bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer Stem Cells: Targets and Potential Biomarkers for Radiotherapy
Authors: Krause Mechthild , Yaromina Ala , Eicheler Wolfgang , Koch Ulrike , Baumann Michael 
Published: October 2011

Abstract
Cancer stem cells (CSC) have the unique ability to cause tumor recurrences if they survive treatment. Radiotherapy has curative potential because it has been functionally shown to sufficiently inactivate CSCs. It is well known that CSCs mediate the radiation resistance of tumors by tumor-specific factors, such as the pretreatment number of CSCs and repopulation or reoxygenation during fractionated radiotherapy. CSCs appear to have a higher intrinsic radioresistance than non-CSCs, a factor that is especially important for the development of predictive biomarkers that, if this finding holds true, can only be successfully established if they are stem-cell specific. Recent clinical data imply that stem-cell–related surface markers may be directly used as predictors for the radiocurability of tumors with comparable risk factors, such as histology and size. Future studies need to address the question of which additional markers need to be considered if more heterogeneous patient collectives are investigated. With the goal of developing a direct targeting approach, investigators are currently evaluating several drugs that are intended to target CSCs by inhibiting stem-cell–related signal transduction pathways. We need to preclinically test such drugs as combined-modality therapies in combination with radiotherapy to evaluate their curative potential, and optimize them by increasing their specificity to CSCs over normal tissue stem cells to avoid increased radiation toxicity. Clin Cancer Res; 17(23); 7224–9. ©2011 AACR.
Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma
Authors: Fruehauf John , Lutzky Jose , McDermott David , Brown Charles K. , Meric Jean-Baptiste , Rosbrook Brad , Shalinsky David R. , Liau Katherine F. , Niethammer Andreas G. , Kim Sinil , Rixe Olivier 
Published: October 2011

Abstract
Purpose: This multicenter, open-label, phase II study evaluated the safety and clinical activity of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR)–1, 2, and 3, in patients with metastatic melanoma.
Experimental Design: Thirty-two patients with a maximum of one prior systemic therapy received axitinib at a starting dose of 5 mg twice daily. The primary endpoint was objective response rate.
Results: Objective response rate was 18.8% [95% confidence interval (CI), 7.2–36.4], comprising one complete and five partial responses with a median response duration of 5.9 months (95% CI, 5.0–17.0). Stable disease at 16 weeks was noted in six patients (18.8%), with an overall clinical benefit rate of 37.5%. Six-month progression-free survival rate was 33.9%, 1-year overall survival rate was 28.1%, and median overall survival was 6.6 months (95% CI, 5.2–9.0). The most frequently (&gt;15%) reported nonhematologic, treatment-related adverse events were fatigue, hypertension, hoarseness, and diarrhea. Treatment-related fatal bowel perforation, a known class effect, occurred in one patient. Axitinib selectively decreased plasma concentrations of soluble VEGFR (sVEGFR)-2 and sVEGFR-3 compared with soluble stem cell factor receptor (sKIT). No significant association was noted between plasma levels of axitinib and response. However, post hoc analyses indicated potential relationships between efficacy endpoints and diastolic blood pressure of 90 mm Hg or higher as well as baseline serum lactate dehydrogenase levels.
Conclusions: Axitinib was well tolerated, showed a selective VEGFR-inhibitory profile, and showed single-agent activity in metastatic melanoma. Further evaluations of axitinib, alone and combined with chemotherapy, are ongoing. Clin Cancer Res; 17(23); 7462–9. ©2011 AACR.
Metadherin Promotes Hepatocellular Carcinoma Metastasis through Induction of Epithelial–Mesenchymal Transition
Authors: Zhu Kai , Dai Zhi , Pan Qi , Wang Zheng , Yang Guo-Huan , Yu Lei , Ding Zhen-Bin , Shi Guo-Ming , Ke Ai-Wu , Yang Xin-Rong , Tao Zhong-Hua , Zhao Yi-Ming , Qin Yi , Zeng Hai-Ying , Tang Zhao-You , Fan Jia , Zhou Jian 
Published: October 2011

