bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host Cell Cathepsins Potentiate Moloney Murine Leukemia Virus Infection
Authors: Kumar Pankaj , Nachagari Deepa , Fields Carolyn , Franks John , Albritton Lorraine M. 
Published: July 2007

ABSTRACT

The roles of cellular proteases in Moloney murine leukemia virus (MLV) infection were investigated using MLV particles pseudotyped with vesicular stomatitis virus (VSV) G glycoprotein as a control for effects on core MLV particles versus effects specific to Moloney MLV envelope protein (Env). The broad-spectrum inhibitors cathepsin inhibitor III and E-64d gave comparable dose-dependent inhibition of Moloney MLV Env and VSV G pseudotypes, suggesting that the decrease did not involve the envelope protein. Whereas, CA-074 Me gave a biphasic response that differentiated between Moloney MLV Env and VSV G at low concentrations, at which the drug is highly selective for cathepsin B, but was similar for both glycoproteins at higher concentrations, at which CA-074 Me inhibits other cathepsins. Moloney MLV infection was lower on cathepsin B knockout fibroblasts than wild-type cells, whereas VSV G infection was not reduced on the B
−/−
cells. Taken together, these results support the notion that cathepsin B acts at an envelope-dependent step while another cathepsin acts at an envelope-independent step, such as uncoating or viral-DNA synthesis. Virus binding was not affected by CA-074 Me, whereas syncytium induction was inhibited in a dose-dependent manner, consistent with cathepsin B involvement in membrane fusion. Western blot analysis revealed specific cathepsin B cleavage of SU in vitro, while TM and CA remained intact. Infection could be enhanced by preincubation of Moloney MLV with cathepsin B, consistent with SU cleavage potentiating infection. These data suggested that during infection of NIH 3T3 cells, endocytosis brings Moloney MLV to early lysosomes, where the virus encounters cellular proteases, including cathepsin B, that cleave SU.
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.
WNT Signaling Pathway and Stem Cell Signaling Network
Authors: Katoh Masuko , Katoh Masaru 
Published: July 2007

Abstract
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

Abstract
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 &lt; 0.001) and the formation of lung metastases was inhibited by 98% (P &lt; 0.004). Microvascular density was reduced by 66% due to VEGF Trap treatment (P &lt; 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

Abstract
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

Abstract
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

AbstractPurpose: 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

Abstract
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

Abstract
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.