bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibiotic treatment in patients with low-back pain associated with Modic changes Type 1 (bone oedema): a pilot study
Authors: Albert H B , Manniche C , Sorensen J S , Deleuran B W 
Published: August 2008

Objective:The aim of this study was to assess the clinical effect of antibiotic treatment in a cohort of patients with low-back pain (LBP) and Modic changes Type 1 (bone oedema) following a lumbar herniated disc.Design:This was a prospective uncontrolled trial of 32 LBP patients who had Modic changes and were treated withAmoxicillin-clavulanate(500 mg/125 mg) 3 × day for 90 days. All patients had previously participated in a randomised controlled trial (RCT) that investigated active conservative treatment for a lumbar herniated disc (n = 166). All patients in that RCT who had Modic changes and LBP at 14 months follow-up (n = 37) were invited to participate in this subsequent antibiotic trial but five did not meet the inclusion criteria.Results:29 patients completed the treatment, as three patients dropped out due to severe diarrhoea. At the end of treatment and at long-term follow-up (mean 10.8 months) there was both clinically important and statistically significant (p⩽0.001) improvement in all outcome measures: LBP intensity, number of days with pain, disease-specific and patient-specific function, and global perceived effect.Conclusions:In this uncontrolled trial, the clinical effect of antibiotic treatment was large in a group of patients with Modic changes suffering from persistent LBP following a disc herniation. These results provide tentative support for a hypothesis that bacterial infection may play a role in LBP with Modic changes and indicate the need for randomised controlled trials to test this hypothesis.
Extracorporeal shockwave therapy for patellar tendinopathy: a review of the literature
Authors: van Leeuwen M T , Zwerver J , van den Akker-Scheek I 
Published: August 2008

Background and purpose:Extracorporeal shockwave therapy (EWST) has become a popular treatment for patellar tendinopathy. The purpose of this review was to study the effectiveness of ESWT treatment for patellar tendinopathy; to draft guidelines for an effective treatment protocol of ESWT treatment; and to identify topics for further research.Methods:A computerised search of the Medline and Embase databases was conducted on 1 August 2007, to identify studies dealing with the effectiveness of ESWT for patellar tendinopathy.Results:Seven articles describing the effectiveness of ESWT on patellar tendinopathy, all published after 2000, were included. These studies included a total of 283 patients (298 tendons), 204 of whom (215 tendons) were assigned to ESWT treatment. The treatment results were positive but most studies had methodological deficiencies, small numbers and/or short follow-up periods. Method of application and shockwave generation, energy level, number and frequency of treatments, use of (local) anaesthesia and method of localisation were variable.Conclusion:ESWT seems to be a safe and promising treatment for patellar tendinopathy with a positive effect on pain and function. Based on current knowledge it is impossible to recommend a specific treatment protocol. Further basic and clinical research into the working mechanism and effectiveness of ESWT for patellar tendinopathy are necessary.
The Spi Lake Formation of the central Hearne domain, western Churchill Province, Canada: an axial intracratonic continental tholeiite trough above the cogenetic Kaminak dyke swarmGeological Survey of Canada Contribution 20070462.
Authors: Sandeman Hamish A. , Ryan James J. 
Published: August 2008

The Spi Group is a package of plagioclase porphyritic, amygdaloidal basalt flows and sandstone (Spi Lake Formation) conformably overlain by coarse conglomerate and sandstone (Old Boot Formation). These unconformably overlie the Kaminak Lake segment of the Central Hearne supracrustal belt, western Churchill Province. The Spi Group developed in a small, isolated basin (8 km2) and is older than the Paleoproterozoic Hurwitz Group. Our data demonstrate that the basalts of the Spi Lake Formation are genetically related to the ca. 2450 Ma Kaminak dyke swarm, a speculation previously promoted by some workers based on field characteristics alone. They are continental tholeiites with large ion lithophile and light rare-earth element enriched multielement profiles with prominent high field-strength element troughs. The 143Nd/144Nd compositions overlap the contemporaneous chondritic bulk-earth data. All of these are features we infer to have resulted from mixing of melts from dominantly depleted mid-ocean ridge basalt (MORB) mantle with low-degree partial melts of metasomatically enriched sub-continental lithospheric mantle. These composite magmas then underwent clinopyroxene + plagioclase ± olivine fractionation with minor assimilation of local tonalitic middle crust. The Spi Lake basin is <1 km wide, trends 020° parallel to Kaminak dykes but is discordant to the more common 045° to 070° trends of fold keels of the Hurwitz Group. The basin is a graben filled first with basalt and then molassoid sediments, representing the expression of crustal extension associated with Kaminak dyke emplacement. This indicates that the present erosional surface in the region is broadly at the same level as at the time of both Hurwitz and Spi Group deposition.
Improved tumor targeting of anti–epidermal growth factor receptor Nanobodies through albumin binding: taking advantage of modular Nanobody technology
Authors: Tijink Bernard M. , Laeremans Toon , Budde Marianne , Walsum Marijke Stigter-van , Dreier Torsten , de Haard Hans J. , Leemans C. René , van Dongen Guus A.M.S. 
Published: August 2008

