bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Functional Variant of Tandem Repeats in Human Telomerase Gene Was Associated with Survival of Patients with Early Stages of Non–Small Cell Lung Cancer
Authors: Wang Luo , Wang Li-E , Mao Li , Spitz Margaret R. , Wei Qingyi 
Published: May 2010

Abstract
Purpose: Elevated levels of human telomerase (hTERT) mRNA in tumors is a marker for poorer survival in patients with stage I non–small cell lung cancer (NSCLC). A functional variant of MNS16A-short tandem repeats in hTERT (S allele) is associated with higher expression levels of hTERT mRNA compared with the MNS16A-long (L) allele. It is unknown, however, whether or not the hTERT MNS16A variant genotype predicts survival of NSCLC patients.
Experimental Design: The hTERT genotypes of 808 patients with NSCLC were determined by direct PCR with genomic DNA. Overall median survival times were estimated by the life-table method, and the log-rank test was used to test for homogeneity of the survival curves. Both univariate and multivariate Cox proportional hazards models were used to assess the associations between survival time and the hTERT genotype as well as other known risk factors.
Results: The hTERT variant genotype was not associated with overall survival among the 808 patients. However, among 221 patients with stage I or II NSCLC, the S allele was associated with shorter survival time (P = 0.027, by log-rank test). The adjusted hazard ratios were 1.30 (95% confidence interval, 0.79-2.14; P = 0.310) for the SL-genotype and 2.34 (95% confidence interval, 1.20-4.56, P = 0.012) for the SS-genotype compared with the LL-genotype (P = 0.021 for trend test). These findings were not evident in 587 patients with stage III or IV NSCLC.
Conclusion: The functional MNS16A-SS genotype may be a marker for poorer survival in early-stage NSCLC. Clin Cancer Res; 16(14); 3779–85. ©2010 AACR.
A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2
Authors: Eder Joseph Paul , Shapiro Geoffrey I. , Appleman Leonard J. , Zhu Andrew X. , Miles Dale , Keer Harold , Cancilla Belinda , Chu Felix , Hitchcock-Bryan Suzanne , Sherman Laurie , McCallum Stewart , Heath Elisabeth I. , Boerner Scott A. , LoRusso Patricia M. 
Published: May 2010

Abstract
Purpose: Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity.
Experimental Design: Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional “3+3” design.
Results: Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non–dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses.
Conclusions: The recommended dose of foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials. Clin Cancer Res; 16(13); 3507–16. ©2010 AACR.
Role of Type 1 IFNs in Antiglioma Immunosurveillance—Using Mouse Studies to Guide Examination of Novel Prognostic Markers in Humans
Authors: Fujita Mitsugu , Scheurer Michael E. , Decker Stacy A. , McDonald Heather A. , Kohanbash Gary , Kastenhuber Edward R. , Kato Hisashi , Bondy Melissa L. , Ohlfest John R. , Okada Hideho 
Published: May 2010

AbstractPurpose: We hypothesized that the type 1 IFNs would play a pivotal role in antiglioma immunosurveillance through promotion of type 1 adaptive immunity and suppression of immunoregulatory cells.Experimental Design: We induced de novo gliomas in Ifnar1−/− (deficient for type 1 IFN receptors) or wild-type mice by intracerebroventricuar transfection of NRas and a short hairpin RNA against P53 using the Sleeping Beauty transposon system. We analyzed the survival of 587 glioma patients for single nucleotide polymorphisms (SNP) in type 1 IFN–related genes.Results: Ifnar1−/− mice exhibited accelerated tumor growth and death. Analyses of brain tumor–infiltrating lymphocytes in Ifnar1−/− mice revealed an increase of cells positive for CD11b+Ly6G+ and CD4+FoxP3+, which represent myeloid-derived suppressor cells and regulatory T cells, respectively, but a decrease of CD8+ cytotoxic T lymphocytes (CTLs) compared with wild-type mice. Ifnar1−/− mouse–derived glioma tissues exhibited a decrease in mRNA for the CTL-attracting chemokine Cxcl10, but an increase of Ccl2 and Ccl22, both of which are known to attract immunoregulatory cell populations. Dendritic cells generated from the bone marrow of Ifnar1−/− mice failed to function as effective antigen-presenting cells. Moreover, depletion of Ly6G+ cells prolonged the survival of mice with developing gliomas. Human epidemiologic studies revealed that SNPs in IFNAR1 and IFNA8 are associated with significantly altered overall survival of patients with WHO grade 2 to 3 gliomas.Conclusions: The novel Sleeping Beauty–induced murine glioma model led us to discover a pivotal role for the type 1 IFN pathway in antiglioma immunosurveillance and relevant human SNPs that may represent novel prognostic markers. Clin Cancer Res; 16(13); 3409–19. ©2010 AACR.
Evaluation of the Bone Bridge Between the Bone Tunnels After Anatomic Double-Bundle Anterior Cruciate Ligament Reconstruction
Authors: Hantes Michael E. , Liantsis Athanasios K. , Basdekis Georgios K. , Karantanas Apostolos H. , Christel Pascal , Malizos Konstantinos N. 
Published: May 2010

