease (P < 0.001).

Conclusions: Expression of IGFBP-rP1 and IGFBPL1 is regulated by aberrant hypermethylation in breast cancer, implying that inactivation of these genes is involved in the pathogenesis of this malignancy. Analysis of methylation of these genes may have utility in prediction of clinical phenotypes, such as nodal disease and response to chemotherapy.
The Convergent Development of Molecular-Targeted Drugs for Cancer Treatment and Prevention
Authors: Lippman Scott M. , Heymach John V.
Published: July 2007

Advances in our understanding of multistep and field carcinogenesis are erasing the clear demarcation of intraepithelial neoplasia from invasive neoplasia. The growing ability to define a very high risk of cancer is forging important commonalities between prevention and therapy, such as in potential prognostic/predictive markers, agents, and side effects that patients would be willing to tolerate, and the logistics of definitive trials. The emergence of promising new molecular-targeted agents and new technologies for screening and early detection provides new opportunities for applying clinical trial designs that integrate therapy and prevention end points. Such trials may be used to facilitate targeted drug development and help identify strategies for both cancer prevention and advanced cancer therapy. These several advances are creating a convergence of cancer therapy with cancer prevention that promises to streamline the development of targeted drugs and improve the control of major cancers.
BRCA Mutations in Women with Ductal Carcinoma In situ
Authors: Smith Karen Lisa , Adank Muriel , Kauff Noah , Lafaro Kelly , Boyd Jeff , Lee Johanna B. , Hudis Clifford , Offit Kenneth , Robson Mark
Published: July 2007

Purpose: The strength of the association between ductal carcinoma in situ (DCIS) and BRCA mutations has not been defined.

Experimental Design: Mutation frequency was compared in three groups: (1) a prevalent series of women with DCIS, (2) an incident series of women with DCIS, and (3) a clinic-based series of women with DCIS referred for hereditary cancer risk assessment. In groups 1 and 2, limited to Ashkenazi Jewish (AJ) cases, mutation frequency was compared with that in age-matched AJ controls with invasive breast cancer (IBC).

Results: In group 1, 3 of 62 (4.8%) women with DCIS and 15 of 130 (11.5%) controls with IBC had BRCA mutations. In group 2, 0 of 58 (0%) women with DCIS and 6 of 116 (5.2%) controls with IBC had BRCA mutations [combined odds ratios (OR) in groups 1 and 2: 3.64, 95% confidence interval (95% CI), 1.06-12.46; P = 0.04]. In group 3, deleterious mutations were identified in 10 of 79 (12.7%) probands with DCIS, similar to the frequency in IBC probands. In group 3, mutations were associated with family history of ovarian cancer (OR, 13.35; 95% CI, 2.48-71.94; P = 0.003) or early onset breast cancer (OR, 16.23; 95% CI, 1.68-157.01; P = 0.02) but not with AJ ethnicity or age at diagnosis.

Conclusions:BRCA mutations were less frequent in women with DCIS not selected for family history or age at diagnosis than in women with IBC. Nonetheless, mutations were found in a significant proportion of women with DCIS who presented for hereditary risk assessment.
Protein Expression Profiling and Molecular Classification of Gastric Cancer by the Tissue Array Method
Authors: Lee Hye Seung , Cho Sung-Bum , Lee Hee Eun , Kim Min A , Kim Ji Hun , Park Do Joong , Kim Ju Han , Yang Han-Kwang , Lee Byung Lan , Kim Woo Ho
Published: July 2007

Purpose: Gastric cancer is heterogeneous clinically and histologically, and prognosis prediction by tumor grade or type is difficult. Although previous studies have suggested that frozen tissue–based molecular classifications effectively predict prognosis, prognostic classification on formalin-fixed tissue is needed, especially in early gastric cancer.

Experimental Design: We immunostained 659 consecutive gastric cancers using 56 tumor-associated antibodies and the tissue array method. Hierarchical cluster analyses were done before and after feature selection. To optimize classifier number and prediction accuracy for prognosis, a supervised analysis using a support vector machine algorithm was used.

