bluuebunny/crossref_metadata_2025_split huggingface dataset:
TheNeisseria meningitidisCapsule Is Important for Intracellular Survival in Human Cells
Authors: Spinosa Maria Rita , Progida Cinzia , Talà Adelfia , Cogli Laura , Alifano Pietro , Bucci Cecilia 
Published: May 2007

ABSTRACTWhile much data exist in the literature about howNeisseria meningitidisadheres to and invades human cells, its behavior inside the host cell is largely unknown. One of the essential meningococcal attributes for pathogenesis is the polysaccharide capsule, which has been shown to be important for bacterial survival in extracellular fluids. To investigate the role of the meningococcal capsule in intracellular survival, we used B1940, a serogroup B strain, and its isogenic derivatives, which lack either the capsule or both the capsule and the lipooligosaccharide outer core, to infect human phagocytic and nonphagocytic cells and monitor invasion and intracellular growth. Our data indicate that the capsule, which negatively affects bacterial adhesion and, consequently, entry, is, in contrast, fundamental for the intracellular survival of this microorganism. The results of in vitro assays suggest that an increased resistance to cationic antimicrobial peptides (CAMPs), important components of the host innate defense system against microbial infections, is a possible mechanism by which the capsule protects the meningococci in the intracellular environment. Indeed, unencapsulated bacteria were more susceptible than encapsulated bacteria to defensins, cathelicidins, protegrins, and polymyxin B, which has long been used as a model compound to define the mechanism of action of CAMPs. We also demonstrate that both the capsular genes (siaDandlipA) and those encoding an efflux pump involved in resistance to CAMPs (mtrCDE) were up-regulated during the intracellular phase of the infectious cycle.
Perceived barriers to walking in the neighbourhood environment and change in physical activity levels over 12 months
Authors: Dawson Jill , Hillsdon Melvyn , Boller Irene , Foster Charlie 
Published: May 2007

Objectives:To investigate whether, and to what extent, perceived barriers to neighbourhood walking (BTNW) may be associated with physical activity levels.Design:Prospective survey with 12-month follow-up.Subjects and methods:750 people attending walking schemes throughout England and Scotland; 551 completed the follow-up. independent variables were demographic characteristics, examples of possible “external” barriers to walking—for example, “worries about personal safety”, and one item concerning ill health. The main outcome measures were “metabolic equivalent” (MET) hours’ walking and overall physical activity in the preceding week.Results:Baseline and follow-up demographic characteristics were similar and physical activity levels generally high. Leisure walking changed little over 12 months, while total physical activity levels reduced significantly from a mean (SD) of 71.26 (78.14) MET hours per week at baseline to 59.57 (181.40) at the 12-month follow-up (p<0.001). External BTNW cited between baseline and 12 months increased significantly from a mean (SD) of 1.24 (1.61) at baseline to 1.43 (1.72) at the 12-month follow-up (p<0.001); only “worries about personal safety” reduced. A significant association was found between citing a health-related BTNW and the total number of external BTNW that were reported at baseline. The strength of this association increased over 12 months. Neither changes in reporting external BTNW that occurred over 12 months (increased vs decreased, vs unchanged) nor changes in the presence of a health-related BTNW were significantly related to levels of leisure walking and overall physical activity (MET hours in the preceding week) over the same period.Conclusion:Among older people who attended walking schemes, having a health problem that restricted walking had a detrimental influence on people’s perceptions about external BTNW, which increased over time. Actual levels of walking and overall physical activity levels did not appear to be significantly affected by this.
Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor
Authors: Norden-Zfoni Anat , Desai Jayesh , Manola Judith , Beaudry Paul , Force Jeremy , Maki Robert , Folkman Judah , Bello Carlo , Baum Charles , DePrimo Sam E. , Shalinsky David R. , Demetri Goerge D. , Heymach John V. 
Published: May 2007

