bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Bioluminescent Mouse Model and Effective Therapy for Adult T-Cell Leukemia/Lymphoma
Authors: Shu Sherry T. , Nadella Murali V.P. , Dirksen Wessel P. , Fernandez Soledad A. , Thudi Nanda K. , Werbeck Jillian L. , Lairmore Michael D. , Rosol Thomas J. 
Published: December 2007

Abstract
Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone–related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor κB (NF-κB). NF-κB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-κB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1α expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy. [Cancer Res 2007;67(24):11859–66]
Novel Noncatalytic Role for Caspase-8 in Promoting Src-Mediated Adhesion and Erk Signaling in Neuroblastoma Cells
Authors: Finlay Darren , Vuori Kristiina 
Published: December 2007

Abstract
Neuroblastomas are extremely aggressive, although heterogeneous, cancers with a poor prognosis upon metastasis. Some evidence has suggested a correlative silencing of caspase-8 with MYCN amplification in neuroblastoma. A prognostic effect of this silencing, however, has been disputed. We report here hitherto undescribed roles for caspase-8 in the modulation of cell adhesion and subsequent activation of the Erk signaling pathway. Re-expression of caspase-8 in neuroblastoma cells lacking endogenous caspase-8 expression was found to promote cell adhesion to extracellular matrix and to activate adhesion-dependent signaling pathways, such as the Erk kinase cascade. This function of caspase-8 occurred irrespective of its proteolytic activity. Additionally, a pool of caspase-8 was shown to co-localize with the Src tyrosine kinase at the cellular periphery. Furthermore, our studies showed that caspase-8 forms a physical protein complex with Src via its death effector domains (DED) and maintains the complex in a detergent-soluble fraction. We also show that the DEDs of caspase-8 alone are necessary and sufficient to recreate the adhesive and biochemical phenotypes observed with the full-length protein, suggesting that caspase-8 may exert these effects via its association with Src. This protein complex association of caspase-8 and Src, and concomitant downstream signaling events, may help reconcile why a potential tumor suppressor such as caspase-8 is rarely absent in cancers. [Cancer Res 2007;67(24):11704–11]
Differential Sensitivity of Malignant Glioma Cells to Methylating and Chloroethylating Anticancer Drugs: p53 Determines the Switch by Regulating xpc, ddb2, and DNA Double-Strand Breaks
Authors: Batista Luís F.Z. , Roos Wynand P. , Christmann Markus , Menck Carlos F.M. , Kaina Bernd 
Published: December 2007

Abstract
Glioblastoma multiforme is the most severe form of brain cancer. First line therapy includes the methylating agent temozolomide and/or the chloroethylating nitrosoureas [1-(2-chloroethyl)-1-nitrosourea; CNU] nimustine [1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea; ACNU], carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea; BCNU], or lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; CCNU]. The mechanism of cell death after CNU treatment is largely unknown. Here we show that ACNU and BCNU induce apoptosis in U87MG [p53 wild-type (p53wt)] and U138MG [p53 mutant (p53mt)] glioma cells. However, contrary to what we observed previously for temozolomide, chloroethylating drugs are more toxic for p53-mutated glioma cells and induce both apoptosis and necrosis. Inactivation of p53 by pifithrin-α or siRNA down-regulation sensitized p53wt but not p53mt glioma cells to ACNU and BCNU. ACNU and BCNU provoke the formation of DNA double-strand breaks (DSB) in glioma cells that precede the onset of apoptosis and necrosis. Although these DSBs are repaired in p53wt cells, they accumulate in p53mt cells. Therefore, functional p53 seems to stimulate the repair of CNU-induced cross-links and/or DSBs generated from CNU-induced lesions. Expression analysis revealed an up-regulation of xpc and ddb2 mRNA in response to ACNU in U87MG but not U138MG cells, indicating p53 regulates a pathway that involves these DNA repair proteins. ACNU-induced apoptosis in p53wt glioma cells is executed via both the extrinsic and intrinsic apoptotic pathway, whereas in p53mt glioma cells, the mitochondrial pathway becomes activated. The data suggest that p53 has opposing effects in gliomas treated with methylating or chloroethylating agents and, therefore, the p53 status should be taken into account when deciding which therapeutic drug to use. [Cancer Res 2007;67(24):11886–95]
Flat Colorectal Cancers Are Genetically Determined and Progress to Invasion without Going through a Polypoid Stage
Authors: Uronis Joshua M. , Herfarth Hans H. , Rubinas Tara C. , Bissahoyo Anika C. , Hanlon Kathleen , Threadgill David W. 
Published: December 2007