Results: Of 56 gene products, 27 survival-associated proteins were selected (feature selection), and hierarchical clustering identified two clusters: cluster 1 and cluster 2. Cluster 1 cancers were more likely to have intestinal type, earlier stage, and better prognosis than cluster 2 (P < 0.05). In 187 early gastric cancers (pT1), cluster 2 was associated with the presence of metastatic lymph nodes (P = 0.026). Kaplan-Meier survival curves stratified by pathologic tumor-lymph node metastasis revealed that cluster 2 was associated with poor prognosis in stage I or II cancer (P < 0.05). Support vector machines and genetic algorithms selected nine classifiers from the whole data set, another nine classifiers for stage I and II, and eight classifiers for stage III and IV. The prediction accuracies for patient outcome were 73.1%, 88.1%, and 76%, respectively.

Conclusions: Protein expression profiling using the tissue array method provided a useful means for the molecular classification of gastric cancer into survival-predictive subgroups. The molecular classification predicted lymph node metastasis and prognosis in early stage gastric cancer.
Dual Targeting of Endothelial Cells and Pericytes in Antivascular Therapy for Ovarian Carcinoma
Authors: Lu Chunhua , Kamat Aparna A. , Lin Yvonne G. , Merritt William M. , Landen Charles N. , Kim Tae Jin , Spannuth Whitney , Arumugam Thiru , Han Liz Y. , Jennings Nicholas B. , Logsdon Craig , Jaffe Robert B. , Coleman Robert L. , Sood Anil K.
Published: July 2007

Purpose: Pericytes are known to provide a survival advantage for endothelial cells. We hypothesize that strategies aimed at dual targeting of tumor-associated endothelial cells and pericytes will be highly efficacious.

Experimental Design: Paclitaxel-sensitive (HeyA8 and SKOV3ip1) or paclitaxel-resistant (HeyA8-MDR) orthotopic tumors in mice were examined for therapeutic efficacy by targeting the endothelial cells (using a vascular endothelial growth factor receptor inhibitor, AEE788) and pericytes (using STI571) alone or in combination. Additional therapy and survival studies in combination with paclitaxel were also done. Following therapy, tumors were examined for endothelial cell apoptosis, pericyte coverage, microvessel density, and proliferation.

Results: AEE788 inhibited tumor growth by 45% and 59% in the HeyA8 and SKOV3ip1 models, respectively, whereas STI571 alone was not effective. AEE788 plus STI571 resulted in 69% to 84% inhibition of tumor growth in both models. Moreover, combination of these agents with paclitaxel was even more effective, resulting in up to 98% inhibition of tumor growth. The triple combination was even effective in the HeyA8-MDR model. Remarkably, this triple combination also resulted in improved survival compared with all other groups (P < 0.001) and caused regression of formed tumors. Pericyte coverage was significantly decreased in the STI571 treatment groups, and microvessel density was significantly reduced in the AEE788 treatment groups. AEE788 induced endothelial cell apoptosis, which was further enhanced by the addition of STI571.

Conclusions: Strategies targeting both endothelial cells and pericytes are highly effective for in vivo treatment of ovarian carcinoma. This antiangiogenic effect may be partially due to decreased pericyte coverage, thus increasing the sensitivity of tumor vasculature to therapy. These encouraging data support the development of clinical trials based on this strategy.
Prognostic Significance of Nuclear ING3 Expression in Human Cutaneous Melanoma
Authors: Wang Yemin , Dai Derek L. , Martinka Magdalena , Li Gang
Published: July 2007

Purpose: The novel tumor-suppressor ING3 has been shown to modulate transcription, cell cycle control, and apoptosis. Our previous study showed that ING3 promotes UV-induced apoptosis via the Fas/caspase-8–dependent pathway in melanoma cells. To investigate the putative role of ING3 in the development of melanoma, we examined the expression of ING3 in melanocytic lesions at different stages and analyzed the correlation between ING3 expression and clinicopathologic variables and patient survival.

Experimental Design: Using tissue microarray and immunohistochemistry, we evaluated nuclear and cytoplasmic ING3 staining in 58 dysplastic nevi, 114 primary melanomas, and 50 metastatic melanomas.