Background: Double-bundle anterior cruciate ligament (ACL) reconstruction is a technically demanding procedure; it requires drilling 2 tibial and 2 femoral tunnels. Tunnel communication, whether intraoperative or postoperative, is a serious complication: It jeopardizes knee stability and graft function. Hypothesis: During double-bundle ACL reconstruction, special aimers would be helpful to avoid intraoperative bone bridge fracture. The bone bridge between the bone tunnels would maintain its structural integrity, and no tunnel communication would be observed postoperatively because of tunnel widening. Study design: Case series; Level of evidence, 4. Methods: This prospective study included 32 patients undergoing double-bundle ACL reconstruction. A multidetector computed tomography study was performed at a mean of 17 months postoperatively. The thickness of the bone bridge between the bone tunnels was measured in the femoral and tibial sides on an axial and sagittal plane, respectively, at 3 locations: the level of the joint line, the midportion of the bone bridge, and the base of the bone bridge. The bone density of the bone bridge was measured in Hounsfield units in the same locations. Bone density of the anterior tibial cortex and lateral femoral condyle was measured for comparisons. Results: Tunnel communication occurred intraoperatively in 1 patient on the tibial side at the level of the joint line. In the rest of the patients, a well-defined triangular bone bridge was present between the 2 tunnels in the femoral and tibial sides. The thickness at the apex of the bone bridge was 2.0 and 2.2 mm for the femur and tibia, respectively. In addition, the density of the bone bridge at its apex was similar to that of cortical bone. Conclusion: This study demonstrated that double-bundle ACL reconstruction, as used with anatomic aimers, produces a low rate of tunnel convergence. The bone bridge remains intact postoperatively, although it is thin at the level of the joint line.
Translation and Cross-Cultural Adaptation of the Brazilian Version of the International Knee Documentation Committee Subjective Knee Form
Authors: Metsavaht Leonardo , Leporace Gustavo , Riberto Marcelo , de Mello Sposito Maria Matilde , Batista Luiz Alberto 
Published: May 2010

Background: The perception of improvement by a patient has assumed a central role in functional evaluation after a variety of knee problems. One of the instruments most used in clinical research is the International Knee Documentation Committee (IKDC) Subjective Knee Form because its psychometric properties are considered to be excellent. Nonetheless, this questionnaire was originally developed for use in the English language. Therefore, to use this questionnaire in the Brazilian population, it is essential to translate and validate it. Purpose: The aim of this study was to translate the IKDC Subjective Knee Form into a Brazilian version and to test its validity and reproducibility. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: The translation of the original IKDC Subjective Knee Form into a Brazilian version was accomplished in accordance with the American Orthopaedic Society for Sports Medicine guidelines and was tested in 32 patients with knee pathologic conditions to develop the first Brazilian version. To test validity and reproducibility, 117 patients with several knee complaints completed the Brazilian IKDC Subjective Knee Form, the Short Form 36 (SF-36), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Lysholm score. From these patients, 85 were retested within a week to achieve reproducibility. The validation was addressed by correlating the Brazilian IKDC Subjective Knee Form to the other outcome measures. The reproducibility was tested by measuring internal consistency, test-retest reliability, and agreement. Results: The Brazilian IKDC Subjective Knee Form was highly related to the physical component summary of the SF-36, the Lysholm score, and the WOMAC, and weakly related to the mental component summary of SF-36 ( r = .79, .89, .85, and .51, respectively). The internal consistency was strong, with a Cronbach α value of .928 and .935 in the test and retest assessment, respectively. The test-retest reliability proved to be excellent, with a high value of the intraclass correlation coefficient (.988), as well as the agreement, demonstrated by the low differences between the means of the test and retest, and the short limit of agreement, observed in the Altman-Bland and survival-agreement plots. Conclusion: The results of this study provide evidence that the Brazilian IKDC Subjective Knee Form has psychometric properties similar to the original version. In addition, it was a reliable evaluation instrument for patients with knee-related problems.
Multicenter study for environmental and biological monitoring of occupational exposure to cyclophosphamide in Japan
Authors: Sugiura Shinichi , Nakanishi Hirokazu , Asano Mika , Hashida Tohru , Tanimura Manabu , Hama Toshihiro , Nabeshima Toshitaka 
Published: May 2010

