bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bexarotene (LGD1069, Targretin), a Selective Retinoid X Receptor Agonist, Prevents and Reverses Gemcitabine Resistance in NSCLC Cells by Modulating Gene Amplification
Authors: Tooker Patricia , Yen Wan-Ching , Ng Shi-Chung , Negro-Vilar Andrès , Hermann Thomas W. 
Published: May 2007

Abstract
Acquired drug resistance is a major obstacle in cancer therapy. As for many other drugs, this is also the case for gemcitabine, a nucleoside analogue with activity against non–small cell lung cancer (NSCLC). Here, we evaluate the ability of bexarotene to modulate the acquisition and maintenance of gemcitabine resistance in Calu3 NSCLC models. In the prevention model, Calu3 cells treated repeatedly with gemcitabine alone gradually developed resistance. However, with inclusion of bexarotene, the cells remained chemosensitive. RNA analysis showed a strong increase of rrm1 (ribonucleotide reductase M1) expression in the resistant cells (Calu3-GemR), a gene known to be involved in gemcitabine resistance. In addition, the expression of genes surrounding the chromosomal location of rrm1 was increased, suggesting that resistance was due to gene amplification at the chr11 p15.5 locus. Analysis of genomic DNA confirmed that the rrm1 gene copy number was increased over 10-fold. Correspondingly, fluorescence in situ hybridization analysis of metaphase chromosomes showed an intrachromosomal amplification of the rrm1 locus. In the therapeutic model, bexarotene gradually resensitized Calu3-GemR cells to gemcitabine, reaching parental drug sensitivity after 10 treatment cycles. This was associated with a loss in rrm1 amplification. Corresponding with the in vitro data, xenograft tumors generated from the resistant cells did not respond to gemcitabine but were growth inhibited when bexarotene was added to the cytotoxic agent. The data indicate that bexarotene can resensitize gemcitabine-resistant tumor cells by reversing gene amplification. This suggests that bexarotene may have clinical utility in cancers where drug resistance by gene amplification is a major obstacle to successful therapy. [Cancer Res 2007;67(9):4425–33]
Stroma-Derived Matrix Metalloproteinase (MMP)-2 Promotes Membrane Type 1-MMP–Dependent Tumor Growth in Mice
Authors: Taniwaki Kaori , Fukamachi Hiroshi , Komori Kiyoshi , Ohtake Yohei , Nonaka Takahiro , Sakamoto Takeharu , Shiomi Takayuki , Okada Yasunori , Itoh Takeshi , Itohara Shigeyoshi , Seiki Motoharu , Yana Ikuo 
Published: May 2007

Abstract
Matrix metalloproteinase-2 (MMP-2) is a stroma-derived MMP belonging to the type IV collagenase family. It is believed to mediate tumor cell behavior by degrading deposits of type IV collagen, a major component of the basement membrane. The membrane type 1-MMP (MT1-MMP) is a highly potent activator of MMP-2 and is expressed in many tumor and stromal cells. However, the roles played by stromal MMP-2 in tumor progression in vivo remain poorly understood. We established a colon epithelial cell line from an Mt1-mmp−/− mouse strain and transfected these cells with an inducible expression system for MT1-MMP (MT1rev cells). Following s.c. implantation into Mmp-2+/+ mice and induction of MT1-MMP expression, MT1rev cells grew rapidly, whereas they grew very slowly in Mmp-2−/− mice, even in the presence of MT1-MMP. This MT1-MMP–dependent tumor growth of MT1rev cells was enhanced in Mmp-2−/− mice as long as MMP-2 was supplied via transfection or coimplantation of MMP-2–positive fibroblasts. MT1rev cells cultured in vitro in a three-dimensional collagen gel matrix also required the MT1-MMP/MMP-2 axis for rapid proliferation. MT1rev cells deposit type IV collagen primarily at the cell-collagen interface, and these deposits seem scarce at sites of invasion and proliferation. These data suggest that cooperation between stroma-derived MMP-2 and tumor-derived MT1-MMP may play a role in tumor invasion and proliferation via remodeling of the tumor-associated basement membrane. To our knowledge, this is the first study demonstrating that MT1-MMP–dependent tumor growth in vivo requires stromal-derived MMP-2. It also suggests that MMP-2 represents a potential target for tumor therapeutics. [Cancer Res 2007;67(9):4311–9]
Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target
Authors: Fernández Ariel , Sanguino Angela , Peng Zhenghong , Crespo Alejandro , Ozturk Eylem , Zhang Xi , Wang Shimei , Bornmann William , Lopez-Berestein Gabriel 
Published: May 2007