Abstract
Purpose: To investigate the expression of metadherin (MTDH) for its prognostic value in hepatocellular carcinoma (HCC) and its role in promoting HCC metastasis.
Experimental Design: This study employed a tissue microarray containing samples from 323 HCC patients to examine the expression of MTDH and its correlation with other clinicopathologic characteristics. The role of MTDH in the regulation of HCC metastasis was investigated both in vitro and in vivo using short hairpin RNA (shRNA)–mediated downregulation of MTDH in HCC cell lines with various metastatic potentials.
Results: The expression of MTDH was markedly higher in HCC tumors than in normal liver tissue. Particularly high MTDH expression was observed in tumors with microvascular invasion, pathologic satellites, poor differentiation, or tumor-node-metastasis stages II to III. Furthermore, the clinical outcome was consistently poorer for the MTDHhigh group than for the MTDHlow group in the 1-, 3-, and 5-year overall survival (OS) rates and in the 1-, 3-, 5-year cumulative recurrence rates. In a nude mice model, the shRNA-mediated downregulation of MTDH resulted in a reduced migratory capacity in HCC cell lines, as well as a reduction in pulmonary and abdominal metastasis. Furthermore, we found that the expression level of MTDH correlated with four epithelial–mesenchymal transition (EMT) markers. Knockdown of MTDH expression in HCC cell lines resulted in downregulation of N-cadherin and snail, upregulation of E-cadherin, and translocation of β-catenin.
Conclusions: MTDH may promote HCC metastasis through the induction of EMT process and may be a candidate biomarker for prognosis as well as a target for therapy. Clin Cancer Res; 17(23); 7294–302. ©2011 AACR.
Heat Shock Protein 90 Inhibitor Is Synergistic with JAK2 Inhibitor and Overcomes Resistance to JAK2-TKI in Human Myeloproliferative Neoplasm Cells
Authors: Fiskus Warren , Verstovsek Srdan , Manshouri Taghi , Rao Rekha , Balusu Ramesh , Venkannagari Sreedhar , Rao Nalabothula Narasimha , Ha Kyungsoo , Smith Jacqueline E. , Hembruff Stacey L. , Abhyankar Sunil , McGuirk Joseph , Bhalla Kapil N. 
Published: October 2011

Abstract
Purpose: We determined the activity of hsp90 inhibitor, and/or Janus-activated kinase 2 (JAK2) tyrosine kinase inhibitor (TKI), against JAK2-V617F–expressing cultured mouse (Ba/F3-JAK2-V617F) and human (HEL92.1.7 and UKE-1) or primary human CD34+ myeloproliferative neoplasm (MPN) cells.
Experimental Design: Following exposure to the hsp90 inhibitor AUY922 and/or JAK2-TKI TG101209, the levels of JAK2-V617F, its downstream signaling proteins, as well as apoptosis were determined.
Results: Treatment with AUY922 induced proteasomal degradation and depletion of JAK2-V617F as well as attenuated the signaling proteins downstream of JAK2-V617F, that is, phospho (p)-STAT5, p-AKT, and p-ERK1/2. AUY922 treatment also induced apoptosis of HEL92.1.7, UKE-1, and Ba/F3-hJAK2-V617F cells. Combined treatment with AUY922 and TG101209 caused greater depletion of the signaling proteins than either agent alone and synergistically induced apoptosis of HEL92.1.7 and UKE-1 cells. Cotreatment with AUY922 and TG101209 also induced significantly more apoptosis of human CD34+ MPN than normal hematopoietic progenitor cells. As compared with the sensitive controls, JAK2-TKI–resistant HEL/TGR and UKE-1/TGR cells exhibited significantly higher IC50 values for JAK2-TKI (P &lt; 0.001), which was associated with higher expression of p-JAK2, p-STAT5, p-AKT, and Bcl-xL, but reduced levels of BIM. Unlike the sensitive controls, HEL/TGR and UKE/TGR cells were collaterally sensitive to the hsp90 inhibitors AUY922 and 17-AAG, accompanied by marked reduction in p-JAK2, p-STAT5, p-AKT, and Bcl-xL, with concomitant induction of BIM.
Conclusions: Findings presented here show that cotreatment with hsp90 inhibitor and JAK2-TKI exerts synergistic activity against cultured and primary MPN cells. In addition, treatment with hsp90 inhibitor may overcome resistance to JAK2-TKI in human MPN cells. Clin Cancer Res; 17(23); 7347–58. ©2011 AACR.
Novel Chromosomal Rearrangements and Break Points at the t(6;9) in Salivary Adenoid Cystic Carcinoma: Association with MYB–NFIB Chimeric Fusion, MYB Expression, and Clinical Outcome
Authors: Mitani Yoshitsugu , Rao Pulivarthi H. , Futreal P. Andrew , Roberts Dianna B. , Stephens Philip J. , Zhao Yi-Jue , Zhang Li , Mitani Mutsumi , Weber Randal S. , Lippman Scott M. , Caulin Carlos , El-Naggar Adel K. 
Published: October 2011