Abstract
Purpose: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors.
Experimental Design: Patients (n = 73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of &gt;6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC).
Results: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus −−0.01 CEC/μL/d, P = 0.03) and smaller decreases in monocyte levels (47% versus 60%, P = 0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment.
Conclusions: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.
A Phase 1 Study of Pralatrexate in Combination with Paclitaxel or Docetaxel in Patients with Advanced Solid Tumors
Authors: Azzoli Christopher G. , Krug Lee M. , Gomez Jorge , Miller Vincent A. , Kris Mark G. , Ginsberg Michelle S. , Henry Roxanne , Jones Jessica , Tyson Leslie , Dunne Megan , Pizzo Barbara , Farmer Amy , Venkatraman Ennapadam , Steffen Robert , Sirotnak F.M. 
Published: May 2007

Abstract
Purpose: Pralatrexate is a rationally designed antifolate with greater preclinical antitumor activity than methotrexate. Pralatrexate was synergistic with paclitaxel and with docetaxel in mouse xenograft experiments. This phase 1 study was designed to determine the maximum tolerated dose and toxicity of pralatrexate plus paclitaxel or docetaxel in patients with advanced cancer.
Experimental Design: Pralatrexate was administered i.v. every 2 weeks (days 1 and 15) in a 4-week cycle. Depending on the taxane used and dose being tested, the taxane was administered on days 1 and 15; days 2 and 16; or days 1, 8, and 15. In the latter part of the study, patients in the docetaxel arm were treated with vitamin B12 and folic acid supplementation to mitigate toxicity and allow pralatrexate dose escalation.
Results: For the combination of pralatrexate plus paclitaxel without vitamin supplementation, dose-limiting stomatitis and peripheral neuropathy were encountered at the lowest dose levels tested. For pralatrexate plus docetaxel plus vitamin supplementation, pralatrexate 120 mg/m2 plus docetaxel 35 mg/m2 administered on the same day every other week was defined as the maximum tolerated dose and schedule, with dose-limiting toxicities at higher dose combinations including stomatitis and asthenia. Significant antitumor activity was observed for this combination in patients with non–small-cell lung cancer.
Conclusions: Pralatrexate (120 mg/m2) plus docetaxel (35 mg/m2) plus vitamin supplementation is well tolerated with signs of efficacy against non–small-cell lung cancer that merit phase 2 testing.
Prognostic Relevance of Clinical and Biological Risk Factors in Childhood Medulloblastoma: Results of Patients Treated in the Prospective Multicenter Trial HIT'91
Authors: Rutkowski Stefan , von Bueren André , von Hoff Katja , Hartmann Wolfgang , Shalaby Tarek , Deinlein Frank , Warmuth-Metz Monika , Soerensen Niels , Emser Angela , Bode Udo , Mittler Uwe , Urban Christian , Benesch Martin , Kortmann Rolf D. , Schlegel Paul G. , Kuehl Joachim , Pietsch Torsten , Grotzer Michael 
Published: May 2007