Abstract
Protein kinases are central targets for drug-based cancer treatment. To avoid functional impairment, the cell develops mechanisms of drug resistance, primarily based on adaptive mutations. Redesigning a drug to target a drug-resistant mutant kinase constitutes a therapeutic challenge. We approach the problem by redesigning the anticancer drug imatinib guided by local changes in interfacial de-wetting propensities of the C-Kit kinase target introduced by an imatinib-resistant mutation. The ligand is redesigned by sculpting the shifting hydration patterns of the target. The association with the modified ligand overcomes the mutation-driven destabilization of the induced fit. Consequently, the redesigned drug inhibits both mutant and wild-type kinase. The modeling effort is validated through molecular dynamics, test tube kinetic assays of downstream phosphorylation activity, high-throughput bacteriophage-display kinase screening, cellular proliferation assays, and cellular immunoblots. The inhibitor redesign reported delineates a molecular engineering paradigm to impair routes for drug resistance. [Cancer Res 2007;67(9):4028–33]
Thanatop: A Novel 5-Nitrofuran that Is a Highly Active, Cell-Permeable Inhibitor of Topoisomerase II
Authors: Polycarpou-Schwarz Maria , Müller Kerstin , Denger Stefanie , Riddell Andrew , Lewis Joe , Gannon Frank , Reid George 
Published: May 2007

Abstract
A series of nitrofuran-based compounds were identified as inhibitors of estrogen signaling in a cell-based, high-throughput screen of a diverse library of small molecules. These highly related compounds were subsequently found to inhibit topoisomerase II in vitro at concentrations similar to that required for the inhibition of estrogen signaling in cells. The most potent nitrofuran discovered is ∼10-fold more active than etoposide phosphate, a topoisomerase II inhibitor in clinical use. The nitrofurans also inhibit topoisomerase I activity, with ∼20-fold less activity. Moreover, the nitrofurans, in contrast to etoposide, induce a profound cell cycle arrest in the G0-G1 phase of the cell cycle, do not induce double-stranded DNA breaks, are not substrates for multidrug resistance protein-1 export from the cell, and are amenable to synthetic development. In addition, the nitrofurans synergize with etoposide phosphate in cell killing. Clonogenic assays done on a panel of human tumors maintained ex vivo in nude mice show that the most active compound identified in the screen is selective against tumors compared with normal hematopoietic stem cells. However, this compound had only moderate activity in a mouse xenograft model. This novel class of topoisomerase II inhibitor may provide additional chemotherapeutic strategies for the development of cytotoxic agents with proven clinical utility. [Cancer Res 2007;67(9):4451–8]
p21 Loss Cooperates with INK4 Inactivation Facilitating Immortalization and Bcl-2–Mediated Anchorage-Independent Growth of Oncogene-Transduced Primary Mouse Fibroblasts
Authors: Carbone Christopher J. , Graña Xavier , Reddy E. Premkumar , Haines Dale S. 
Published: May 2007

Abstract
The INK4 and CIP cyclin-dependent kinase (Cdk) inhibitors (CKI) activate pocket protein function by suppressing Cdk4 and Cdk2, respectively. Although these inhibitors are lost in tumors, deletion of individual CKIs results in modest proliferation defects in murine models. We have evaluated cooperativity between loss of all INK4 family members (using cdk4r24c mutant alleles that confer resistant to INK4 inhibitors) and p21Waf1/Cip1 in senescence and transformation of mouse embryo fibroblasts (MEF). We show that mutant cdk4r24c and p21 loss cooperate in pRb inactivation and MEF immortalization. Our studies suggest that cdk4r24c mediates resistance to p15INK4B/p16INK4A that accumulates over passage, whereas loss of p21 suppresses hyperoxia-induced Cdk2 inhibition and pRb dephosphorylation on MEF explantation in culture. Although cdk4r24c and p21 loss cooperate in H-rasV12/c-myc–induced foci formation, they are insufficient for oncogene-induced anchorage-independent growth. Interestingly, p21−/−; cdk4r24c MEFs expressing H-rasV12 and c-myc display detachment-induced apoptosis and are transformed by c-myc, H-rasV12, and Bcl-2. We conclude that the INK4 family and p21 loss cooperate in promoting pRb inactivation, cell immortalization, and H-rasV12/c-myc–induced loss of contact inhibition. In addition, absence of pRb function renders H-rasV12 + c-myc–transduced fibroblasts prone to apoptosis when deprived of the extracellular matrix, and oncogene-induced anchorage-independent growth of pocket protein–deficient cells requires apoptotic suppression. [Cancer Res 2007;67(9):4130–7]
Paradoxes of the EphB4 Receptor in Cancer
Authors: Noren Nicole K. , Pasquale Elena B. 
Published: May 2007

