bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stress-Related Signaling Pathways in Lethal and Nonlethal Prostate Cancer
Authors: Lu Donghao , Sinnott Jennifer A. , Valdimarsdóttir Unnur , Fang Fang , Gerke Travis , Tyekucheva Svitlana , Fiorentino Michelangelo , Lambe Mats , Sesso Howard D. , Sweeney Christopher J. , Wilson Kathryn M. , Giovannucci Edward L. , Loda Massimo , Mucci Lorelei A. , Fall Katja 
Published: October 2015

Abstract
Purpose: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and nonlethal disease.
Experimental Design: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n = 150; n = 82 with normal) and the Health Professionals Follow-Up Study (n = 254; n = 120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome and to biomarkers as secondary outcomes.
Results: Differential mRNA expression of genes within the adrenergic (P = 0.001), glucocorticoid (P &lt; 0.0001), serotoninergic (P = 0.0019), and muscarinic (P = 0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (P = 0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and nonlethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion.
Conclusions: Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies. Clin Cancer Res; 22(3); 765–72. ©2015 AACR.
Fluorescent Image–Guided Surgery with an Anti-Prostate Stem Cell Antigen (PSCA) Diabody Enables Targeted Resection of Mouse Prostate Cancer Xenografts in Real Time
Authors: Sonn Geoffrey A. , Behesnilian Andrew S. , Jiang Ziyue Karen , Zettlitz Kirstin A. , Lepin Eric J. , Bentolila Laurent A. , Knowles Scott M. , Lawrence Daniel , Wu Anna M. , Reiter Robert E. 
Published: October 2015

Abstract
Purpose: The inability to visualize cancer during prostatectomy contributes to positive margins, cancer recurrence, and surgical side effects. A molecularly targeted fluorescent probe offers the potential for real-time intraoperative imaging. The goal of this study was to develop a probe for image-guided prostate cancer surgery.
Experimental Design: An antibody fragment (cys-diabody, cDb) against prostate stem cell antigen (PSCA) was conjugated to a far-red fluorophore, Cy5. The integrity and binding of the probe to PSCA was confirmed by gel electrophoresis, size exclusion, and flow cytometry, respectively. Subcutaneous models of PSCA-expressing xenografts were used to assess the biodistribution and in vivo kinetics, whereas an invasive intramuscular model was utilized to explore the performance of Cy5-cDb–mediated fluorescence guidance in representative surgical scenarios. Finally, a prospective, randomized study comparing surgical resection with and without fluorescent guidance was performed to determine whether this probe could reduce the incidence of positive margins.
Results: Cy5-cDb demonstrated excellent purity, stability, and specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 6 hours. In mice carrying PSCA+ and negative (−) dual xenografts, the mean fluorescence ratio of PSCA+/− tumors was 4.4:1. In surgical resection experiments, residual tumors &lt;1 mm that were missed on white light surgery were identified and resected using fluorescence guidance, which reduced the incidence of positive surgical margins (0/8) compared with white light surgery alone (7/7).
Conclusions: Fluorescently labeled cDb enables real-time in vivo imaging of prostate cancer xenografts in mice, and facilitates more complete tumor removal than conventional white light surgery alone. Clin Cancer Res; 22(6); 1403–12. ©2015 AACR.
See related commentary by van Leeuwen and van der Poel, p. 1304
Prognostic Utility of Molecular Factors by Age at Diagnosis of Colorectal Cancer
Authors: McCleary Nadine J. , Sato Kaori , Nishihara Reiko , Inamura Kentaro , Morikawa Teppei , Zhang Xuehong , Wu Kana , Yamauchi Mai , Kim Sun A. , Sukawa Yasutaka , Mima Kosuke , Qian Zhi Rong , Fuchs Charles S. , Ogino Shuji , Meyerhardt Jeffrey A. 
Published: October 2015