Abstract
Objective: To investigate the molecular genetic heterogeneity associated with the t(6:9) in adenoid cystic carcinoma (ACC) and correlate the findings with patient clinical outcome.
Experimental Design: Multimolecular and genetic techniques complemented with massive pair-ended sequencing and single-nucleotide polymorphism array analyses were used on tumor specimens from 30 new and 52 previously analyzed fusion transcript–negative ACCs by reverse transcriptase PCR (RT-PCR). MYB mRNA expression level was determined by quantitative RT-PCR. The results of 102 tumors (30 new and 72 previously reported cases) were correlated with the clinicopathologic factors and patients' survival.
Results: The FISH analysis showed 34 of 82 (41.5%) fusion-positive tumors and molecular techniques identified fusion transcripts in 21 of the 82 (25.6%) tumors. Detailed FISH analysis of 11 out the 15 tumors with gene fusion without transcript formation showed translocation of NFIB sequences to proximal or distal sites of the MYB gene. Massive pair-end sequencing of a subset of tumors confirmed the proximal translocation to an NFIB sequence and led to the identification of a new fusion gene (NFIB–AIG1) in one of the tumors. Overall, MYB–NFIB gene fusion rate by FISH was in 52.9% whereas fusion transcript forming incidence was 38.2%. Significant statistical association between the 5′ MYB transcript expression and patient survival was found.
Conclusions: We conclude that: (i) t(6;9) results in complex genetic and molecular alterations in ACC, (ii) MYB–NFIB gene fusion may not always be associated with chimeric transcript formation, (iii) noncanonical MYB–NFIB gene fusions occur in a subset of tumors, (iv) high MYB expression correlates with worse patient survival. Clin Cancer Res; 17(22); 7003–14. ©2011 AACR.
IL-6 Promotes Head and Neck Tumor Metastasis by Inducing Epithelial–Mesenchymal Transition via the JAK-STAT3-SNAIL Signaling Pathway
Authors: Yadav Arti , Kumar Bhavna , Datta Jharna , Teknos Theodoros N. , Kumar Pawan 
Published: October 2011

Abstract
Epithelial–mesenchymal transition (EMT) is a key process in tumor metastatic cascade that is characterized by the loss of cell–cell junctions and cell polarity, resulting in the acquisition of migratory and invasive properties. However, the precise molecular events that initiate this complex EMT process in head and neck cancers are poorly understood. Increasing evidence suggests that tumor microenvironment plays an important role in promoting EMT in tumor cells. We have previously shown that head and neck tumors exhibit significantly higher Bcl-2 expression in tumor-associated endothelial cells and overexpression of Bcl-2 alone in tumor-associated endothelial cells was sufficient to enhance tumor metastasis of oral squamous cell carcinoma in a severe combined immunodeficient (SCID) mouse model. In this study, we show that endothelial cells expressing Bcl-2 (EC-Bcl-2), when cocultured with head and neck tumor cells (CAL27), significantly enhance EMT-related changes in tumor cells predominantly by the secretion of IL-6. Treatment with recombinant IL-6 or stable IL-6 overexpression in CAL27 cells or immortalized oral epithelial cells (IOE) significantly induced the expression of mesenchymal marker, vimentin, while repressing E-cadherin expression via the JAK/STAT3/Snail signaling pathway. These EMT-related changes were further associated with enhanced tumor and IOE cell scattering and motility. STAT3 knockdown significantly reversed IL-6–mediated tumor and IOE cell motility by inhibiting FAK activation. Furthermore, tumor cells overexpressing IL-6 showed marked increase in lymph node and lung metastasis in a SCID mouse xenograft model. Taken together, these results show a novel function for IL-6 in mediating EMT in head and neck tumor cells and increasing their metastatic potential. Mol Cancer Res; 9(12); 1658–67. ©2011 AACR.
Role of protein S and tissue factor pathway inhibitor in the development of activated protein C resistance early in pregnancy in women with a history of preeclampsia
Authors: Thomassen M. Christella , Costa Serban-Dan , Peeters Louis , Rosing Jan , Tchaikovski Svetlana 
Published: October 2011