Abstract
Recent findings have started to uncover the intriguing roles of the Eph family of receptor tyrosine kinases in normal epithelial cells and during oncogenic transformation. This review focuses on EphB4, an Eph receptor that has both tumor-suppressing and tumor-promoting activities in breast cancer. Understanding the multifaceted role of EphB4 in tumorigenesis may allow the development of new anticancer therapies. [Cancer Res 2007;67(9):3994–7]
Removal of Fkbp12/12.6 From Endothelial Ryanodine Receptors Leads to an Intracellular Calcium Leak and Endothelial Dysfunction
Authors: Long Cheng , Cook Leslie G. , Wu Gang-Yi , Mitchell Brett M. 
Published: May 2007

Objectives—FK506BindingProtein 12 and its related isoform 12.6 (FKBP12/12.6) stabilize a closed state of intracellular Ca2+release channels (ryanodine receptors [RyRs]), and in myocytes removal of FKBP12/12.6 from RyRs alters intracellular Ca2+levels. The immunosuppressive drugs rapamycin and FK506 bind and displace FKBP12/12.6 from RyRs, and can also cause endothelial dysfunction and hypertension. We tested whether rapamycin and FK506 cause an intracellular Ca2+leak in endothelial cells and whether this affects endothelial function and blood pressure regulation.Methods and Results—Rapamycin or FK506 concentration-dependently caused a Ca2+leak in isolated endothelial cells, decreased aortic NO production and endothelium-dependent dilation, and increased systolic blood pressure in control mice. Rapamycin or FK506 at 10 μmol/L abolished aortic NO production and endothelium-dependent dilation. Similar results were obtained in isolated endothelial cells and aortas from FKBP12.6−/−mice after displacement of FKBP12 with 1 μmol/L rapamycin or FK506. In hypertensive FKBP12.6−/−mice, systolic blood pressures were further elevated after treatment with either rapamycin or FK506. Blockade of the Ca2+leak with ryanodine normalized NO production and endothelium-dependent dilation.Conclusions—Complete removal of FKBP12 and 12.6 from endothelial RyRs induces an intracellular Ca2+leak which may contribute to the pathogenesis of endothelial dysfunction and hypertension caused by rapamycin or FK506.
The Passive Compression Test
Authors: Kim Yang-Soo , Kim Jung-Man , Ha Kee-Yong , Choy Soon , Joo Min-Wook , Chung Yang-Guk 
Published: May 2007

Background Even though there are several physical tests available for superior labrum anterior posterior lesions, there have been very few reports on their accuracy, and none can be regarded as completely predictive for the presence of a superior labrum anterior posterior lesion in the shoulder joint. Hypothesis This new clinical test is a useful and accurate technique for detecting superior labral tears in the shoulder joint. Study Design Cohort study (diagnosis); Level of evidence, 2. Methods This test was conducted independently by 2 physicians before any other diagnostic evaluation. In all cases, the glenohumeral joint was investigated first, and the appropriate treatments were performed on the lesion. A protocol was established to evaluate the sensitivity, specificity, and positive and negative predictive values of this new clinical test. The reproducibility of this test was evaluated with a κ coefficient. Results Sixty-one patients (61 shoulders) were examined with the passive compression test, and all underwent arthroscopic surgery. In 31 patients with a positive passive compression test result, 27 had a superior labrum anterior posterior lesion, and in 30 patients with a negative passive compression test result, 6 had a superior labrum anterior posterior lesion. The sensitivity of the test was 81.8%, and the specificity was 85.7%. The positive predictive value was 87.1%, and the negative predictive value was 80.0%. The κ coefficient was 0.771 between the 2 independent examiners (P < .01). Conclusion The passive compression test is a useful and accurate technique for predicting superior labral tears of the shoulder joint.
Achilles Tendinosis
Authors: de Mos Marieke , van El Benno , DeGroot Jeroen , Jahr Holger , van Schie Hans T. M. , van Arkel Ewoud R. , Tol Hans , Heijboer Rien , van Osch Gerjo J. V. M. , Verhaar Jan A. N. 
Published: May 2007