Abstract
Growing evidence suggests that flat colorectal cancers (CRC) account for 10% to 20% of all CRCs and that these are frequently associated with more advanced pathologies. However, controversy exists as to the origin and progression of flat CRCs compared with the more common polypoid-type morphology. We report using the azoxymethane mouse model for human CRC that KK/HIJ and I/LNJ mice develop different frequencies of flat and polypoid tumors; 83% of colon tumors in I/LNJ mice are flat compared with only 19% in KK/HIJ mice, indicating a strong genetic predisposition to the development of specific CRC morphologies. Like polypoid tumors, all flat tumors show a significant increase in the level of nuclear β-catenin (CATNNB1), supported by similar frequencies of mutations in the phosphorylation domain–coding region (codons 32–41) of Catnnb1. However, in contrast to previous reports, tumors bearing higher “oncogenic potential” do not cluster in codon 41 of Catnnb1. There are no differences between flat and polypoid tumors in the frequency of mutations in codons 12 and 13 of Kras or codon 624 of Braf. Similarly, there are no differences between tumor morphologies in their location along the proximal-to-distal colonic axis or in the relative quantity of intratumor stromal myofibrobasts as marked by the expression of α-smooth muscle actin. Using a combination of serial colonoscopic and histologic analyses, we definitively show that flat CRCs do not develop de novo but progress through a flat adenomatous stage to invasive carcinoma without transit through an intermediary polypoid stage. [Cancer Res 2007;67(24):11594–600]
Altered MicroRNA Expression Confined to Specific Epithelial Cell Subpopulations in Breast Cancer
Authors: Sempere Lorenzo F. , Christensen Mette , Silahtaroglu Asli , Bak Mads , Heath Catherine V. , Schwartz Gary , Wells Wendy , Kauppinen Sakari , Cole Charles N. 
Published: December 2007

Abstract
MicroRNAs (miRNAs) are a new class of short noncoding regulatory RNAs (18–25 nucleotides) that are involved in diverse developmental and pathologic processes. Altered miRNA expression has been associated with several types of human cancer. However, most studies did not establish whether miRNA expression changes occurred within cells undergoing malignant transformation. To obtain insight into miRNA deregulation in breast cancer, we implemented an in situ hybridization (ISH) method to reveal the spatial distribution of miRNA expression in archived formalin-fixed, paraffin-embedded specimens representing normal and tumor tissue from &gt;100 patient cases. Here, we report that expression of miR-145 and miR-205 was restricted to the myoepithelial/basal cell compartment of normal mammary ducts and lobules, whereas their accumulation was reduced or completely eliminated in matching tumor specimens. Conversely, expression of other miRNAs was detected at varying levels predominantly within luminal epithelial cells in normal tissue; expression of miR-21 was frequently increased, whereas that of let-7a was decreased in malignant cells. We also analyzed the association of miRNA expression with that of epithelial markers; prognostic indicators such as estrogen receptor, progesterone receptor, and HER2; as well as clinical outcome data. This ISH approach provides a more direct and informative assessment of how altered miRNA expression contributes to breast carcinogenesis compared with miRNA expression profiling in gross tissue biopsies. Most significantly, early manifestation of altered miR-145 expression in atypical hyperplasia and carcinoma in situ lesions suggests that this miRNA may have a potential clinical application as a novel biomarker for early detection. [Cancer Res 2007;67(24):11612–20]
Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O6-Methylguanine-DNA Methyltransferase Promoter
Authors: Alonso Marta M. , Gomez-Manzano Candelaria , Bekele B. Nebiyou , Yung W.K. Alfred , Fueyo Juan 
Published: December 2007