SummaryPregnancy increases the risk of venous thromboembolism. Particularly in early pregnancy, the thrombosis risk can be attributed to the changes in coagulation. Elevated thrombin generation and resistance to activated protein C (APC) are likely to contribute to the increased thrombosis risk during pregnancy. We studied changes and the determinants of thrombin generation and APC resistance in the first 16 weeks of gestation in women with history of preeclampsia. Additionally, we investigated the influence of pregnancy-induced haemodilution on the coagulation system. We measured thrombin generation, APC resistance and plasma levels of prothrombin, factor V, factor X, protein S and tissue factor pathway inhibitor (TFPI) in 30 non-pregnant and 21 pregnant women at 8, 12 and 16 weeks of gestation. All participants shared a history of a hypertensive complication in the preceding pregnancy. Thrombin generation and APC resistance were higher at eight weeks of pregnancy than in the non-pregnant state, and progressively increased between eight and 16 weeks of gestation. Changes in the TFPI and protein S levels accounted for ~70% of pregnancy-induced APC resistance. Interestingly, a significant correlation (slope 2.23; 95%CI: 1.56 to 2.91; r= 0.58) was observed between protein Stotal or protein Sfree levels and haematocrit. In conclusion, pregnancy induces a decrease of TFPIfree and protein Sfree levels that attenuates the function of the TFPI and protein C systems and results in elevated thrombin generation and increased APC resistance. Besides, our data suggest that pregnancy-dependent haemodilution may contribute to the decreased peripheral protein S levels.
Primary Teacher Conceptions of Giftedness: Image, Evidence, and Nonevidence
Authors: Rohrer Jane C. 
Published: October 2011

This qualitative multisite single case study is designed to explore the conception of giftedness held by four experienced teachers. These teachers were from three school districts piloting the Early Assessment for Exceptional Potential portfolio assessment model (Shaklee, Barbour, Ambrose, Viechnicki, & Rohrer, 1991). Teacher interviews triangulated by multiple secondary sources were analyzed to answer the research question guiding the study: How do primary teachers conceptualize giftedness in young children! Findings revealed that the four teachers shared a similar image of giftedness. This conception had two dimensions: classroom performance and affective style of the students. Teachers assessed children developmentally against their peers for extremely unusual intellectual and/or academic ability as demonstrated by what children said and did, and a “spark, ” or qualitative difference in these children characterized by intensity, high visibility, and/or uniqueness. Four strands of evidence created the teachers' image of child potential.
A cost analysis of specialist inpatient neurorehabilitation services in the UK
Authors: Turner-Stokes Lynne , Bill Alan , Dredge Robert 
Published: October 2011

Objective: To determine the range and variation in costs and service characteristics between different levels of specialist neurorehabilitation services in England, and to determine key predictors of service costs. Design: A retrospective analysis of service costs, staffing and activity levels, with comparison across service types. Setting: Specialist neurorehabilitation services ( n = 17) from different areas of England, were divided into three types according to predefined criteria: adult level 1 (tertiary) ( n = 8) and level 2a (supra-district) ( n = 7) services; and children’s services ( n = 2). Main measures: Annual service costs were collated using a standard costing template, and divided according to principal cost type (direct/indirect/overheads) and behaviour (variable/non-variable). For comparison between the level 1 and 2a services, costs and service characteristics were calculated per occupied bed. Results: The percentage breakdown of costs was consistent across all three service types, with direct costs making up 83%, indirect 10%, and overheads 7% of total costs. The median variable component ranged from 75 to 76%. Staff pay made up 66% and accounted for 95% of the variance of the total costs in adult services. Level 1 services had higher total staffing costs, mainly reflecting higher therapy staff numbers ( z = –2.0, P = 0.05). The median total costs/bed-day were: level 1 £530 (interquartile range (IQR) 435–574) (equivalent to US$860 or €650) and level 2a £402 (US$650 or €459) (IQR 326–451) ( z = –2.5, P = 0.009). Children’s services cost almost twice that (£1017–1177). Conclusions: Expected variations in cost are largely due to differences in staff costs. Total staff costs projected by 150% provided a reasonable estimate of total unit costs.
Systematic back muscle exercise after percutaneous vertebroplasty for spinal osteoporotic compression fracture patients: a randomized controlled trial
Authors: Chen Bai-Ling , Zhong Yi , Huang Yang-Liang , Zeng Li-Wen , Li Yi-Qiang , Yang Xiao-Xi , Jiang Qin , Wang Chu-Huai 
Published: October 2011