Purpose. A multicenter field survey of environmental contamination and exposure of healthcare professionals to anticancer drugs were performed. Setting. Three university hospitals, one cancer specialty hospital and two corporate hospitals from across Japan. Method. The environmental contamination with cyclophosphamide (CP) was investigated. A wipe examination was performed at six sites apiece in two divisions. The urinary excretion of the CP over 24 h was determined. The subjects of the survey included physicians, pharmacists, and nurses, for a total of seven at each facility irrespective of job title. The wipe samples were collected at 12 sites within two divisions at each facility. For the exposure survey, the total urine volume was determined, and a portion of the urine sample was then collected from each participants at each facility. Urine was collected for 24 h. The samples were determined by using the GC-MS method. Results. Wipe examination: contamination with CP was identified at 50% of the sites. The concentration was high (CP > 1.00 ng/cm2) in the general environment in two hospitals and in the safety cabinet in one hospital. In the survey for the exposure of staff to anticancer drugs, 276 samples were obtained from 41 healthcare professionals. CP was detected in 90 samples obtained from 23 subjects. The amount of exposure was greatly different among the facilities. The urinary excretion of CP per subject was between 2.7 and 462.8 ng/24 h. The range of urinary excretion for each hospital was between 4.6 and 211.2 ng/24 h.
Anesthesia Management of a Patient With a Ventricular Assist Device for Noncardiac Surgery
Authors: Riha Hynek , Netuka Ivan , Kotulak Tomas , Maly Jiri , Pindak Marian , Sedlacek Jiri , Lomova Jitka 
Published: May 2010

Congestive heart failure represents a severe health condition with unfavourable long-term prognosis despite all the progress in pharmacological therapy of heart failure. Another therapeutic option is represented by mechanical cardiac support devices. Ventricular assist devices (VAD) constitute largest subgroup of these devices. Patients supported with VAD carry many considerations which are important for successful perioperative management of these patients for noncardiac surgery. The general perioperative considerations include consultation with VAD management personnel, detailed assessment of end-organ dysfunction before surgery, appropriate antibiotic prophylaxis, deactivation of implantable cardioverter-defibrillator for the time of surgical procedure, and the choice between general and regional anesthesia. Intraoperative monitoring depends primarily on the type of blood flow generated by VAD. For devices generating pulsatile blood flow, standard monitoring arrangements are needed. In the patients supported by devices which provide nonpulsatile blood flow, pulse oximetry and noninvasive blood pressure measurement are not reliable monitoring methods, and placement of intra-arterial catheter is warranted. In all the patients supported with VAD, transesophageal echocardiography is extremely useful method for monitoring the function of VAD itself, and in the case of univentricular VAD for monitoring the function of nonsupported cardiac ventricle. The most important issue in hemodynamic management of the patients with VAD is avoiding hypovolemia because it can cause inadequate VAD output with resulting low cardiac output and hypotension. All the patients with VAD need some degree of anticoagulation, and for noncardiac surgery the question of interrupting or decreasing the level of anticoagulation should be discussed among members of the caring team.
Interferon-γ and tumor necrosis factor-α induce an immunoinhibitory molecule, B7-H1, via nuclear factor-κB activation in blasts in myelodysplastic syndromes
Authors: Kondo Asaka , Yamashita Taishi , Tamura Hideto , Zhao Wanhong , Tsuji Takashi , Shimizu Masumi , Shinya Eiji , Takahashi Hidemi , Tamada Koji , Chen Lieping , Dan Kazuo , Ogata Kiyoyuki 
Published: May 2010