Abstract
Purpose: We hypothesized that adverse prognostic associations of specific tumor molecular factors vary by patient age at colorectal cancer diagnosis.
Experimental Design: We examined the prognostic associations and interactions by age at colorectal cancer diagnosis (&lt;60 vs. 60–74 vs. ≥75 years old) of key molecular factors—CpG island methylator phenotype (CIMP), microsatellite instability (MSI), KRAS, BRAF, and PIK3CA mutations, and nuclear CTNNB1 expression status—on colorectal cancer–specific survival (CSS) and overall survival (OS), using 1,280 incident colorectal cancer cases (median age, 69 years; range, 38–91 years) within the Nurses' Health Study and Health Professionals Follow-up Study cohorts.
Results: MSI-high was associated with better survival, whereas BRAF mutation was associated with worse survival, but these associations did not appreciably differ by age group. Status of CIMP, KRAS mutation, or PIK3CA mutation was not associated with prognosis regardless of age. Nuclear CTNNB1 expression was associated with a trend toward worse prognosis among older adults [age ≥ 75 years; multivariate HR, 1.67; 95% confidence interval (CI), 0.89–3.13 (for CSS); multivariate HR, 1.44; 95% CI, 0.93–2.24 (for OS)] but not among younger patients, and there was a statistically significant interaction by age (Pinteraction = 0.03 for CSS; Pinteraction = 0.007 for OS).
Conclusions: Tumor nuclear CTNNB1 expression may be associated with higher mortality among older patients with colorectal cancer but not among younger patients. Our findings need to be confirmed in independent datasets. Detailed exploration of tumor molecular signatures in older patients with colorectal cancer in large populations is warranted. Clin Cancer Res; 22(6); 1489–98. ©2015 AACR.
Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination
Authors: Jackson Christopher M. , Kochel Christina M. , Nirschl Christopher J. , Durham Nicholas M. , Ruzevick Jacob , Alme Angela , Francica Brian J. , Elias Jimmy , Daniels Andrew , Dubensky Thomas W. , Lauer Peter , Brockstedt Dirk G. , Baxi Emily G. , Calabresi Peter A. , Taube Janis M. , Pardo Carlos A. , Brem Henry , Pardoll Drew M. , Lim Michael , Drake Charles G. 
Published: October 2015

AbstractPurpose: Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown.Experimental Design: The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor–bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model.Results: CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFβ; however, blocking TGFβ signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen–specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFβ secretion from microglia.Conclusions: These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in contemporary melanoma models as well as human trials. Clin Cancer Res; 22(5); 1161–72. ©2015 AACR.
In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma
Authors: Lussey-Lepoutre Charlotte , Bellucci Alexandre , Morin Aurélie , Buffet Alexandre , Amar Laurence , Janin Maxime , Ottolenghi Chris , Zinzindohoué Franck , Autret Gwennhael , Burnichon Nelly , Robidel Estelle , Banting Benjamin , Fontaine Sébastien , Cuenod Charles-André , Benit Paule , Rustin Pierre , Halimi Philippe , Fournier Laure , Gimenez-Roqueplo Anne-Paule , Favier Judith , Tavitian Bertrand 
Published: October 2015

Abstract
Purpose: Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy.
Experimental Design: A pulsed proton magnetic resonance spectroscopy (1H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb−/− or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n = 5) or not (n = 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors.
Results: A succinate peak was observed at 2.44 ppm by 1H-MRS in all Sdhb−/−-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, 1H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene.
Conclusions: Detection of succinate by 1H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This noninvasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. ©2015 AACR.
Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer
Authors: Świerniak Michał , Wójcicka Anna , Czetwertyńska Małgorzata , Długosińska Joanna , Stachlewska Elżbieta , Gierlikowski Wojciech , Kot Adam , Górnicka Barbara , Koperski Łukasz , Bogdańska Magdalena , Wiechno Wiesław , Jażdżewski Krystian 
Published: October 2015