Abstract
Currently, the most efficacious treatment for malignant gliomas is temozolomide; however, gliomas expressing the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are resistant to this drug. Strong clinical evidence shows that gliomas with methylation and subsequent silencing of the MGMT promoter are sensitive to temozolomide. Based on the fact that adenoviral proteins directly target and inactivate key DNA repair genes, we hypothesized that the oncolytic adenovirus Δ-24-RGD could be successfully combined with temozolomide to overcome the reported MGMT-mediated resistance. Our studies showed that the combination of Δ-24-RGD and temozolomide induces a profound therapeutic synergy in glioma cells. We observed that Δ-24-RGD treatment overrides the temozolomide-mediated G2-M arrest. Furthermore, Δ-24-RGD infection was followed by down-modulation of the RNA levels of MGMT. Chromatin immunoprecipitation assays showed that Δ-24-RGD prevented the recruitment of p300 to the MGMT promoter. Importantly, using mutant adenoviruses and wild-type and dominant-negative forms of the p300 protein, we showed that Δ-24-RGD interaction with p300 was required to induce silencing of the MGMT gene. Of further clinical relevance, the combination of Δ-24-RGD and temozolomide significantly improved the survival of glioma-bearing mice. Collectively, our data provide a strong mechanistic rationale for the combination of oncolytic adenoviruses and temozolomide, and should propel the clinical testing of this therapy approach in patients with malignant gliomas. [Cancer Res 2007;67(24):11499–504]
Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma
Authors: Scavelli Claudio , Di Pietro Giulia , Cirulli Teresa , Coluccia Mauro , Boccarelli Angela , Giannini Teresa , Mangialardi Giuseppe , Bertieri Raffaello , Coluccia Addolorata Maria Luce , Ribatti Domenico , Dammacco Franco , Vacca Angelo 
Published: December 2007

Abstract
Therapeutic doses of zoledronic acid markedly inhibit in vitro proliferation, chemotaxis, and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma. Zoledronic acid also induces a sizeable reduction of angiogenesis in the in vivo chorioallantoic membrane assay. These effects are partly sustained by gene and protein inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in an autocrine loop. Mevastatin, a specific inhibitor of the mevalonate pathway, reverts the zoledronic acid antiangiogenic effect, indicating that the drug halts this pathway. Our results provide evidence of a direct antiangiogenic activity of zoledronic acid on multiple myeloma patient-derived endothelial cells due to at least four different mechanisms identified either in vitro or in vivo. Tentatively, we suggest that the zoledronic acid antitumoral activity in multiple myeloma is also sustained by antiangiogenesis, which would partly account for its therapeutic efficacy in multiple myeloma. [Mol Cancer Ther 2007;6(12):3256–62]
New inhibitors of ABCG2 identified by high-throughput screening
Authors: Henrich Curtis J. , Robey Robert W. , Bokesch Heidi R. , Bates Susan E. , Shukla Suneet , Ambudkar Suresh V. , Dean Michael , McMahon James B. 
Published: December 2007