Objective: To analyze the clinical significance of postoperative back muscle exercises after percutaneous vertebroplasty for spinal osteoporotic compression fracture patients. Design: Clinical randomized controlled trials of parallel group nonpharmacologic study. Setting: Patients practised back muscle exercises in the spinal surgery department, rehabilitation department and at their residences. Subjects: Osteoporotic compression fracture patients who had undergone percutaneous vertebroplasty and processed sufficient muscle strength to participate in the training were studied. Interventions: Patients were randomized into two groups, which were titled A and B. General postoperation therapy, including antiosteoporotic medications and education, was offered to all patients. Group B patients received additional systematic back muscle exercise. Main measures: Both Oswestry Disability Index (ODI) and visual analogue scale (VAS) were recorded preoperatively and postoperatively at three-day, one-month, six-month, one-year and two-year follow-up. Results: From January 2006 to January 2009, a total of 82 patients were assessed for eligibility, 60 patients were enrolled and randomized into two groups. Forty-two (70%) patients (20 of 30 in Group A and 22 of 30 in Group B) were successfully followed-up for two years. Systematic back muscle exercises resulted in a significant advantage in both measurements. The ODI of Group B was significantly better than Group A at the six-month, one-year and two-year follow-ups ( P < 0.05). The pain level of Group B was significantly lower than in Group A at the one- and two-year follow-ups ( P < 0.05). At the end of our study, the mean (SD) of the ODI in Groups A and B were 39.1 (9.14) and 23.4 (5.62); the mean (SD) of the VAS in Groups A and B were 3.4 (1.15) and 2.1 (0.84), respectively. Conclusions: Our findings suggest that the benefit of the exercises required at least six months to be observed; however, the favourable effects could last for two years. Therefore, systematic back muscle exercise should be recommended as one of the treatment guidelines for postpercutaneous vertebroplasty patients.
Patient and Surgeon Characteristics Associated With Primary Anterior Cruciate Ligament Reconstruction Graft Selection
Authors: Inacio Maria C.S. , Paxton Elizabeth W. , Maletis Gregory B. , Csintalan Rick P. , Granan Lars-Petter , Fithian Donald C. , Funahashi Tadashi T. 
Published: October 2011

Background: It has been suggested that a surgeon’s experience and training are the most important factors associated with graft selection, but no studies have qualified this association. Graft usage prevalence has not been described for large anterior cruciate ligament reconstruction (ACLR) populations in the United States. Purpose: To describe the prevalence of graft usage in a large community-based practice and evaluate the association of patient, surgeon, and site characteristics with choice of primary ACLR graft. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Primary ACLRs performed between February 2005 and June 2010 were selected for the study. A community-based ligament registry was used to identify cases and variables used for analysis. Graft choice (any allograft, hamstring autograft, and bone–patellar tendon–bone [BPTB] autograft) was compared by patient characteristics and surgeon and site characteristics. Associations between independent variables and graft choice were evaluated using a polychotomous regression model. Results: Of the 9849 patients included in the study, 64% were male, and overall median age was 28 years. Of these, 2796 (28.4%) received BPTB autografts, 3013 (30.6%) received hamstring autografts, and 4040 (41.0%) received allografts. The prevalence of graft source by patients’ gender, race, age, body mass index (BMI), as well as surgeons’ fellowship training status, average volume, and site volume were significantly different (all P < .001). Adjusted models showed that patients’ gender ( P < .001), race ( P = .018), age ( P < .001), BMI ( P < .001), as well as surgeons’ fellowship training status ( P < .001), average volume ( P < .001), and site volume ( P < .001) are associated with graft selection. Older and female patients with lower BMI were more likely to receive allografts and hamstring autografts than BPTB autografts. Cases performed by non–fellowship-trained surgeons, lower volume sites, and/or lower volume surgeons were also more likely to be performed with allografts or hamstring autografts than BPTB autografts. Conclusion: Gender, age, race, as well as facility and surgeon characteristics such as volume and location are associated with ACL graft choices.