Abstract
Purpose: Five germline genetic variants (rs116909374, rs965513, rs944289, rs966423, and rs2439302) have been associated in genome-wide association studies (GWAS) with increased risk of differentiated thyroid cancer (DTC), but their role in mortality of patients has not been established. Also, no preoperative marker of the clinical outcome of thyroid cancer had yet been identified. The aim of the study was to investigate the relationship between the variants and overall mortality in patients with DTC.
Experimental Design: Retrospective study of 1,836 patients (1,643 women, 193 men) with median age at diagnosis of 49 years and overall median follow-up time of 8.7 years after initial treatment at a single comprehensive cancer center between 1990 and 2013.
Results: Among 5 variants, rs966423 was associated with increased mortality, which was 6.4% (33 of 518) versus 3.7% (47 of 1,259) in TT carriers versus CC/CT carriers (P = 0.017). The HR of TT versus TC/CC carriers was 1.6 [95% confidence interval (CI), 1.02–2.49; P = 0.038] after adjustment for age at diagnosis and sex. Importantly, the association of rs966423 with mortality remained valid when clinicopathologic risk factors were included in the model (HR, 1.89; 95% CI, 1.14–3.13; P = 0.014). Higher rs966423–associated patient mortality of TT versus CC/CT carriers was also observed in interaction with angioinvasion (adjusted HR, 3.48; 95% CI, 1.67–7.22; P &lt; 0.001), lymph node metastasis (adjusted HR, 3.47; 95% CI, 1.16–10.4; P = 0.018), extrathyroidal invasion (adjusted HR, 2.07; 95% CI, 1.15–3.73; P = 0.013).
Conclusions: The presence of the rs966423-TT genotype was associated with a significant increase in overall mortality of patients with DTC. Contrary to BRAF mutation and other somatic changes, the status of germline rs966423 is known before the treatment and might be used in the management of mortality risk by means of modification of therapy. Clin Cancer Res; 22(5); 1111–9. ©2015 AACR.
Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma
Authors: Devlin Jennifer R. , Hannan Katherine M. , Hein Nadine , Cullinane Carleen , Kusnadi Eric , Ng Pui Yee , George Amee J. , Shortt Jake , Bywater Megan J. , Poortinga Gretchen , Sanij Elaine , Kang Jian , Drygin Denis , O'Brien Sean , Johnstone Ricky W. , McArthur Grant A. , Hannan Ross D. , Pearson Richard B. 
Published: October 2015

Abstract
Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I–mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K–AKT–mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma–bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies.
Significance: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma–bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1); 59–70. ©2015 AACR.
This article is highlighted in the In This Issue feature, p. 1
JAK-2 V617F mutation increases heparanase procoagulant activity
Authors: Kogan Inna , Chap Dafna , Hoffman Ron , Axelman Elena , Brenner Benjamin , Nadir Yona 
Published: October 2015

SummaryPatients with polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are at increased risk of arterial and venous thrombosis. In patients with ET a positive correlation was observed between JAK-2 V617F mutation, that facilitates erythropoietin receptor signalling, and thrombotic events, although the mechanism involved is not clear. We previously demonstrated that heparanase protein forms a complex and enhances the activity of the blood coagulation initiator tissue factor (TF) which leads to increased factor Xa production and subsequent activation of the coagulation system. The present study was aimed to evaluate heparanase procoagulant activity in myeloproliferative neoplasms. Forty bone marrow biopsies of patients with ET, PV, PMF and chronic myelogenous leukaemia (CML) were immunostained to heparanase, TF and TF pathway inhibitor (TFPI). Erythropoietin receptor positive cell lines U87 human glioma and MCF-7 human breast carcinoma were studied. Heparanase and TFPI staining were more prominent in ET, PV and PMF compared to CML. The strongest staining was in JAK-2 positive ET biopsies. Heparanase level and procoagulant activity were higher in U87 cells transfected to over express JAK-2 V617F mutation compared to control and the effect was reversed using JAK-2 inhibitors (Ruxolitinib, VZ3) and hydroxyurea, although the latter drug did not inhibit JAK-2 phosphorylation. Erythropoietin increased while JAK-2 inhibitors decreased the heparanase level and procoagulant activity in U87 and MCF-7 parental cells. In conclusion, JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor. The present findings may potentially point to a new mechanism of thrombosis in JAK-2 positive ET patients.
Zinc promotes clot stability by accelerating clot formation and modifying fibrin structure
Authors: Henderson Sara J. , Xia Jing , Wu Huayin , Stafford Alan R. , Leslie Beverly A. , Fredenburgh James C. , Weitz David A. , Weitz Jeffrey I. 
Published: October 2015

