bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncogenic NRAS, Required for Pathogenesis of Embryonic Rhabdomyosarcoma, Relies upon the HMGA2–IGF2BP2 Pathway
Authors: Li Zhizhong , Zhang Yunyu , Ramanujan Krishnan , Ma Yan , Kirsch David G. , Glass David J. 
Published: March 2013

Abstract
Embryonic rhabdomyosarcoma (ERMS) is the most common soft-tissue tumor in children. Here, we report the identification of the minor groove DNA-binding factor high mobility group AT-hook 2 (HMGA2) as a driver of ERMS development. HMGA2 was highly expressed in normal myoblasts and ERMS cells, where its expression was essential to maintain cell proliferation, survival in vitro, and tumor outgrowth in vivo. Mechanistic investigations revealed that upregulation of the insulin–like growth factor (IGF) mRNA-binding protein IGF2BP2 was critical for HMGA2 action. In particular, IGF2BP2 was essential for mRNA and protein stability of NRAS, a frequently mutated gene in ERMS. shRNA-mediated attenuation of NRAS or pharmacologic inhibition of the MAP–ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) effector pathway showed that NRAS and NRAS-mediated signaling was required for tumor maintenance. Taken together, these findings implicate the HMGA2–IGFBP2–NRAS signaling pathway as a critical oncogenic driver in ERMS. Cancer Res; 73(10); 3041–50. ©2013 AACR.
The 19th Annual Prostate Cancer Foundation Scientific Retreat
Authors: Walia Guneet , Pienta Kenneth J. , Simons Jonathan W. , Soule Howard R. 
Published: March 2013

Abstract
Prostate Cancer Foundation (PCF) convened its 19th Annual Scientific Retreat October 25–27, 2012, in Carlsbad, CA. Each year, this event brings together diverse researchers in a collaborative forum to present and discuss new and largely unpublished findings for prostate cancer diagnosis, prognosis, and treatment and defines the challenges to ending this disease as a threat to life and well-being. Several themes resonated at the multidisciplinary meeting, notably (i) the roles of field cancerization, tumor microenvironment, epithelial plasticity, signal transduction pathways in cancer progression, and disease resistance; (ii) intratumoral heterogeneity and consequences for precision medicine; (iii) resistance mechanisms to androgen axis inhibitors; and (iv) advances in molecular imaging and therapeutics for better detection and treatment. Cancer Res; 73(16); 4988–91. ©2013 AACR.
Cancer Survivors in the United States: Prevalence across the Survivorship Trajectory and Implications for Care
Authors: de Moor Janet S. , Mariotto Angela B. , Parry Carla , Alfano Catherine M. , Padgett Lynne , Kent Erin E. , Forsythe Laura , Scoppa Steve , Hachey Mark , Rowland Julia H. 
Published: March 2013

Abstract
Background: Cancer survivors represent a growing population, heterogeneous in their need for medical care, psychosocial support, and practical assistance. To inform survivorship research and practice, this manuscript will describe the prevalent population of cancer survivors in terms of overall numbers and prevalence by cancer site and time since diagnosis.
Methods: Incidence and survival data from 1975–2007 were obtained from the Surveillance, Epidemiology, and End Results Program and population projections from the United States Census Bureau. Cancer prevalence for 2012 and beyond was estimated using the Prevalence Incidence Approach Model, assuming constant future incidence and survival trends but dynamic projections of the U.S. population.
Results: As of January 1, 2012, approximately 13.7 million cancer survivors were living in the United States with prevalence projected to approach 18 million by 2022. Sixty-four percent of this population have survived 5 years or more; 40% have survived 10 years or more; and 15% have survived 20 years or more after diagnosis. Over the next decade, the number of people who have lived 5 years or more after their cancer diagnosis is projected to increase approximately 37% to 11.9 million.
Conclusions: A coordinated agenda for research and practice is needed to address cancer survivors' long-term medical, psychosocial, and practical needs across the survivorship trajectory.
Impact: Prevalence estimates for cancer survivors across the survivorship trajectory will inform the national research agenda as well as future projections about the health service needs of this population. Cancer Epidemiol Biomarkers Prev; 22(4); 561–70. ©2013 AACR.
Phase I Trial, Pharmacokinetics, and Pharmacodynamics of Vandetanib and Dasatinib in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma
Authors: Broniscer Alberto , Baker Sharyn D. , Wetmore Cynthia , Pai Panandiker Atmaram S. , Huang Jie , Davidoff Andrew M. , Onar-Thomas Arzu , Panetta John C. , Chin Thomas K. , Merchant Thomas E. , Baker Justin N. , Kaste Sue C. , Gajjar Amar , Stewart Clinton F. 
Published: March 2013