Results: Nuclear ING3 expression was remarkably reduced in malignant melanomas compared with dysplastic nevi (P < 0.001), which was significantly correlated with the increased ING3 level in cytoplasm (P < 0.05). Furthermore, the reduced nuclear ING3 expression was significantly correlated with a poorer disease-specific 5-year survival of patients with primary melanoma, especially for the high-risk melanomas (thickness ≥2.0 mm) with the survival rate reducing from 93% for patients with strong nuclear ING3 staining in their tumor biopsies to 44% for those with negative-to-moderate nuclear ING3 staining (P = 0.004). Strikingly, our multivariate Cox regression analysis revealed that reduced nuclear ING3 expression is an independent prognostic factor to predict patient outcome in primary melanomas (P = 0.038).

Conclusions: Our data indicate that ING3 may be an important marker for human melanoma progression and prognosis as well as a potential therapeutic target.
Evaluation of MM5 Optically Thin Clouds over Europe in Fall Using ICESat Lidar Spaceborne Observations
Authors: Chepfer H. , Chiriaco M. , Vautard R. , Spinhirne J.
Published: July 2007

The description of clouds in mesoscale models has progressed significantly during recent years by improving microphysical schemes with more physical parameterizations deduced from observations. Recently, the first lidar in space, the Ice, Cloud, and Land Elevation Satellite (ICESat)/Geosciences Laser Altimeter System, has collected a valuable dataset that improves the knowledge of occurrence and macrophysical properties of clouds, and particularly high-altitude clouds, which are usually optically thin. This study evaluates the capability of the fifth-generation Pennsylvania State University–NCAR Mesoscale Model (MM5) to reproduce optically thin clouds using the ICESat October–November 2003 dataset. Initial and boundary conditions are prescribed from NCEP products and MM5 run over the European continent with a 40-km spatial resolution. Spaceborne lidar profiles are diagnosed from model outputs and compared with the observed ones at the same location and time. One month of simulations–observations comparisons shows that the model correctly reproduces cloud structures on average, but underestimates the thinnest clouds (by 0%–20%) and overestimates less thin clouds in the upper troposphere (altitude >6 km). The total low-level water cloud amount (altitude <6 km) appears fairly well reproduced, although the masking effect of higher clouds does not allow for a firm conclusion. The clouds are rarely simulated and observed simultaneously, 50% for high clouds and 20% for low clouds. The lack of high-altitude very thin clouds is possibly due to dry biases in the upper-troposphere humidity fields used to force the model. The overestimation of optically less thin cloud may be due to an overestimation of the cloud lifetime or water vapor supersaturation around ice clouds that is not taken into account in the model. When the upper troposphere and low warm clouds appear in the model at the same time and location as in the observations, they are optically too thick, likely because their water/ice content and particle concentration are overestimated simultaneously.
Regional Climate Model–Simulated Timing and Character of Seasonal Rains in South America
Authors: Rauscher Sara A. , Seth Anji , Liebmann Brant , Qian Jian-Hua , Camargo Suzana J.
Published: July 2007

The potential of an experimental nested prediction system to improve the simulation of subseasonal rainfall statistics including daily precipitation intensity, rainy season onset and withdrawal, and the frequency and duration of dry spells is evaluated by examining a four-member ensemble of regional climate model simulations performed for the period 1982–2002 over South America. The study employs the International Centre for Theoretical Physics (ICTP) regional climate model, version 3 (RegCM3), driven with the NCEP–NCAR reanalysis and the European Centre–Hamburg GCM, version 4.5. Statistics were examined for five regions: the northern Amazon, southern Amazon, the monsoon region, Northeast Brazil, and southeastern South America. RegCM3 and the GCM are able to replicate the distribution of daily rainfall intensity in most regions. The analysis of the rainy season timing shows the observed onset occurring first over the monsoon region and then spreading northward into the southern Amazon, in contrast to some previous studies. Correlations between the onset and withdrawal date and SSTs reveal a strong relationship between the withdrawal date in the monsoon region and SSTs in the equatorial Pacific, with above-average SSTs associated with late withdrawal. Over Northeast Brazil, the regional model errors are smaller than those shown by the GCM, and the strong interannual variability in the timing of the rainy season is better simulated by RegCM3. However, the regional model displays an early bias in onset and withdrawal over the southern Amazon and the monsoon regions. Both RegCM3 and the GCM tend to underestimate (overestimate) the frequency of shorter (longer) dry spells, although the differences in dry spell frequency during warm and cold ENSO events are well simulated. The results presented here show that there is potential for added value from the regional model in simulating subseasonal statistics; however, improvements in the physical parameterizations are needed for this tropical region.
Barack Obama and the Dilemma of Power
Authors: Asante Molefi Kete
Published: July 2007

