bluuebunny/crossref_metadata_2025_split huggingface dataset:
Production of 3-Nitrosoindole Derivatives by
Escherichia coli
during Anaerobic Growth
Authors: Kwon Young-Man , Weiss Bernard 
Published: June 2009

ABSTRACT

When
Escherichia coli
K-12 is grown anaerobically in medium containing tryptophan and sodium nitrate, it produces red compounds. The reaction requires functional genes for trytophanase (
tnaA
), a tryptophan permease (
tnaB
), and a nitrate reductase (
narG
), as well as a natural drop in the pH of the culture. Mass spectrometry revealed that the purified chromophores had mass/charge ratios that closely match those for indole red, indoxyl red, and an indole trimer. These compounds are known products of chemical reactions between indole and nitrous acid. They are derived from an initial reaction of 3-nitrosoindole with indole. Apparently, nitrite that is produced from the metabolic reduction of nitrate is converted in the acid medium to nitrous acid, which leads to the nitrosation of the indole that is generated by tryptophanase. An
nfi
(endonuclease V) mutant and a
recA
mutant were selectively killed during the period of chromophore production, and a
uvrA
strain displayed reduced growth. These effects depended on the addition of nitrate to the medium and on tryptophanase activity in the cells. Unexpectedly, the killing of a
tnaA
+
nfi
mutant was not accompanied by marked increases in mutation frequencies for several traits tested. The vulnerability of three DNA repair mutants indicates that a nitrosoindole or a derivative of a nitrosoindole produces lethal DNA damage.
A Novel Lung Metastasis Signature Links Wnt Signaling with Cancer Cell Self-Renewal and Epithelial-Mesenchymal Transition in Basal-like Breast Cancer
Authors: DiMeo Theresa A. , Anderson Kristen , Phadke Pushkar , Feng Chang , Perou Charles M. , Naber Steven , Kuperwasser Charlotte 
Published: July 2009

Abstract
The establishment of metastasis depends on the ability of cancer cells to acquire a migratory phenotype combined with their capacity to recreate a secondary tumor in a distant tissue. In epithelial cancers, such as those of the breast, the epithelial-mesenchymal transition (EMT) is associated with basal-like breast cancers, generates cells with stem-like properties, and enables cancer cell dissemination and metastasis. However, the molecular mechanism(s) that connects stem cell–like characteristics with EMT has yet to be defined. Using an orthotopic model of human breast cancer metastasis to lung, we identified a poor prognosis gene signature, in which several components of the wnt signaling pathway were overexpressed in early lung metastases. The wnt genes identified in this signature were strongly associated with human basal-like breast cancers. We found that inhibiting wnt signaling through LRP6 reduced the capacity of cancer cells to self-renew and seed tumors in vivo. Furthermore, inhibition of wnt signaling resulted in the reexpression of breast epithelial differentiation markers and repression of EMT transcription factors SLUG and TWIST. Collectively, these results provide a molecular link between self-renewal, EMT, and metastasis in basal-like breast cancers. [Cancer Res 2009;69(13):5364–73]
Antitumor Activity of Gemcitabine and Oxaliplatin Is Augmented by Thymoquinone in Pancreatic Cancer
Authors: Banerjee Sanjeev , Kaseb Ahmed O. , Wang Zhiwei , Kong Deujan , Mohammad Mussop , Padhye Subhash , Sarkar Fazlul H. , Mohammad Ramzi M. 
Published: July 2009