Abstract
The ∼15-kDa variable domains of camelid heavy-chain-only antibodies (called Nanobodies) can easily be formatted as multivalent or multispecific single-chain proteins. Because of fast excretion, however, they are less suitable for therapy of cancer. In this study, we aimed for improved tumor targeting of a bivalent anti–epidermal growth factor receptor (EGFR) Nanobody (αEGFR-αEGFR) by fusion to a Nanobody unit binding to albumin (αAlb). Biodistributions of αEGFR-αEGFR, αEGFR-αEGFR-αAlb (∼50 kDa), αTNF-αTNF-αAlb (control, binding tumor necrosis factor-α), and the ∼150-kDa anti-EGFR antibody cetuximab were compared in A431 xenograft-bearing mice. The proteins were radiolabeled with 177Lu to facilitate quantification. Tumor uptake of 177Lu-αEGFR-αEGFR decreased from 5.0 ± 1.4 to 1.1 ± 0.1 %ID/g between 6 and 72 h after injection. Due to its rapid blood clearance, tumor-to-blood ratios &gt;80 were obtained within 6 h after injection. Blood clearance became dramatically slower and tumor uptake became significantly higher by introduction of αAlb. Blood levels of αEGFR-αEGFR-αAlb were 21.2 ± 2.5, 11.9 ± 0.6, and 4.0 ± 1.4 and tumor levels were 19.4 ± 5.5, 35.2 ± 7.5, and 28.0 ± 6.8 %ID/g at 6, 24, and 72 h after injection, respectively. Tumor uptake was at least as high as for cetuximab (15.5 ± 3.9, 27.1 ± 7.9, and 25.6 ± 6.1 %ID/g) and significantly higher than for αTNF-αTNF-αAlb. αEGFR-αEGFR-αAlb showed faster and deeper tumor penetration than cetuximab. These data show that simple fusion of αEGFR and αAlb building blocks results in a bifunctional Nanobody format, which seems more favorable for therapy as far as pharmacokinetics and tumor deposition are concerned. [Mol Cancer Ther 2008;7(8):2288–97]
Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1
Authors: Blasina Alessandra , Hallin Jill , Chen Enhong , Arango Maria Elena , Kraynov Eugenia , Register James , Grant Stephan , Ninkovic Sacha , Chen Ping , Nichols Tim , O'Connor Patrick , Anderes Kenna 
Published: August 2008

Abstract
Checkpoints are present in all phases of the cell cycle and are regarded as the gatekeepers maintaining the integrity of the genome. Many conventional agents used to treat cancer impart damage to the genome and activate cell cycle checkpoints. Many tumors are defective in the tumor suppressor p53 and therefore lack a functional G1 checkpoint. In these tumors, however, the S-G2 checkpoints remain intact and, in response to DNA damage, arrest cell cycle progression allowing time for DNA repair. Checkpoint kinase 1 (Chk1) is a key element in the DNA damage response pathway and plays a crucial role in the S-G2-phase checkpoints. Inhibiting Chk1 represents a therapeutic strategy for creating a “synthetic lethal” response by overriding the last checkpoint defense of tumor cells against the lethal damage induced by DNA-directed chemotherapeutic agents. Chk1 inhibition is consistent with emerging targeted therapies aiming to exploit molecular differences between normal and cancer cells. Adding a Chk1 inhibitor to DNA-damaging cytotoxic therapy selectively targets tumors with intrinsic checkpoint defects while minimizing toxicity in checkpoint-competent normal cells. PF-00477736 was identified as a potent, selective ATP-competitive small-molecule inhibitor that inhibits Chk1 with a Ki of 0.49 nM. PF-00477736 abrogates cell cycle arrest induced by DNA damage and enhances cytotoxicity of clinically important chemotherapeutic agents, including gemcitabine and carboplatin. In xenografts, PF-00477736 enhanced the antitumor activity of gemcitabine in a dose-dependent manner. PF-00477736 combinations were well tolerated with no exacerbation of side effects commonly associated with cytotoxic agents. [Mol Cancer Ther 2008;7(8):2394–404]
Jadomycin B, an Aurora-B kinase inhibitor discovered through virtual screening
Authors: Fu Da-Hua , Jiang Wei , Zheng Jian-Ting , Zhao Gui-Yu , Li Yan , Yi Hong , Li Zhuo-Rong , Jiang Jian-Dong , Yang Ke-Qian , Wang Yanchang , Si Shu-Yi 
Published: August 2008