AbstractDuring disease progression in myelodysplastic syndromes (MDS), clonal blasts gain a more aggressive nature, whereas nonclonal immune cells become less efficient via an unknown mechanism. Using MDS cell lines and patient samples, we showed that the expression of an immunoinhibitory molecule, B7-H1 (CD274), was induced by interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα) on MDS blasts. This induction was associated with the activation of nuclear factor-κB (NF-κB) and nearly completely blocked by an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC). B7-H1+ MDS blasts had greater intrinsic proliferative capacity than B7-H1− MDS blasts when examined in various assays. Furthermore, B7-H1+ blasts suppressed T-cell proliferation and induced T-cell apoptosis in allogeneic cocultures. When fresh bone marrow samples from patients were examined, blasts from high-risk MDS patients expressed B7-H1 molecules more often compared with those from low-risk MDS patients. Moreover, MDS T cells often overexpressed programmed cell death 1 (PD-1) molecules that transmit an inhibitory signal from B7-H1 molecules. Taken together, these findings provide new insight into MDS pathophysiology. IFNγ and TNFα activate NF-κB that in turn induces B7-H1 expression on MDS blasts. B7-H1+ MDS blasts have an intrinsic proliferative advantage and induce T-cell suppression, which may be associated with disease progression in MDS.
EGR-1 activation by EGF inhibits MMP-9 expression and lymphoma growth
Authors: Bouchard Frédéric , Bélanger Simon D. , Biron-Pain Katherine , St-Pierre Yves 
Published: May 2010

AbstractProgression of hematologic malignancies is strongly dependent on bidirectional interactions between tumor cells and stromal cells. Expression of members of the matrix metalloproteinase (MMP) family by stromal cells is a central event during these interactions. However, although several studies have focused on the mechanisms responsible for induction of MMP in stromal cells, the signals that negatively regulate their secretion of in these cells remain largely unknown. Here, we provide evidence that MMP-9 production by stromal cells is suppressed through activation of early growth response protein 1 (EGR-1), thereby inhibiting the growth of thymic lymphoma. We found that EGR-1 expression is induced in stromal cells after contact with lymphoma cells via epidermal growth factor (EGF). Moreover, development of thymic lymphoma was inhibited when induced by lymphoma cells overexpressing EGF compared with control lymphoma cells. Using transgenic mice containing MMP-9 promoter-driven luciferase transgene in its genome, we further demonstrated that EGF/EGR-1 repressed transcriptional activation of the MMP-9 gene by stromal cells. De novo expression of EGR-1 alone by gene transfer or exposure to recombinant human EGF also inhibited MMP-9 expression. Taken together, these results indicate that EGR-1 could be a source of novel targets for therapeutic intervention in lymphoid tumors in which MMP-9 plays a critical role.
Elucidation of the integrin LFA-1–mediated signaling pathway of actin polarization in natural killer cells
Authors: Mace Emily M. , Zhang Jinyi , Siminovitch Katherine A. , Takei Fumio 
Published: May 2010