Abstract
Purpose: To identify better risk stratification systems in childhood medulloblastoma based on clinical factors and analysis of routinely processed formalin-fixed tumor material.
Experimental Design: Formalin-fixed paraffin-embedded tumor samples from well-documented patients treated within the prospective randomized multicenter trial HIT'91 were analyzed for DNA amplification of c-myc and N-myc (n = 133) and mRNA expression of c-myc and trkC (n = 104; compared with human cerebellum) using validated methods of quantitative PCR and reverse transcription-PCR. Results were related to clinical data and outcome.
Results: TrkC and c-myc mRNA expression were identified as independent prognostic factors by multivariate analysis. Three risk groups were identified. (a) Favorable risk group: all 8 patients (2 metastatic) with high trkC (&gt;1× human cerebellum) and low c-myc mRNA expression (≤1× human cerebellum) remained relapse-free [7-year event-free survival (EFS), 100%]. (b) Poor risk group: 10 of 15 patients with metastatic disease and high c-myc and low trkC mRNA expression relapsed (7-year EFS, 33%). (c) Intermediate risk group: the 7-year EFS of the remaining 78 patients was 65%. Among 47 M0 stage patients, all 10 patients with high trkC mRNA expression remained relapse-free compared with 15 events in 37 patients with low trkC mRNA expression levels (7-year EFS, 100% versus 62%; P = 0.056).
Conclusions: Whereas the collection of fresh-frozen tumor samples remains a major challenge in large clinical trials, routinely processed paraffin-embedded tissue samples can be used to quantitate the prognostic biological markers trkC and c-myc. On prospective validation of cutoff levels, this may lead to improved stratification of treatment for children with medulloblastoma.
Clinical Significance of CD99 Down-Regulation in Gastric Adenocarcinoma
Authors: Lee Jung Hyun , Kim Seok-Hyung , Wang Li-Hui , Choi Yoon-La , Kim Young Chul , Kim Jin Hee , Park Tae Sung , Hong Yun-Chul , Shin Young Kee 
Published: May 2007

AbstractPurpose: CD99 is a cell adhesion molecule associated with human tumors. The aim of the present study was to characterize its role in the development and progression of human gastric adenocarcinoma.Experimental Design: The expression of CD99 was investigated in 283 gastric adenocarcinomas and related lesions and 9 gastric carcinoma cell lines. We also analyzed the methylation status of CD99 gene by using methylation-specific PCR and examined loss of heterozygosity (LOH) of this gene locus by using an intragenic marker. Moreover, we assessed whether SP1, a positive transcription factor for CD99, is expressed in these samples.Results: We found that the decreased expression of CD99 was strongly associated with poor survival and unfavorable clinicopathologic variables. Promoter region methylation (15 of 89, 16.9%) and LOH (21 of 74, 28.4%) were observed and significantly associated with CD99 down-regulation (P &lt; 0.05). In addition, most of the gastric adenocarcinoma cases with CD99 down-regulation had reduced expression of SP1 (47 of 103, 45.6%; P &lt; 0.01). This relationship between CD99 and SP1 was consolidated by using SP1 small interfering RNA transfection experiment and CD99 promoter luciferase assay. Furthermore, we showed that CD99 down-regulation was associated with proliferation and migration in gastric carcinoma cell line.Conclusion: These observations suggest that CD99 down-regulation is a critical event in the progression of gastric adenocarcinoma, and CD99 promoter methylation, CD99 LOH, and SP1 down-regulation were responsible for the down-regulation of CD99.
c-Myc–Induced Chemosensitization Is Mediated by Suppression of Cyclin D1 Expression and Nuclear Factor-κB Activity in Pancreatic Cancer Cells
Authors: Biliran Hector , Banerjee Sanjeev , Thakur Archana , Sarkar Fazlul H. , Bollig Aliccia , Ahmed Fakhara , Wu Jiusheng , Sun Yuan , Liao Joshua D. 
Published: May 2007