Abstract
Previous studies have shown biological activity of thymoquinone, an active compound extracted from Nigella sativa, in pancreatic cancer cells; however, preclinical animal studies are lacking. Here, we report, for the first time, the chemosensitizing effect of thymoquinone to conventional chemotherapeutic agents both in vitro and in vivo using an orthotopic model of pancreatic cancer. In vitro studies revealed that preexposure of cells with thymoquinone (25 μmol/L) for 48 h followed by gemcitabine or oxaliplatin resulted in 60% to 80% growth inhibition compared with 15% to 25% when gemcitabine or oxaliplatin was used alone. Moreover, we found that thymoquinone could potentiate the killing of pancreatic cancer cells induced by chemotherapeutic agents by down-regulation of nuclear factor-κB (NF-κB), Bcl-2 family, and NF-κB-dependent antiapoptotic genes (X-linked inhibitors of apoptosis, survivin, and cyclooxygenase-2). As shown previously by our laboratory, NF-κB gets activated on exposure of pancreatic cancer cells to conventional chemotherapeutic agents; interestingly, thymoquinone was able to down-regulate NF-κB in vitro, resulting in chemosensitization. In addition to in vitro results, here we show for the first time, that thymoquinone in combination with gemcitabine and/or oxaliplatin is much more effective as an antitumor agent compared with either agent alone. Most importantly, our data also showed that a specific target, such as NF-κB, was inactivated in animal tumors pretreated with thymoquinone followed by gemcitabine and/or oxaliplatin. These results provide strong in vivo molecular evidence in support of our hypothesis that thymoquinone could abrogate gemcitabine- or oxaliplatin-induced activation of NF-κB, resulting in the chemosensitization of pancreatic tumors to conventional therapeutics. [Cancer Res 2009;69(13):5575–83]
Spleen Tyrosine Kinase Is Overexpressed and Represents a Potential Therapeutic Target in Chronic Lymphocytic Leukemia
Authors: Buchner Maike , Fuchs Simon , Prinz Gabriele , Pfeifer Dietmar , Bartholomé Kilian , Burger Meike , Chevalier Nina , Vallat Laurent , Timmer Jens , Gribben John G. , Jumaa Hassan , Veelken Hendrik , Dierks Christine , Zirlik Katja 
Published: July 2009

Abstract
B-cell receptor signaling contributes to apoptosis resistance in chronic lymphocytic leukemia (CLL), limiting the efficacy of current therapeutic approaches. In this study, we investigated the expression of spleen tyrosine kinase (SYK), a key component of the B-cell receptor signaling pathway, in CLL and its role in apoptosis. Gene expression profiling identified enhanced expression of SYK and downstream pathways in CLL compared with healthy B cells. Immunoblotting showed increased expression and phosphorylation of SYK, PLCγ2, signal transducers and activators of transcription 3, and extracellular signal regulated kinase 1/2 in CLL compared with healthy B cells, suggesting enhanced activation of these mediators in CLL. SYK inhibitors reduced phosphorylation of SYK downstream targets and induced apoptosis in primary CLL cells. With respect to prognostic factors, SYK inhibitors exerted stronger cytotoxic effects in unmutated and ZAP70+ cases. Cytotoxic effects of SYK inhibitors also associated with SYK protein expression, potentially predicting response to therapy. Combination of fludarabine with SYK Inhibitor II or R406 increased cytotoxicity compared with fludarabine therapy alone. We observed no stroma-contact–mediated drug resistance for SYK inhibitors as described for fludarabine treatment. CD40 ligation further enhanced efficacy of SYK inhibition. Our data provide mechanistic insight into the recently observed therapeutic effects of the SYK inhibitor R406 in CLL. Combination of SYK inhibitors with fludarabine might be a novel treatment option particularly for CLL patients with poor prognosis and should be further evaluated in clinical trials. [Cancer Res 2009;69(13):5424–32]
Secretion of Tumor-Specific Antigen by Myeloma Cells Is Required for Cancer Immunosurveillance by CD4+ T Cells
Authors: Corthay Alexandre , Lundin Katrin U. , Lorvik Kristina Berg , Hofgaard Peter O. , Bogen Bjarne 
Published: July 2009