AbstractThe leukocyte integrin LFA-1 is critical for natural killer (NK) cell cytotoxicity as it mediates NK-cell adhesion to target cells and generates activating signals that lead to polarization of the actin cytoskeleton. However, the LFA-1–mediated signaling pathway is not fully understood. Here, we examined the subcellular localization of actin-associated proteins in wild-type, talin-deficient, and Wiskott-Aldrich Syndrome protein (WASP)–deficient NK cells bound to beads coated with the LFA-1 ligand intercellular adhesion molecule-1 (ICAM-1). In addition, we carried out coimmunoprecipitation analyses and also used a pharmacologic reagent to reduce the level of phosphatidylinositol-4,5-bisphosphate (PIP2). The results revealed the following signaling pathways. Upon ICAM-1 binding to LFA-1, talin redistributes to the site of LFA-1 ligation and initiates 2 signaling pathways. First, talin recruits the actin nucleating protein complex Arp2/3 via constitutive association of vinculin with talin and Arp2/3. Second, talin also associates with type I phosphatidylinositol 4-phosphate 5-kinase (PIPKI) and binding of LFA-1 to ICAM-1 results in localized increase in PIP2. This increase in PIP2 recruits WASP to the site of LFA-1 ligation where WASP promotes Arp2/3-mediated actin polymerization. These processes are critical for the initiation of NK cell–mediated cytotoxicity.
B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance
Authors: Park Jang-June , Omiya Ryusuke , Matsumura Yumiko , Sakoda Yukimi , Kuramasu Atsuo , Augustine Mathew M. , Yao Sheng , Tsushima Fumihiko , Narazaki Hidehiko , Anand Sudarshan , Liu Yingjia , Strome Scott E. , Chen Lieping , Tamada Koji 
Published: May 2010

AbstractT-cell tolerance is the central program that prevents harmful immune responses against self-antigens, in which inhibitory PD-1 signal given by B7-H1 interaction plays an important role. Recent studies demonstrated that B7-H1 binds CD80 besides PD-1, and B7-H1/CD80 interaction also delivers inhibitory signals in T cells. However, a role of B7-H1/CD80 signals in regulation of T-cell tolerance has yet to be explored. We report here that attenuation of B7-H1/CD80 signals by treatment with anti–B7-H1 monoclonal antibody, which specifically blocks B7-H1/CD80 but not B7-H1/PD-1, enhanced T-cell expansion and prevented T-cell anergy induction. In addition, B7-H1/CD80 blockade restored Ag responsiveness in the previously anergized T cells. Experiments using B7-H1 or CD80-deficient T cells indicated that an inhibitory signal through CD80, but not B7-H1, on T cells is responsible in part for these effects. Consistently, CD80 expression was detected on anergic T cells and further up-regulated when they were re-exposed to the antigen (Ag). Finally, blockade of B7-H1/CD80 interaction prevented oral tolerance induction and restored T-cell responsiveness to Ag previously tolerized by oral administration. Taken together, our findings demonstrate that the B7-H1/CD80 pathway is a crucial regulator in the induction and maintenance of T-cell tolerance.
The human collagen beta(1-O)galactosyltransferase, GLT25D1, is a soluble endoplasmic reticulum localized protein
Authors: Liefhebber Jolanda MP , Punt Simone , Spaan Willy JM , van Leeuwen Hans C 
Published: May 2010

Abstract

Background
Glycosyl transferases transfer glycosyl groups onto their substrate. Localization partially defines their function. Glycosyl transferase 25 domain 1 (GLT25D1) was recently shown to have galactosyltransferase activity towards collagens and another well known substrate, mannose binding lectin (MBL). To gain more insight in the role of galactosylation of lysines in the Gly-X-Lys repeats of collagenous proteins, we investigated the subcellular localization of GLT25D1.

Results
Immunofluorescence analysis of GLT25D1 expressed in the human hepatoma cell line (Huh7), revealed a perinuclear lattice like staining, resembling localization to the endoplasmic reticulum (ER). Possible targeting signals, an N-terminal signal sequence and a C-terminal ER-retention signal, were identified using prediction programs. These signals were then investigated by constructing a series of epitope-tagged forms of GLT25D1 that were analyzed by immunofluorescence and western blotting. In agreement with the predictions our results show that GLT25D1 is directed to the ER lumen as a soluble protein and retained there. Moreover, using two endoglycosidase enzymes EndoH and EndoF, we demonstrate that the putative bi-functional glycosyl transferase itself is a glycoprotein. Additionally we examined co-localization of GLT25D1 with MBL and lysyl hydroxylase 3 (LH3, PLOD3), which is a protein able to catalyze hydroxylation of lysine residues before they can be glycosylated. We demonstrate overlapping localization patterns of GLT25D1, MBL and LH3.

Conclusions
Taken together our data indicate that galactosylation of collagenous proteins by the soluble GLT25D1 occurs in the early secretory pathway.