Background Understanding biochemical and structural changes of the extracellular matrix in Achilles tendinosis might be important for developing mechanism-based therapies. Hypothesis In Achilles tendinosis, changes occur in biochemical composition and collagen turnover rate. Study Design Descriptive laboratory study. Methods From 10 patients undergoing surgery for Achilles tendinopathy, 1 tendinosis biopsy specimen and 1 biopsy specimen of macroscopically healthy tendon tissue adjacent to the lesion were collected. Furthermore, biopsy samples were collected from 3 donors with asymptomatic Achilles tendons. Water content, collagen content, percentage of denatured collagen, amount of lysine hydroxylation, number of enzymatic and nonenzymatic crosslinks, matrix metalloproteinase activity, and matrix metalloproteinase and collagen gene-expression levels were analyzed. Results In tendinotic lesions, the water content was highest, and collagen content was subnormal with higher amounts of denatured/damaged collagen. Low pentosidine levels in tendinotic tissue indicated the presence of relatively young collagenous matrix. More hydroxylated lysine residues were present in tendinotic samples, but enzymatic crosslinks revealed no differences between tendinotic, adjacent, and healthy samples. In tendinotic specimens, matrix metalloproteinase activity was higher, matrix metalloproteinase gene-expression profile was altered, and collagen type I and III gene expression were upregulated. Conclusion In Achilles tendinosis, the collagen turnover rate is increased, and the natural biochemical composition of the collagenous matrix is compromised. Clinical Relevance Although tendon tissue directly adjacent to an Achilles tendinosis lesion looks macroscopically healthy, histological and biochemical degenerative changes in adjacent tissue are evident, which may have implications for surgical interventions.
Reconstitution of FOXP3+ regulatory T cells (Tregs) after CD25-depleted allotransplantion in elderly patients and association with acute graft-versus-host disease
Authors: Mielke Stephan , Rezvani Katayoun , Savani Bipin N. , Nunes Raquel , Yong Agnes S. M. , Schindler John , Kurlander Roger , Ghetie Victor , Read Elizabeth J. , Solomon Scott R. , Vitetta Ellen S. , Barrett A. John 
Published: May 2007

AbstractSelective depletion (SD) of host-reactive donor T cells from allogeneic stem-cell transplants (SCTs) using an anti-CD25 immunotoxin (IT) is a strategy to prevent acute graft-versus-host disease (aGvHD). There is concern that concurrent removal of regulatory T cells (Tregs) with incomplete removal of alloactivated CD25+ T cells could increase the risk of aGvHD. We therefore measured Tregs in the blood of 16 patients receiving a T-cell–depleted allograft together with anti–CD25-IT–treated SD lymphocytes, in 13 of their HLA-identical donors, and in 10 SD products. Tregs were characterized by intracellular staining for forkhead box protein 3 (FOXP3) and by quantitative reverse-transcription–polymerase chain reaction (qRT-PCR) for FOXP3 gene in CD4+ cells. Patients received a median of 1.0 × 108/kg SD T cells and a stem cell product containing a median of 0.25 × 104/kg residual T cells. Tregs reconstituted promptly after SCT and underwent further expansion. Of the CD4+ T cells in SD products, 1.5% to 4.8% were CD25− Tregs. Acute GvHD (≥ grade II) was restricted to 5 patients whose donors had significantly (P = .019) fewer Tregs compared with those without clinically significant aGvHD. These results suggest that rapid Treg reconstitution can occur following SD allografts, either from CD25− Tregs escaping depletion, or from residual CD25− and CD25+ Tregs contained in the stem-cell product that expand after transplantation and may confer additional protection against GvHD.
Mutations in the SBDS gene in acquired aplastic anemia
Authors: Calado Rodrigo T. , Graf Solomon A. , Wilkerson Keisha L. , Kajigaya Sachiko , Ancliff Philip J. , Dror Yigal , Chanock Stephen J. , Lansdorp Peter M. , Young Neal S. 
Published: May 2007