AbstractTumor-specific CD4+ T cells orchestrate the adaptive immune responses against cancer. We have previously shown that CD4+ T cells recognize MHC class II–negative myeloma cells indirectly by collaborating with tumor-infiltrating macrophages. We, here, hypothesize that this critical step may be dependent on secretion of tumor-specific antigens by cancer cells. This was investigated using T-cell receptor–transgenic mice, in which CD4+ T cells mediate rejection of syngeneic MOPC315 myeloma cells. We analyzed the immune response against myeloma cell variants, which either secrete or retain intracellularly a tumor-specific idiotypic (Id) antigen. Our results reveal that CD4+ T cells helped by macrophages are capable of detecting nonsecreted tumor antigens from MHC class II–negative cancer cells. However, Id secretion was required for successful myeloma immunosurveillance. Antigen secretion resulted in stronger priming of naive myeloma-specific CD4+ T cells in tumor-draining lymph nodes. Secretion of antigen by at least some cancer cells within a tumor was shown to facilitate immunosurveillance. Treatment by local injection of purified tumor-specific antigen successfully enhanced immunity against nonsecreting myeloma cells. Collectively, the data indicate that antigen concentration within the tumor extracellular matrix must reach a certain threshold to allow successful cancer immunosurveillance by CD4+ T cells. [Cancer Res 2009;69(14):5901–7]
Therapeutics by Cytotoxic Metabolite Accumulation: Pemetrexed Causes ZMP Accumulation, AMPK Activation, and Mammalian Target of Rapamycin Inhibition
Authors: Racanelli Alexandra C. , Rothbart Scott B. , Heyer Cortney L. , Moran Richard G. 
Published: July 2009

AbstractPemetrexed represents the first antifolate cancer drug to be approved by the Food and Drug Administration in 20 years; it is currently in widespread use for first line therapy of mesothelioma and non–small cell lung cancer. Pemetrexed has more than one site of action; the primary site is thymidylate synthase. We now report that the secondary target is the downstream folate-dependent enzyme in de novo purine synthesis, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART). The substrate of the AICART reaction, ZMP, accumulated in intact pemetrexed-inhibited tumor cells, identifying AICART as the step in purine synthesis that becomes rate-limiting after drug treatment. The accumulating ZMP causes an activation of AMP-activated protein kinase with subsequent inhibition of the mammalian target of rapamycin (mTOR) and hypophosphorylation of the downstream targets of mTOR that control initiation of protein synthesis and cell growth. We suggest that the activity of pemetrexed against human cancers is a reflection of its direct inhibition of folate-dependent target proteins combined with prolonged inhibition of the mTOR pathway secondary to accumulation of ZMP. [Cancer Res 2009;69(13):5467–74]
Mice Heterozygous for Germ-line Mutations in Methylthioadenosine Phosphorylase (MTAP) Die Prematurely of T-Cell Lymphoma
Authors: Kadariya Yuwaraj , Yin Bu , Tang Baiqing , Shinton Susan A. , Quinlivan Eoin P. , Hua Xiang , Klein-Szanto Andres , Al-Saleem Tahseen I. , Bassing Craig H. , Hardy Richard R. , Kruger Warren D. 
Published: July 2009

Abstract
Large homozygous deletions of 9p21 that inactivate CDKN2A, ARF, and MTAP are common in a wide variety of human cancers. The role for CDKN2A and ARF in tumorigenesis is well established, but whether MTAP loss directly affects tumorigenesis is unclear. MTAP encodes the enzyme methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway. To determine if loss of MTAP plays a functional role in tumorigenesis, we have created an MTAP-knockout mouse. Mice homozygous for a MTAP null allele (MtaplacZ) have an embryonic lethal phenotype dying around day 8 postconception. Mtap/MtaplacZ heterozygotes are born at Mendelian frequencies and appear indistinguishable from wild-type mice during the first year of life, but they tend to die prematurely with a median survival of 585 days. Autopsies on these animals reveal that they have greatly enlarged spleens, altered thymic histology, and lymphocytic infiltration of their livers, consistent with lymphoma. Immunohistochemical staining and fluorescence-activated cell sorting analysis indicate that these lymphomas are primarily T-cell in origin. Lymphoma-infiltrated tissues tend to have reduced levels of Mtap mRNA and MTAP protein in addition to unaltered levels of methyldeoxycytidine. These studies show that Mtap is a tumor suppressor gene independent of CDKN2A and ARF. [Cancer Res 2009;69(14):OF5961–8]
Evaluation of the 8q24 Prostate Cancer Risk Locus and MYC Expression
Authors: Pomerantz Mark M. , Beckwith Christine A. , Regan Meredith M. , Wyman Stacia K. , Petrovics Gyorgy , Chen Yongmei , Hawksworth Dorota J. , Schumacher Fredrick R. , Mucci Lorelei , Penney Kathryn L. , Stampfer Meir J. , Chan Jennifer A. , Ardlie Kristin G. , Fritz Brian R. , Parkin Rachael K. , Lin Daniel W. , Dyke Michelle , Herman Paula , Lee Steve , Oh William K. , Kantoff Philip W. , Tewari Muneesh , McLeod David G. , Srivastava Shiv , Freedman Matthew L. 
Published: July 2009