Abstract
In order to identify novel inhibitors of the ATP-binding cassette transporter, ABCG2, a high-throughput assay measuring the accumulation of the ABCG2 substrate pheophorbide a in ABCG2-overexpressing NCI-H460 MX20 cells was used to screen libraries of compounds. Out of a library of 7,325 natural products and synthetic compounds from the National Cancer Institute/Developmental Therapeutics Program collection, 18 were found to inhibit ABCG2 at 10 μmol/L. After eliminating flavonoids and compounds of limited availability from the 18 original compounds, 10 of the 11 remaining compounds reversed mitoxantrone resistance in NCI-H460/MX20 cells and prevented ABCG2-mediated BODIPY-prazosin transport in ABCG2-transfected HEK293 cells, confirming an interaction with ABCG2. Based on the activity profiles and the availability of materials, five inhibitors were examined for their ability to compete with [125I]iodoarylazidoprazosin labeling of ABCG2, increase binding of the anti-ABCG2 antibody 5D3, and prevent P-glycoprotein or multidrug resistance protein 1–mediated transport. At a concentration of 20 μmol/L, all of the compounds reduced iodoarylazidoprazosin labeling by 50% to 80% compared with controls. All five compounds also increased 5D3 labeling of ABCG2, indicating that these compounds are inhibitors but not substrates of ABCG2. None of the compounds affected P-glycoprotein–mediated rhodamine 123 transport, whereas three affected multidrug resistance protein-1–mediated calcein transport at 25 μmol/L, suggesting that the compounds are relatively specific for ABCG2. These five novel inhibitors of ABCG2 activity may provide a basis for further investigation of ABCG2 function and its relevance in multidrug resistance. [Mol Cancer Ther 2007;6(12):3271–8]
Antineoplastic agents target the 25-hydroxyvitamin D3 24-hydroxylase messenger RNA for degradation: implications in anticancer activity
Authors: Tan Joseph , Dwivedi Prem P. , Anderson Paul , Nutchey Barbara K. , O'Loughlin Peter , Morris Howard A. , May Brian K. , Ferrante Antonio , Hii Charles S. 
Published: December 2007

Abstract
Calcitriol or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] has antitumor activity and hence its levels in patients may play an important role in disease outcome. Here, we report that the antineoplastic agents, daunorubicin hydrochloride, etoposide, and vincristine sulfate inhibited the ability of 1,25(OH)2D3 to cause the accumulation of mRNA for kidney 25-hydroxyvitamin D3 24-hydroxylase (CYP24), an enzyme which catabolizes this hormone. This was not due to a drug-induced cytotoxic effect, reduction in the expression of the vitamin D receptor or inhibition of the vitamin D receptor–mediated activation of the mitogen-activated protein kinases or CYP24 promoter activity. Interestingly, there was selective degradation of CYP24 mRNA in the presence of the drugs. This was accompanied by an enhancement in the levels of 1,25(OH)2D3 in cells incubated with 25-hydroxy vitamin D3. These data identify a novel mechanism of action of some commonly used antineoplastic agents which by decreasing the stability of CYP24 mRNA would prolong the bioavailability of 1,25(OH)2D3 for anticancer actions. [Mol Cancer Ther 2007;6(12):3131–8]
Chemopreventive effects of silymarin and silibinin on N-butyl-N-(4-hydroxybutyl) nitrosamine–induced urinary bladder carcinogenesis in male ICR mice
Authors: Tyagi Alpna , Raina Komal , Singh Rana P. , Gu Mallikarjuna , Agarwal Chapla , Harrison Gail , Glode L. Michael , Agarwal Rajesh 
Published: December 2007

Abstract
Effective strategies are lacking for the management of urinary bladder cancer for which smoking is a potential risk factor. Herein, we evaluated chemoprevention of urinary bladder cancer by natural chemopreventive agents, silymarin and silibinin, in a preclinical animal (ICR mouse) model of bladder cancer induced by tobacco smoke carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBN). Mice were fed p.o. with saline or OH-BBN (0.05%, w/v) in drinking water for 6 weeks or with silymarin or silibinin (200 mg/kg body weight for both) starting 1 week before OH-BBN exposure for 51 weeks. Silymarin and silibinin strongly arrested OH-BBN–induced tumor progression at the stage of mucosal dysplasia with a striking reduction in papillary nodular dysplasia as well as invasive carcinoma. Some silymarin- or silibinin-treated mice developed no urothelial lesions in spite of OH-BBN exposure. Immunohistochemical analyses at study conclusion revealed that silymarin and silibinin decreased cell proliferation by 42% (P &lt; 0.001) and 44% (P &lt; 0.001) and increased apoptosis by 4-fold (P &lt; 0.05) and 6-fold (P &lt; 0.05) in OH-BBN–induced urothelium, respectively. Antiproliferative and apoptotic effects of silymarin and silibinin were associated with decreases in (a) cyclin D1 protein level and extracellular signal–regulated kinase-1/2 phosphorylation and in (b) protein levels of survivin and nuclear phospho-p65 (Ser276 and Ser536), respectively. Together, these results suggest that silymarin and silibinin inhibit chemically induced urinary bladder tumor growth and progression possibly by inhibiting cell proliferation and enhancing apoptosis. [Mol Cancer Ther 2007;6(12):3248–55]
The effectiveness of a motivation programme for lifestyle change in the course of aortocoronary bypass graft surgery
Authors: Krannich Jens-Holger , Weyers Peter , Lueger Stefan , Schimmer Christoph , Faller Hermann , Elert Olaf 
Published: December 2007