Abstract
Shwachman-Diamond syndrome (SDS; OMIM 260400), an inherited bone marrow failure syndrome, is caused by mutations in both alleles of the SBDS gene, which encodes a protein of unknown function. Here we report heterozygosity for the 258 + 2 T>C SBDS gene mutation previously identified in SDS patients in 4 of 91 patients with apparently acquired aplastic anemia (AA) but not in 276 ethnically matched controls (Fisher exact test, P < .004). Affected patients were young and had a poor outcome; they had reduced SBDS expression but no evidence of the pancreatic exocrine failure or skeletal abnormalities typical of SDS. Length of telomeres in granulocytes of SBDS heterozygous patients was short for their age, and in SDS patients with both SBDS alleles affected further analyzed, granulocytes' telomeres were even shorter, correlating in length with SBDS expression. Higher heterogeneity in telomere length also was observed in SDS patients. Telomerase activity of SBDS-deficient patients' lymphocytes was comparable with controls, and no physical interaction between SBDS protein and telomerase complex components (TERT or TERC) was established. We propose that heterozygosity for the 258 + 2 T>C SBDS mutation predisposes to AA by accelerating telomere shortening of leukocytes via a telomerase-independent mechanism.
The zebrafish lysozyme C promoter drives myeloid-specific expression in transgenic fish
Authors: Hall Chris , Flores Maria Vega , Storm Thilo , Crosier Kathy , Crosier Phil 
Published: May 2007

Abstract

Background
How different immune cell compartments contribute to a successful immune response is central to fully understanding the mechanisms behind normal processes such as tissue repair and the pathology of inflammatory diseases. However, the ability to observe and characterize such interactions, in real-time, within a living vertebrate has proved elusive. Recently, the zebrafish has been exploited to model aspects of human disease and to study specific immune cell compartments using fluorescent reporter transgenic lines. A number of blood-specific lines have provided a means to exploit the exquisite optical clarity that this vertebrate system offers and provide a level of insight into dynamic inflammatory processes previously unavailable.

Results
We used regulatory regions of the zebrafish lysozyme C (lysC) gene to drive enhanced green fluorescent protein (EGFP) and DsRED2 expression in a manner that completely recapitulated the endogenous expression profile of lysC. Labeled cells were shown by co-expression studies and FACS analysis to represent a subset of macrophages and likely also granulocytes. Functional assays within transgenic larvae proved that these marked cells possess hallmark traits of myelomonocytic cells, including the ability to migrate to inflammatory sources and phagocytose bacteria.

Conclusion
These reporter lines will have utility in dissecting the genetic determinants of commitment to the myeloid lineage and in further defining how lysozyme-expressing cells participate during inflammation.
Influenza vaccine supply, 2005–2006: did we come up short?
Authors: Bardenheier Barbara H , Strikas Raymond , Kempe Allison , Stokley Shannon , Ellis Jean 
Published: May 2007

Abstract
Background
Although total influenza vaccine doses available in the 2005/2006 influenza season were over 80 million, CDC received many reports of delayed and diminished vaccine shipments in October to November of 2005. To better understand the supply problems, CDC and partners surveyed several health care professional groups.

Methods
Surveys were sent to representative samples of influenza vaccine providers including pediatricians, internists, federally qualified health centers, visiting nurse organizations, and all 64 state and other health departments receiving federal immunization funds directly. In November and December, 2005, providers were asked questions about their experience in ordering influenza vaccine, sources where orders were placed, proportion of orders received, and referral of patients to other vaccination sites.

Results
The number of providers surveyed (median: 154; range: 64 – 308) and response rates (median: 62%; range: 51% – 77%) varied among groups. Less than half of the providers in most groups placed a single order that was accepted (median: 31%; range: 8% – 53%), and most placed multiple orders. Only 57% of federally qualified health centers and 60% of internists reported they received at least 40% of their orders by the middle of December; the other provider groups received a greater proportion of their orders. Most internists (80%) and federally qualified health centers (54%) reported that they had referred priority group patients to other locations to receive the influenza vaccine due to inadequate supplies. Vaccine providers who ordered only from Chiron received a lower proportion of their orders than providers that ordered from another source or ordered from multiple sources.

Conclusion
Most of the providers surveyed received only part of their orders by the middle of December. Disruptions in receipt of influenza vaccine during the fall of 2005 were due primarily to shortfalls in vaccine from Chiron and also due to delays and partial shipments from other distributors.