Abstract
Purpose: Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.
Experimental Design: Dasatinib was started concurrently with radiotherapy. Vandetanib was started 8 days later. We tested increasing doses of vandetanib (65 and 85 mg/m2 once daily) and dasatinib (65 and 85 mg/m2 twice daily). Dose-limiting toxicities were evaluated during the first 6 weeks of therapy. Plasma pharmacokinetics was obtained on days 8 and 42 ± 3 in all patients and concomitantly with cerebrospinal fluid (CSF) when possible. Inhibition of targets of dasatinib in peripheral blood mononuclear cells (PBMC) was evaluated.
Results: Twenty-five patients were treated. Treatment was well tolerated. The median duration of treatment was 184 days. Diarrhea was the most significant toxicity. Three patients experienced substantial myelosuppression. The steady-state plasma pharmacokinetics of vandetanib was comparable with previous studies. Although the plasma exposure to dasatinib decreased from days 8 to 42, it remained similar to adult studies. CSF to plasma exposure of vandetanib and dasatinib were approximately 2% in 2 patients. Phosphorylated 70S6K decreased during therapy in PBMCs.
Conclusions: The MTD of vandetanib and dasatinib in combination was 65 mg/m2 for each drug. Other studies are underway to test dasatinib and other PDGFR inhibitors alone or in combination for this deadly cancer. Clin Cancer Res; 19(11); 3050–8. ©2013 AACR.
The Novel Chk1 Inhibitor MK-8776 Sensitizes Human Leukemia Cells to HDAC Inhibitors by Targeting the Intra-S Checkpoint and DNA Replication and Repair
Authors: Dai Yun , Chen Shuang , Kmieciak Maciej , Zhou Liang , Lin Hui , Pei Xin-Yan , Grant Steven 
Published: March 2013

Abstract
Interactions between the novel Chk1 inhibitor MK-8776 and the histone deacetylase (HDAC) inhibitor (HDACI) vorinostat were examined in human leukemia cells harboring wild-type (wt) or deficient p53. MK-8776 synergistically potentiated vorinostat-mediated apoptosis in various p53-wt or -deficient leukemia cell lines, whereas p53 knockdown by short hairpin RNA (shRNA) sensitized p53-wt cells to lethality of this regimen. Leukemia cell lines carrying FLT3-ITD were also sensitive to the MK-8776/vorinostat regimen. Synergistic interactions were associated with inhibition of Chk1 activity, interference with the intra-S-phase checkpoint, disruption of DNA replication, and downregulation of proteins involved in DNA replication (e.g., Cdt1) and repair (e.g., CtIP and BRCA1), resulting in sharp increases in DNA damage, reflected by enhanced γ-H2A.X formation, and apoptosis. Moreover, leukemia cells expressing kinase-dead Chk1 (D130A) or Chk1 shRNA were significantly more sensitive to HDACIs compared with their wt counterparts and displayed downregulation of CtIP and BRCA1 phosphorylation following HDACI exposure. Finally, the MK-8776/vorinostat regimen was active in primary acute myelogenous leukemia (AML) blasts, particularly against the CD34+/CD38−/CD123+ population enriched for leukemia-initiating cells. In contrast, identical regimens were relatively sparing toward normal cord blood CD34+ cells. Together, these findings indicate that the novel Chk1 inhibitor MK-8776 markedly potentiates HDACI lethality in leukemia cells displaying various genetic backgrounds through mechanisms involving disruption of the intra-S checkpoint, DNA replication, and DNA repair. They also argue that leukemic cells, including those bearing oncogenic mutations associated with poor prognosis, for example, p53 deletion/mutation or FLT3-ITD, may also be susceptible to this strategy. Mol Cancer Ther; 12(6); 878–89. ©2013 AACR.
Potential Advantages of CUDC-101, a Multitargeted HDAC, EGFR, and HER2 Inhibitor, in Treating Drug Resistance and Preventing Cancer Cell Migration and Invasion
Authors: Wang Jing , Pursell Natalie W. , Samson Maria Elena S. , Atoyan Ruzanna , Ma Anna W. , Selmi Abdelkader , Xu Wanlu , Cai Xiong , Voi Maurizio , Savagner Pierre , Lai Cheng-Jung 
Published: March 2013