Objective: To evaluate the effectiveness of a motivation programme the motivation for lifestyle change in patients was measured before and after coronary artery bypass graft (CABG) surgery by comparing a usual care group with a group attending a motivation programme. Design: Prospective controlled study. Setting: University hospital cardiothoracic surgery department. Subjects: One hundred and forty patients (mean age 64.9; SD 8.5 years) who had an elective CABG surgery. Interventions: Each patient was evaluated regarding his or her motivation for lifestyle change two days before and 10 days after CABG surgery. Between January and May 2002 patients in usual care were investigated as a control group (n=70). From January to May 2003 patients had the opportunity to take part in a motivation programme that was provided by a trained clinical psychologist (n = 70). The programme consists of both personalized single sessions and group lectures. Measures: A 30-item questionnaire measuring the six factors Vulnerability, Intention, Social expectation, Outcome expectation, Self-efficacy expectation, and Perceived severity was developed. Results: ANOVA procedures with repeated measurements indicate significant effects in terms of higher motivation for lifestyle change in the treatment group in Vulnerability (F(1, 138) = 4.04; P=0.04), Intention (F(1, 138) = 19.81; P<0.001), Social expectation (F(1, 138)=21.97; P<0.001), Outcome expectation (F(1, 138) =17.95; P<0.001), and Self-efficacy expectation (F(1, 138) =14.31; P<0.001). Conclusions: This motivation programme performed in a cardiac surgery hospital after CABG may increase the motivation for a positive lifestyle change.
The Roman Bridge: a "double pulley – suture bridges" technique for rotator cuff repair
Authors: Franceschi Francesco , Longo Umile Giuseppe , Ruzzini Laura , Rizzello Giacomo , Maffulli Nicola , Denaro Vincenzo 
Published: December 2007

Abstract

Background
With advances in arthroscopic surgery, many techniques have been developed to increase the tendon-bone contact area, reconstituting a more anatomic configuration of the rotator cuff footprint and providing a better environment for tendon healing.

Methods
We present an arthroscopic rotator cuff repair technique which uses suture bridges to optimize rotator cuff tendon-footprint contact area and mean pressure.

Results
Two medial row 5.5-mm Bio-Corkscrew suture anchors (Arthrex, Naples, FL), which are double-loaded with No. 2 FiberWire sutures (Arthrex, Naples, FL), are placed in the medial aspect of the footprint. Two suture limbs from a single suture are both passed through a single point in the rotator cuff. This is performed for both anchors. The medial row sutures are tied using the double pulley technique. A suture limb is retrieved from each of the medial anchors through the lateral portal, and manually tied as a six-throw surgeon's knot over a metal rod. The two free suture limbs are pulled to transport the knot over the top of the tendon bridge. Then the two free suture limbs that were used to pull the knot down are tied. The end of the sutures are cut. The same double pulley technique is repeated for the other two suture limbs from the two medial anchors, but the two free suture limbs are used to produce suture bridges over the tendon, by means of a Pushlock (Arthrex, Naples, FL), placed 1 cm distal to the lateral edge of the footprint.

Conclusion
This technique maximizes the advantages of two techniques. On the one hand, the double pulley technique provides an extremely secure fixation in the medial aspect of the footprint. On the other hand, the suture bridges allow to improve pressurized contact area and mean footprint pressure. In this way, the bony footprint in not compromised by the distal-lateral fixation, and it is thus possible to share the load between fixation points. This maximizes the strength of the repair and provides a barrier preventing penetration of synovial fluid into the healing area of tendon and bone.