This article examines the prospects and possibilities of presidential power in the event of the election of Obama. A great discourse has ensued about the Obama candidacy for the Democratic nomination because he is the first African American to gain such widespread popular support so soon in the campaign. Indeed, he is the first candidate in history to receive secret service protection so early in the primary campaign because of serious threats against his person by numerous detractors. An Afrocentric examination of the political campaign and presidential prospects of Obama begins with an interrogation of the nature of the political process in relationship to history, location, the American imperium, and the dilemma of power in a racial politic. Any intense interrogation of Obama's concept of himself as an African American locates him in a particular space and time. The overwhelming racial characteristics of American society, even at this date, suggest that should Obama be nominated and elected, he would still face enormous social and political hurdles institutionalized as White racial hegemony, thus complicating an Obama presidency.
Perceptions of Leadership and the Challenge of Obama's Blackness
Authors: McIlwain Charlton D.
Published: July 2007

This article analyzes the relationship between race and perceptions of leadership as a way of assessing the presidential prospects of Barack Obama's 2008 campaign. Analysis of the 1988 Super Tuesday National Election Studies data demonstrates that for White voters, perceptions of leadership serve as a proxy for racial evaluations of an African American candidate. A content analysis of newspaper coverage during the first 3 months of Obama's candidacy was conducted and demonstrates that questions of leadership and race are prominently featured in media reporting about Obama.
Compensating Thermoset Composite Panel Deformation using Corrective Molding
Authors: Capehart T.W. , Muhammad Nouman , Kia Hamid G.
Published: July 2007

Open mold composite (OMC) body panels, comprising three thermosetting layers, warp significantly after removal from the mold. Due to an asymmetric layup of these laminates, a residual stress develops due to chemical shrinkage of the gel coat resin during cure. The resulting bending moment distorts the panel. This work first develops a finite element model (FEM) to calculate panel deformation based on the chemical shrinkage and mechanical properties of the laminated panel. The FEM is then validated by a direct comparison with the measured distortion of door-outer panels produced using a conventional panel-shaped mold. This FEM is then integrated into an algorithm to calculate a mold shape that corrects for this distortion. Starting with a mold duplicating the desired panel shape, the initial panel deformation is calculated using the FEM. Trial molds are then generated by partial inversion of the deformed panel's deviation from the desired shape. The algorithm is iterated until it converges to a corrective mesh that deforms to the mesh of the desired shape of the panel. A corrective mold for a door-outer panel is fabricated and the effectiveness of the corrective mold is evaluated by measuring the distortion of the door-outer panels it produces. Compared to the panels produced by the conventional mold, the corrective mold reduces panel distortion by 45%.
Breaking Progress Simulation and Strength Prediction of Woven Fabric under Uni-axial Tensile Loading
Authors: Chen Guohua , Ding Xin
Published: July 2007

The chain-of-bundles model and a Monte Carlo method were used to simulate the breaking progress of plain weave woven fabrics under uni-axial tensile load and to predict the tensile strength of the fabrics. The variations of the bending outline at the cross-over point between warp and weft and the additional strains of the crossing yarns by crimp interchange have been considered in order to analyze yarn interaction and to determine the critical length. Two approaches, shear-lag analysis (SLA) and the local load-sharing (LLS) rule, were used to calculate the stress concentration factors, which determine the load redistribution scheme once a yarn breaks. Then the Monte Carlo simulation was conducted to simulate the failure progress of woven fabrics. The simulation strength distributions of fabric samples can be fitted with two-parameter Weibull distribution. By comparison with the test data, it was found that the shape parameter of simulated strength by LLS rule was larger and the value of scale parameter smaller than that by SLA. The predicted strength by LLS was smaller than the test data, whereas that by SLA showed better agreement with the test data. It is likely that the SLA approach is more suitable for predicting the strength of woven fabrics under uni-axial tensile load.