Abstract
Aurora kinases have emerged as promising targets for cancer therapy because of their critical role in mitosis. These kinases are well-conserved in all eukaryotes, and IPL1 gene encodes the single Aurora kinase in budding yeast. In a virtual screening attempt, 22 compounds were identified from nearly 15,000 microbial natural products as potential small-molecular inhibitors of human Aurora-B kinase. One compound, Jadomycin B, inhibits the growth of ipl1-321 temperature-sensitive mutant more dramatically than wild-type yeast cells, raising the possibility that this compound is an Aurora kinase inhibitor. Further in vitro biochemical assay using purified recombinant human Aurora-B kinase shows that Jadomycin B inhibits Aurora-B activity in a dose-dependent manner. Our results also indicate that Jadomycin B competes with ATP for the kinase domain, which is consistent with our docking prediction. Like other Aurora kinase inhibitors, Jadomycin B blocks the phosphorylation of histone H3 on Ser10 in vivo. We also present evidence suggesting that Jadomycin B induces apoptosis in tumor cells without obvious effects on cell cycle. All the results indicate that Jadomycin B is a new Aurora-B kinase inhibitor worthy of further investigation. [Mol Cancer Ther 2008;7(7):2386–93]
Human endothelial precursor cells express tumor endothelial marker 1/endosialin/CD248
Authors: Bagley Rebecca G. , Rouleau Cecile , St. Martin Thia , Boutin Paula , Weber William , Ruzek Melanie , Honma Nakayuki , Nacht Mariana , Shankara Srinivas , Kataoka Shiro , Ishida Isao , Roberts Bruce L. , Teicher Beverly A. 
Published: August 2008

Abstract
Angiogenesis occurs during normal physiologic processes as well as under pathologic conditions such as tumor growth. Serial analysis of gene expression profiling revealed genes [tumor endothelial markers (TEM)] that are overexpressed in tumor endothelial cells compared with normal adult endothelial cells. Because blood vessel development of malignant tumors under certain conditions may include endothelial precursor cells (EPC) recruited from bone marrow, we investigated TEM expression in EPC. The expression of TEM1 or endosialin (CD248) and other TEM has been discovered in a population of vascular endothelial growth factor receptor 2+/CD31+/CD45−/VE-cadherin+ EPC derived from human CD133+/CD34+ cells. EPC share some properties with fully differentiated endothelial cells from normal tissue, yet reverse transcription-PCR and flow cytometry reveal that EPC express higher levels of endosialin at the molecular and protein levels. The elevated expression of endosialin in EPC versus mature endothelial cells suggests that endosialin is involved in the earlier stages of tumor angiogenesis. Anti-endosialin antibodies inhibited EPC migration and tube formation in vitro. In vivo, immunohistochemistry indicated that human EPC continued to express endosialin protein in a Matrigel plug angiogenesis assay established in nude mice. Anti-endosialin antibodies delivered systemically at 25 mg/kg were also able to inhibit circulating murine EPC in nude mice bearing s.c. SKNAS tumors. EPC and bone marrow–derived cells have been shown previously to incorporate into malignant blood vessels in some instances, yet they remain controversial in the field. The data presented here on endothelial genes that are up-regulated in tumor vasculature and in EPC support the hypothesis that the angiogenesis process in cancer can involve EPC. [Mol Cancer Ther 2008;7(8):2536–46]
New insights into the pharmacology and cytotoxicity of gemcitabine and 2′,2′-difluorodeoxyuridine
Authors: Veltkamp Stephan A. , Pluim Dick , van Eijndhoven Maria A.J. , Bolijn Maria J. , Ong Felix H.G. , Govindarajan Rajgopal , Unadkat Jashvant D. , Beijnen Jos H. , Schellens Jan H.M. 
Published: August 2008