AbstractPurpose: Pancreatic cancer is a highly aggressive disease that remains refractory to various chemotherapeutic agents. Because the proto-oncogene c-myc can modulate apoptosis in response to cytotoxic insults and is commonly overexpressed in pancreatic cancer, we investigated the value of c-myc as a potential modulator of cellular response to various chemotherapeutic agents.Experimental Design: Stable overexpression or small interfering RNA (siRNA)–mediated knockdown of c-myc and restoration of cyclin D1 were done in the Ela-myc pancreatic tumor cell line. Cell viability after cisplatin treatment of c-myc–overexpressing, control, and siRNA-transfected cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and drug-induced apoptosis was measured by DNA fragmentation, sub-G1, and poly(ADP-ribose) polymerase cleavage analyses. Protein expression profile after cisplatin treatment was determined by Western blotting and DNA binding activity of nuclear factor-κB was examined by electrophoretic mobility shift assay.Results: Ectopic overexpression of c-myc in murine and human pancreatic cancer cell lines, Ela-myc and L3.6pl, respectively, resulted in increased sensitivity to cisplatin and other chemotherapeutic drugs. Increased sensitivity to cisplatin in c-myc–overexpressing cells was due, in part, to the marked increase in cisplatin-induced apoptosis. Conversely, down-regulation of c-myc expression in stable c-myc–overexpressing cells by c-myc siRNA resulted in decreased sensitivity to cisplatin-induced cell death. These results indicate an important role of c-myc in chemosensitivity of pancreatic cancer cells. The c-myc–induced cisplatin sensitivity correlated with inhibition of nuclear factor κB activity, which was partially restored by ectopic cyclin D1 overexpression.Conclusions: Our results suggest that the c-myc–dependent sensitization to chemotherapy-induced apoptosis involves suppression of cyclin D1 expression and nuclear factor κB activity.
Implication of the Insulin-like Growth Factor-IR Pathway in the Resistance of Non–small Cell Lung Cancer Cells to Treatment with Gefitinib
Authors: Morgillo Floriana , Kim Woo-Young , Kim Edward S. , Ciardiello Fortunato , Hong Waun Ki , Lee Ho-Young 
Published: May 2007

AbstractPurpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been found to be effective against lung cancer in vitro, but clinical resistance to these agents has developed as their usage has increased. In this study, we determined whether the insulin-like growth factor I (IGF-I) signaling pathway induces resistance of non–small cell lung cancer (NSCLC) cells to the EGFR tyrosine kinase inhibitor gefitinib.Experimental Design: The effects of gefitinib and cetuximab on NSCLC cells, alone or with an IGF-I receptor (IGF-IR) inhibitor, were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the flow cytometry–based terminal nucleotidyl transferase–mediated nick end labeling assay, coimmunoprecipitation, and Western blot analysis. EGFR and IGFR expression in NSCLC tissues were examined by Western blot analysis.Results: Gefitinib inhibited NSCLC cell proliferation by inducing apoptosis when IGF-IR signaling was suppressed. Treatment with gefitinib, but not cetuximab, induced EGFR:IGF-IR heterodimerization and activation of IGF-IR and its downstream signaling mediators, resulting in increased survivin expression in NSCLC cell lines with high levels of IGF-IR expression. Inhibition of IGF-IR activation and knockdown of survivin expression led to increased apoptosis. In contrast, overexpression of survivin protected cells with low IGF-IR expression from gefitinib-induced apoptosis. Most NSCLC tissues with EGFR overexpression had associated high levels of IGF-IR expression.Conclusions: IGF-IR expression may be useful as a predictive marker for gefitinib treatment of NSCLC. Suppression of IGF-IR signaling pathways may prevent or delay development of gefitinib resistance in patients with NSCLC.
The Unfolded Protein Response and Integrated Stress Response to Anoxia
Authors: Rzymski Tomasz , Harris Adrian L. 
Published: May 2007

Abstract
The lack of oxygen delivery to tumor cells has profound consequences for tumor growth and correlates with poor prognosis. Some tumors contain regions of very severe hypoxia called anoxia, which constitutes a functionally different state to hypoxia. In response to anoxia, mammalian cells induce coordinated cytoprotective programs that are critical for tumor survival: the unfolded protein response and integrated stress response. Therefore, targeting additional components of anoxic pathways, besides the hypoxia-inducible response, may be effective for future anticancer therapies.
Collagen XXIII Expression Is Associated with Prostate Cancer Recurrence and Distant Metastases
Authors: Banyard Jacqueline , Bao Lere , Hofer Matthias D. , Zurakowski David , Spivey Kristin A. , Feldman Adam S. , Hutchinson Lloyd M. , Kuefer Rainer , Rubin Mark A. , Zetter Bruce R. 
Published: May 2007