Abstract
Polymorphisms at 8q24 are robustly associated with prostate cancer risk. The risk variants are located in nonprotein coding regions and their mechanism has not been fully elucidated. To further dissect the function of this locus, we tested two hypotheses: (a) unannotated microRNAs (miRNA) are transcribed in the region, and (b) this region is a cis-acting enhancer. Using next generation sequencing, 8q24 risk regions were interrogated for known and novel miRNAs in histologically normal radical prostatectomy tissue. We also evaluated the association between the risk variants and transcript levels of multiple genes, focusing on the proto-oncogene, MYC. RNA expression was measured in histologically normal and tumor tissue from 280 prostatectomy specimens (from 234 European American and 46 African American patients), and paired germline DNA from each individual was genotyped for six 8q24 risk single nucleotide polymorphisms. No evidence was found for significant miRNA transcription within 8q24 prostate cancer risk loci. Likewise, no convincing association between RNA expression and risk allele status was detected in either histologically normal or tumor tissue. To our knowledge, this is one of the first and largest studies to directly assess miRNA in this region and to systematically measure MYC expression levels in prostate tissue in relation to inherited risk variants. These data will help to direct the future study of this risk locus. [Cancer Res 2009;69(13):5568–74]
Compartment-Specific Roles of ATP-Binding Cassette Transporters Define Differential Topotecan Distribution in Brain Parenchyma and Cerebrospinal Fluid
Authors: Shen Jun , Carcaboso Angel M. , Hubbard K. Elaine , Tagen Michael , Wynn Henry G. , Panetta John C. , Waters Christopher M. , Elmeliegy Mohamed A. , Stewart Clinton F. 
Published: July 2009

AbstractTopotecan is a substrate of the ATP-binding cassette transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). To define the role of these transporters in topotecan penetration into the ventricular cerebrospinal fluid (vCSF) and brain parenchymal extracellular fluid (ECF) compartments, we performed intracerebral microdialysis on transporter-deficient mice after an intravenous dose of topotecan (4 mg/kg). vCSF penetration of unbound topotecan lactone was measured as the ratio of vCSF-to-plasma area under the concentration-time curves. The mean ± SD ratios for wild-type, Mdr1a/b−/−, Bcrp1−/−, and Mdr1a/b−/−Bcrp1−/− mice were 3.07 ± 0.09, 2.57 ± 0.17, 1.63 ± 0.12, and 0.86 ± 0.05, respectively. In contrast, the ECF-to-plasma ratios for wild-type, Bcrp1−/−, and Mdr1a/b−/−Bcrp1−/− mice were 0.36 ± 0.06, 0.42 ± 0.06, and 0.88 ± 0.07. Topotecan lactone was below detectable limits in the ECF of Mdr1a/b−/− mice. When gefitinib (200 mg/kg) was preadministered to inhibit Bcrp1 and P-gp, the vCSF-to-plasma ratio decreased to 1.29 ± 0.09 in wild-type mice and increased to 1.13 ± 0.13 in Mdr1a/b−/−Bcrp1−/− mice, whereas the ECF-to-plasma ratio increased to 0.74 ± 0.14 in wild-type and 1.07 ± 0.03 in Mdr1a/b−/−Bcrp1−/− mice. Preferential active transport of topotecan lactone over topotecan carboxylate was shown in vivo by vCSF lactone-to-carboxylate area under the curve ratios for wild-type, Mdr1a/b−/−, Bcrp1−/−, and Mdr1a/b−/−Bcrp1−/− mice of 5.69 ± 0.83, 3.85 ± 0.64, 3.61 ± 0.46, and 0.78 ± 0.19, respectively. Our results suggest that Bcrp1 and P-gp transport topotecan into vCSF and out of brain parenchyma through the blood-brain barrier. These findings may help to improve pharmacologic strategies to treat brain tumors. [Cancer Res 2009;69(14):5885–92]
Aneuploidy: Cancer's Fatal Flaw?
Authors: Williams Bret R. , Amon Angelika 
Published: July 2009