AbstractIn a clinical study with oral gemcitabine (2′,2′-difluorodeoxycytidine, dFdC), 2′,2′-difluorodeoxyuridine (dFdU) was extensively formed and accumulated after multiple oral dosing. Here, we have investigated the in vitro cytotoxicity, cellular uptake, efflux, biotransformation, and nucleic acid incorporation of dFdC and dFdU. Short-term and long-term cytotoxicity assays were used to assess the cytotoxicity of dFdC and dFdU in human hepatocellular carcinoma HepG2, human lung carcinoma A549, and Madin-Darby canine kidney cell lines transfected with the human concentrative or equilibrative nucleoside transporter 1 (hCNT1 or hENT1), or empty vector. Radiolabeled dFdC and dFdU were used to determine cellular uptake, efflux, biotransformation, and incorporation into DNA and RNA. The compounds dFdC, dFdU, and their phosphorylated metabolites were quantified by high-performance liquid chromatography with UV and radioisotope detection. dFdU monophosphate, diphosphate, and triphosphate (dFdU-TP) were formed from dFdC and dFdU. dFdU-TP was incorporated into DNA and RNA. The area under the intracellular concentration-time curve of dFdC-TP and dFdU-TP and their extent of incorporation into DNA and RNA inversely correlated with the IC50 of dFdC and dFdU, respectively. The cellular uptake and cytotoxicity of dFdU were significantly enhanced by hCNT1. dFdU inhibited cell cycle progression and its cytotoxicity significantly increased with longer duration of exposure. dFdU is taken up into cells with high affinity by hCNT1 and phosphorylated to its dFdU-TP metabolite. dFdU-TP is incorporated into DNA and RNA, which correlated with dFdU cytotoxicity. These data provide strong evidence that dFdU can significantly contribute to the cytotoxicity of dFdC. [Mol Cancer Ther 2008;7(8):2415–25]
Anticancer steroid sulfatase inhibitors: synthesis of a potent fluorinated second-generation agent, in vitro and in vivo activities, molecular modeling, and protein crystallography
Authors: Woo L.W. Lawrence , Fischer Delphine S. , Sharland Christopher M. , Trusselle Melanie , Foster Paul A. , Chander Surinder K. , Di Fiore Anna , Supuran Claudiu T. , De Simone Giuseppina , Purohit Atul , Reed Michael J. , Potter Barry V.L. 
Published: August 2008

Abstract
An improved steroid sulfatase inhibitor was prepared by replacing the N-propyl group of the second-generation steroid-like inhibitor (2) with a N-3,3,3-trifluoropropyl group to give (10). This compound is 5-fold more potent in vitro, completely inhibits rat liver steroid sulfatase activity after a single oral dose of 0.5 mg/kg, and exhibits a significantly longer duration of inhibition over (2). These biological properties are attributed to the increased lipophilicity and metabolic stability of (10) rendered by its trifluoropropyl group and also the potential H-bonding between its fluorine atom(s) and Arg98 in the active site of human steroid sulfatase. Like other sulfamates, (10) is expected to be sequestered, and transported by, erythrocytes in vivo because it inhibits human carbonic anhydrase II (hCAII) potently (IC50, 3 nmol/L). A congener (4), which possesses a N-(pyridin-3-ylmethyl) substituent, is even more active (IC50, 0.1 nmol/L). To rationalize this, the hCAII-(4) adduct, obtained by cocrystallization, reveals not only the sulfamate group and the backbone of (4) interacting with the catalytic site and the associated hydrophobic pocket, respectively, but also the potential H-bonding between the N-(pyridin-3-ylmethyl) group and Nε2 of Gln136. Like (2), both (10) and its phenolic precursor (9) are non-estrogenic using a uterine weight gain assay. In summary, a highly potent, long-acting, and nonestrogenic steroid sulfatase inhibitor was designed with hCAII inhibitory properties that should positively influence in vivo behavior. Compound (10) and other related inhibitors of this structural class further expand the armory of steroid sulfatase inhibitors against hormone-dependent breast cancer. [Mol Cancer Ther 2008;7(8):2435–44]
Optimization of antibody binding to FcγRIIa enhances macrophage phagocytosis of tumor cells
Authors: Richards John O. , Karki Sher , Lazar Greg A. , Chen Hsing , Dang Wei , Desjarlais John R. 
Published: August 2008