SummaryZinc released from activated platelets binds fibrin(ogen) and attenuates fibrinolysis. Although zinc also affects clot formation, the mechanism and consequences are poorly understood. To address these gaps, the effect of zinc on clot formation and structure was examined in the absence or presence of factor (F) XIII. Zinc accelerated a) plasma clotting by 1.4-fold, b) fibrinogen clotting by 3.5- and 2.3-fold in the absence or presence of FXIII, respectively, c) fragment X clotting by 1.3-fold, and d) polymerisation of fibrin monomers generated with thrombin or batroxobin by 2.5– and 1.8-fold, respectively. Whereas absorbance increased up to 3.3-fold when fibrinogen was clotted in the presence of zinc, absorbance of fragment X clots was unaffected by zinc, consistent with reports that zinc binds to the αC-domain of fibrin(ogen). Scanning electron microscopic analysis revealed a twofold increase in fibre diameter in the presence of zinc and in permeability studies, zinc increased clot porosity by 30-fold with or without FXIII. Whereas FXIII increased clot stiffness from 128 ± 19 Pa to 415 ± 27 Pa in rheological analyses, zinc reduced clot stiffness by 10– and 8.5-fold in the absence and presence of FXIII, respectively. Clots formed in the presence of zinc were more stable and resisted rupture with or without FXIII. Therefore, zinc accelerates clotting and reduces fibrin clot stiffness in a FXIII-independent manner, suggesting that zinc may work in concert with FXIII to modulate clot strength and stability.
Opening doors to participation of youth with physical disabilities: An intervention study
Authors: Anaby Dana R. , Law Mary C. , Majnemer Annette , Feldman Debbie 
Published: October 2015

Background. While participation in leisure activities is beneficial to youth’s health, little is known about effective intervention strategies to promote participation. Purpose. The aim of this study was to examine the effectiveness of environment-based interventions on participation of youth with physical disabilities. Method. Six adolescents ages 14 to 17 years participated in a 12-week intervention aimed at removing environmental barriers and coaching parents. An interrupted time series design was employed and a systematic replication of the intervention effect was examined across three individualized participation goals and across participants (17 goals overall). Goal performance was measured repeatedly using the Canadian Occupational Performance Measure and analyzed using visual inspection and a celeration line approach. Findings. A clinically significant improvement in performance scores ( M = 4.5, SD = 1.77) was observed across all 17 goals, and a statistically significant treatment effect was replicated in 13 goals (76%). Implications. Findings support the effectiveness of environment-based interventions in promoting youth participation, but larger studies are required.
The Effects of Cell Phone and Text Message Conversations on Simulated Street Crossing
Authors: Banducci Sarah E. , Ward Nathan , Gaspar John G. , Schab Kurt R. , Crowell James A. , Kaczmarski Henry , Kramer Arthur F. 
Published: October 2015

Objective: A fully immersive, high-fidelity street-crossing simulator was used to examine the effects of texting on pedestrian street-crossing performance. Background: Research suggests that street-crossing performance is impaired when pedestrians engage in cell phone conversations. Less is known about the impact of texting on street-crossing performance. Method: Thirty-two young adults completed three distraction conditions in a simulated street-crossing task: no distraction, phone conversation, and texting. A hands-free headset and a mounted tablet were used to conduct the phone and texting conversations, respectively. Participants moved through the virtual environment via a manual treadmill, allowing them to select crossing gaps and change their gait. Results: During the phone conversation and texting conditions, participants had fewer successful crossings and took longer to initiate crossing. Furthermore, in the texting condition, smaller percentage of time with head orientation toward the tablet, fewer number of head orientations toward the tablet, and greater percentage of total characters typed before initiating crossing predicted greater crossing success. Conclusion: Our results suggest that (a) texting is as unsafe as phone conversations for street-crossing performance and (b) when subjects completed most of the texting task before initiating crossing, they were more likely to make it safely across the street. Application: Sending and receiving text messages negatively impact a range of real-world behaviors. These results may inform personal and policy decisions.