Abstract
Aneuploidy is a characteristic of cancer, with greater than 90% of all solid tumors in humans carrying an aberrant karyotype. Yet, whether or how this condition contributes to tumorigenesis is not understood. Here we summarize our recent findings on the effects of aneuploidy on cell physiology and proliferation. These studies suggest that aneuploidy puts significant stress on the cell, which responds to this condition in what can be viewed as an aneuploidy stress response. We will discuss how our results may bear on our understanding of the role of this condition in tumorigenesis and how they may provide new opportunities for treatment of the disease. [Cancer Res 2009;69(13):5289–91]
Mediators of Glioblastoma Resistance and Invasion during Antivascular Endothelial Growth Factor Therapy
Authors: Lucio-Eterovic Agda K. , Piao Yuji , de Groot John F. 
Published: July 2009

Abstract
Purpose: Vascular endothelial growth factor (VEGF) has been identified as a critical regulator of angiogenesis. Currently, several different strategies are being used to target the VEGF-VEGF receptor signal transduction pathway in glioblastoma. Although anti-VEGF therapy seems be effective in normalizing abnormal tumor vasculature, leading to an enhanced response to radiation and chemotherapy, tumors eventually become resistant to the therapy and adopt a highly infiltrative and invasive phenotype.
Experimental Design: In the present study, we evaluated the effects of anti-VEGF therapy (bevacizumab) on glioblastoma invasion both in vitro and in vivo and evaluated the angiogenesis- and invasion-related mediators of developed resistance to this therapy.
Results: We found that glioblastoma tumors escaped from antiangiogenic treatment by (a) reactivating angiogenesis through up-regulation of other proangiogenic factors and (b) invading normal brain areas, which was seen in association with up-regulation of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-12; secreted protein, acidic, cysteine-rich; and tissue inhibitor of metalloproteinase 1. In addition to the paracrine effects of VEGF on endothelial cells, autocrine VEGF signaling seemed to regulate glioblastoma invasion because anti-VEGF therapy increased tumor invasiveness in vitro.
Conclusions: Collectively, these findings reinforce the importance of VEGF in regulating tumor invasion and identify potential mediators of resistance to targeted VEGF therapy. These results will be important for developing novel combination therapies to overcome this resistance phenotype.
An antagonist of the chemokine receptor CXCR4 induces mitotic catastrophe in ovarian cancer cells
Authors: Kwong Joseph , Kulbe Hagen , Wong Donald , Chakravarty Probir , Balkwill Fran 
Published: July 2009