AbstractThe contribution of Fc-mediated effector functions to the therapeutic efficacy of some monoclonal antibodies has motivated efforts to enhance interactions with Fcγ receptors (FcγR). Although an early goal has been enhanced FcγRIIIa binding and natural killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), other relevant cell types such as macrophages are dependent on additional activating receptors such as FcγRIIa. Here, we describe a set of engineered Fc variants with diverse FcγR affinities, including a novel substitution G236A that provides selectively enhanced binding to FcγRIIa relative to FcγRIIb. Variants containing this substitution have up to 70-fold greater FcγRIIa affinity and 15-fold improvement in FcγRIIa/FcγRIIb ratio and mediate enhanced phagocytosis of antibody-coated target cells by macrophages. Specific double and triple combination variants with this substitution are simultaneously capable of exhibiting high NK-mediated ADCC and high macrophage phagocytosis. In addition, we have used this unique set of variants to quantitatively probe the relative contributions of individual FcγR to effector functions mediated by NK cells and macrophages. These experiments show that FcγRIIa plays the most influential role for macrophages and, surprisingly, that the inhibitory receptor FcγRIIb has little effect on effector function. The enhancements in phagocytosis described here provide the potential to improve the performance of therapeutic antibodies targeting cancers. [Mol Cancer Ther 2008;7(8):2517–27]
IRC-083927 is a new tubulin binder that inhibits growth of human tumor cells resistant to standard tubulin-binding agents
Authors: Liberatore Anne-Marie , Coulomb Hélène , Pons Dominique , Dutruel Olivier , Kasprzyk Philip G. , Carlson Mark , Nelson Ann Savola , Newman Simon P. , Stengel Chloe , Auvray Pierrïck , Hesry Vincent , Foll Béatrice , Narboux Nadine , Morlais Delphine , Le Moing Mélissa , Bernetiere Sonia , Dellile Raphael , Camara Jose , Ferrandis Eric , Bigg Dennis C. , Prévost Grégoire P. 
Published: August 2008

AbstractTubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site. IRC-083927 inhibits in vitro cell growth of human cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (taxanes, Vinca alkaloids, or epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to navelbine and paclitaxel) and/or the presence of mutations on β-tubulin and on α-tubulin and β-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G2-M phase in tumor cells, including in the drug-resistant cells. In addition, IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with IRC-083927 (5 mg/kg) inhibits the growth of two human tumor xenografts in nude mice (C33-A, human cervical cancer and MDA-MB-231, human hormone-independent breast cancer). Together, the antitumor effects induced by IRC-083927 on tumor models resistant to tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced cancers, particularly those resistant to current clinically available drugs. [Mol Cancer Ther 2008;7(8):2426–34]
Androgen receptor inactivation contributes to antitumor efficacy of 17α-hydroxylase/17,20-lyase inhibitor 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer
Authors: Vasaitis Tadas , Belosay Aashvini , Schayowitz Adam , Khandelwal Aakanksha , Chopra Pankaj , Gediya Lalji K. , Guo Zhiyong , Fang Hong-Bin , Njar Vincent C.O. , Brodie Angela M.H. 
Published: August 2008

AbstractWe previously reported that our novel compound 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent 17α-hydroxylase/17,20-lyase (CYP17) inhibitor/antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in severe combined immunodeficient mice. In this study, we report that VN/124-1 and other novel CYP17 inhibitors also cause down-regulation of androgen receptor (AR) protein expression in vitro and in vivo. This mechanism of action seems to contribute to their antitumor efficacy. We compared the in vivo antitumor efficacy of VN/124-1 with that of castration and a clinically used antiandrogen, Casodex, and show that VN/124-1 is more potent than castration in the LAPC4 xenograft model. Treatment with VN/124-1 (0.13 mmol/kg twice daily) was also very effective in preventing the formation of LAPC4 tumors (6.94 versus 2410.28 mm3 in control group). VN/124-1 (0.13 mmol/kg twice daily) and VN/124-1 (0.13 mmol/kg twice daily) + castration induced regression of LAPC4 tumor xenografts by 26.55% and 60.67%, respectively. Treatments with Casodex (0.13 mmol/kg twice daily) or castration caused significant tumor suppression compared with control. Furthermore, treatment with VN/124-1 caused marked down-regulation of AR protein expression, in contrast to treatments with Casodex or castration that caused significant up-regulation of AR protein expression. The results suggest that VN/124-1 acts by several mechanisms (CYP17 inhibition, competitive inhibition, and down-regulation of the AR). These actions contribute to inhibition of the formation of LAPC4 tumors and cause regression of growth of established tumors. VN/124-1 is more efficacious than castration in the LAPC4 xenograft model, suggesting that the compound has potential for the treatment of prostate cancer. [Mol Cancer Ther 2008;7(8):2348–57]