Abstract
Purpose: We had previously identified a new transmembrane collagen, type XXIII, in metastatic rat prostate carcinoma cells. The purpose of this study was to determine the expression of collagen XXIII in human prostate cancer and investigate its relationship with disease progression.
Experimental Design: We investigated collagen XXIII expression in prostate cancer tissue and did a retrospective analysis of association with prostate-specific antigen (PSA)–defined disease recurrence. The presence of collagen XXIII in prostate cancer patient urine was also assessed before and after prostatectomy.
Results: Collagen XXIII protein was detected at very low levels in benign prostate tissue and was significantly increased in prostate cancer. Distant metastases exhibited significantly higher collagen XXIII levels compared with either localized prostate cancer or regional (lymph node) metastases. Patients with high collagen XXIII levels had a 2.8-fold higher risk of PSA failure with median time to failure of 8.1 months, compared with low collagen XXIII patients with a median time to failure of 5 years. Multivariate Cox regression showed that the presence of collagen XXIII was significantly associated with time to PSA recurrence, independent of other clinical variables. Collagen XXIII was also detected in prostate cancer patient urine, with reduced levels after prostatectomy, indicating potential as a noninvasive fluid biomarker.
Conclusions: We present the first report demonstrating increased collagen XXIII expression in prostate cancer tissue. We show that collagen XXIII level is a significant independent predictor of PSA-defined disease recurrence, suggesting a potential role as a molecular biomarker of prostate cancer progression and metastasis.
Pulsed-High Intensity Focused Ultrasound and Low Temperature–Sensitive Liposomes for Enhanced Targeted Drug Delivery and Antitumor Effect
Authors: Dromi Sergio , Frenkel Victor , Luk Alfred , Traughber Bryan , Angstadt Mary , Bur Monica , Poff Jason , Xie Jianwu , Libutti Steven K. , Li King C.P. , Wood Bradford J. 
Published: May 2007

Abstract
Purpose: To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors.
Experimental Design: Comparisons in vitro and in vivo were carried out between non–thermosensitive liposomes (NTSL) and low temperature–sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors.
Results: In vitro incubations simulating the pulsed-HIFU thermal dose (42°C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups.
Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.
T-Cell Distribution and Adhesion Receptor Expression in Metastatic Melanoma
Authors: Weishaupt Carsten , Munoz Karla N. , Buzney Elizabeth , Kupper Thomas S. , Fuhlbrigge Robert C. 
Published: May 2007

Abstract
Purpose: Metastatic malignant melanoma is a devastating disease with a poor prognosis. Recent therapeutic trials have focused on immunotherapy to induce development of endogenous antitumor immune responses. To date, such protocols have shown success in activation of tumor-specific CTL but no overall improvement in survival. To kill tumor, antigen-specific CTL must efficiently target and enter tumor tissue. The purpose of this study was to examine the pathway of leukocyte migration to metastatic melanoma.
Experimental design: Peripheral blood and metastatic melanoma tissues (n = 65) were evaluated for expression of adhesion molecules using immunohistochemistry of tumor sections and flow cytometry of tumor-associated and peripheral blood CTL and compared with healthy controls. CTL expressing T-cell receptors for the melanoma antigen MART-1 were identified in a subset of samples by reactivity with HLA-A2 tetramers loaded with MART-1 peptide.
Results: Results show that the majority of metastatic melanoma samples examined do not express the vascular adhesion receptors E-selectin (CD62E), P-selectin (CD62P), and intercellular adhesion molecule-1 (CD54) on vessels within the tumor boundaries. Strong adhesion receptor expression was noted on vessels within adjacent tissue. Tumor-associated T lymphocytes accumulate preferentially in these adjacent areas and are not enriched for skin- or lymph node–homing receptor phenotype.
Conclusion: Expression of leukocyte homing receptors is dysregulated on the vasculature of metastatic melanoma. This results in a block to recruitment of activated tumor-specific CTL to melanoma metastases and is a likely factor limiting the effectiveness of current immunotherapy protocols.