AbstractThe chemokine receptor CXCR4 is expressed by malignant cells in ovarian cancer and is implicated in their growth and spread. We report here a unique mechanism of action of a small peptide antagonist of CXCR4 on ovarian cancer cells: induction of cell death by mitotic catastrophe. CTCE-9908 inhibited ovarian cancer cell migration to CXCL12, but on longer incubation, caused cell death in CXCR4-positive cells. CTCE-9908 did not cause apoptosis or cellular senescence, but induced multinucleation, G2-M arrest, and abnormal mitosis in ovarian cancer cells. This suggests that cell death was caused by mitotic catastrophe. Using microarray and Western blot analysis, we showed that CTCE-9908 deregulated DNA damage checkpoint proteins and spindle assembly checkpoint proteins at G2-M phases of the cell cycle. Combination treatment of CTCE-9908 and the drug paclitaxel led to an additive cytotoxicity that also involved mitotic catastrophe. We conclude that CTCE-9908 has a unique mechanism of action in ovarian cancer cells that seems to be CXCR4 specific. [Mol Cancer Ther 2009;8(7):1893–905]
Gene expression profiling of imatinib and PD166326-resistant CML cell lines identifies Fyn as a gene associated with resistance to BCR-ABL inhibitors
Authors: Grosso Sébastien , Puissant Alexandre , Dufies Maeva , Colosetti Pascal , Jacquel Arnaud , Lebrigand Kevin , Barbry Pascal , Deckert Marcel , Cassuto Jill Patrice , Mari Bernard , Auberger Patrick 
Published: July 2009

AbstractImatinib is used to treat chronic myelogenous leukemia (CML), but resistance develops in all phases of this disease. The purpose of the present study was to identify the mode of resistance of newly derived imatinib-resistant (IM-R) and PD166326-resistant (PD-R) CML cells. IM-R and PD-R clones exhibited an increase in viability and a decrease in caspase activation in response to various doses of imatinib and PD166326, respectively, as compared with parental K562 cells. Resistance involved neither mutations in BCR-ABL nor increased BCR-ABL, MDR1 or Lyn expression, all known modes of resistance. To gain insight into the resistance mechanisms, we used pangenomic microarrays and identified 281 genes modulated in parental versus IM-R and PD-R cells. The gene signature was similar for IM-R and PD-R cells, accordingly with the cross-sensitivity observed for both inhibitors. These genes were functionally associated with pathways linked to development, cell adhesion, cell growth, and the JAK-STAT cascade. Especially relevant were the increased expression of the tyrosine kinases AXL and Fyn as well as CD44 and HMGA2. Small interfering RNA experiments and pharmacologic approaches identified FYN as a candidate for resistance to imatinib. Our findings provide a comprehensive picture of the transcriptional events associated with imatinib and PD166326 resistance and identify Fyn as a new potential target for therapeutic intervention in CML. [Mol Cancer Ther 2009;8(7):1924–33]
Vibration therapy in multiple sclerosis: a pilot study exploring its effects on tone, muscle force, sensation and functional performance
Authors: Schyns F. , Paul L. , Finlay K. , Ferguson C. , Noble E. 
Published: June 2009

Objective: To examine the effectiveness of whole body vibration (WBV) on tone, muscle force, sensation and functional performance in people with multiple sclerosis. Design: A randomized cross-over pilot study. Setting: Revive MS Support Therapy Centre. Glasgow, UK. Subjects: Sixteen people with multiple sclerosis were randomly allocated to one of two groups. Intervention: Group 1 received four weeks of whole body vibration plus exercise three times per week, two weeks of no intervention and then four weeks of exercise alone three times per week. Group 2 were given the two treatment interventions in the reverse order to group 1. Main measures: Ten-metre walk, Timed Up and Go Test, Modified Ashworth Scale, Multiple Sclerosis Spasticity Scale (MSSS-88), lower limb muscle force, Nottingham Sensory Assessment and Multiple Sclerosis Impact Scale (MSIS-29) were used before and after intervention. Results: The exercise programme had positive effects on muscle force and well-being, but there was insufficient evidence that the addition of whole body vibration provided any further benefit. The Modified Ashworth Scale was generally unaffected by either intervention, although, for each group, results from the MSSS-88 showed whole body vibration and exercises reduced muscle spasms (P = 0.02). Although results for the 10-m walk and Timed Up and Go Test improved, this did not reach statistical significance (P = 0.56; P = 0.70, respectively). For most subjects sensation was unaffected by whole body vibration. Conclusion: Exercise may be beneficial to those with multiple sclerosis, but there is limited evidence that the addition of whole body vibration provides any additional improvements. Further larger scale studies into the effects of whole body vibration in people with multiple sclerosis are essential.