Abstract
CUDC-101 is a novel, small-molecule, anticancer agent targeting histone deacetylase (HDAC), EGF receptor (EGFR), and HER2. It is currently in phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent antiproliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET- and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non–small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration. Mol Cancer Ther; 12(6); 925–36. ©2013 AACR.
Profiling Bortezomib Resistance Identifies Secondary Therapies in a Mouse Myeloma Model
Authors: Stessman Holly A.F. , Baughn Linda B. , Sarver Aaron , Xia Tian , Deshpande Raamesh , Mansoor Aatif , Walsh Susan A. , Sunderland John J. , Dolloff Nathan G. , Linden Michael A. , Zhan Fenghuang , Janz Siegfried , Myers Chad L. , Van Ness Brian G. 
Published: March 2013

Abstract
Multiple myeloma is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. Although the first-to-market proteasome inhibitor bortezomib (Velcade) has been successfully used to treat patients with myeloma, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive (BzS) and bortezomib-resistant (BzR) cell lines created from the Bcl-XL/Myc double-transgenic mouse model of multiple myeloma. Notably, these BzR cell lines show cross-resistance to the next-generation proteasome inhibitors, MLN2238 and carfilzomib (Kyprolis) but not to other antimyeloma drugs. We further characterized the response to bortezomib using the Connectivity Map database, revealing a differential response between these cell lines to histone deacetylase (HDAC) inhibitors. Furthermore, in vivo experiments using the HDAC inhibitor panobinostat confirmed that the predicted responder showed increased sensitivity to HDAC inhibitors in the BzR line. These findings show that GEP may be used to document bortezomib resistance in myeloma cells and predict individual sensitivity to other drug classes. Finally, these data reveal complex heterogeneity within multiple myeloma and suggest that resistance to one drug class reprograms resistant clones for increased sensitivity to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy for patients with multiple myeloma. Mol Cancer Ther; 12(6); 1140–50. ©2013 AACR.
Antithrombotic therapy in obesity
Authors: Hernández Vera Rodrigo , Padró Teresa , Vilahur Gemma , Badimon Lina 
Published: March 2013

summaryClinical management of obese subjects to reduce their risk of suffering cardiovascular events is complex. Obese patients typically require preventive strategies, life-style modifications, and multi-drug therapy to address obesity-induced co-morbidities. Data regarding the effects of excess weight on the pharmacokinetics of most drugs is scarce as these individuals are often excluded from clinical trials. However, the physiological alterations observed in obese patients and their lower response to some antiplatelet agents and anticoagulants have suggested that dosage regimes need to be adjusted for these subjects. In this review we will briefly discuss platelet alterations that can contributeto increased thrombotic risk, analyse existing data regarding the effects of obesity on drug pharmacokinetics focusing on antiplatelet agents and anticoagulants, and we will describe the beneficial effects of weight loss on thrombosis.
Nonculprit Coronary Plaque Characteristics of Chronic Kidney Disease
Authors: Kato Koji , Yonetsu Taishi , Jia Haibo , Abtahian Farhad , Vergallo Rocco , Hu Sining , Tian Jinwei , Kim Soo-Joong , Lee Hang , McNulty Iris , Lee Stephen , Uemura Shiro , Jang Yangsoo , Park Seung-Jung , Mizuno Kyoichi , Yu Bo , Jang Ik-Kyung 
Published: March 2013

Background—
Chronic kidney disease (CKD) promotes the development of atherosclerosis and increases the risk of cardiovascular disease. The aim of the present study was to compare the coronary plaque characteristics of patients with and without CKD using optical coherence tomography.

Methods and Results—

We identified 463 nonculprit plaques from 287 patients from the Massachusetts General Hospital (MGH) optical coherence tomography registry. CKD was defined as estimated glomerular filtration rate <60 mL/min per 1.73 m
2
. A total of 402 plaques (250 patients) were in the non-CKD group and 61 plaques (37 patients) were in the CKD group. Compared with non-CKD plaques, plaques with CKD had a larger lipid index (mean lipid arc×lipid length, 1248.4±782.8 mm° [non-CKD] versus 1716.1±1116.2 mm° [CKD];
P
=0.003). Fibrous cap thickness was not significantly different between the groups. Calcification (34.8% [non-CKD] versus 50.8% [CKD];
P
=0.041), cholesterol crystals (11.2% [non-CKD] versus 23.0% [CKD];
P
=0.048), and plaque disruption (5.5% [non-CKD] versus 13.1% [CKD];
P
=0.049) were more frequently observed in the CKD group. In the multivariate linear regression model, a lower estimated glomerular filtration rate and diabetes mellitus were independent risk factors for a larger lipid index.

Conclusions—
Compared with non-CKD patients, the patients with CKD had a larger lipid index with a higher prevalence of calcium, cholesterol crystals, and plaque disruption. The multivariate linear regression model demonstrated that a lower estimated glomerular filtration rate was an independent risk factor for a larger lipid index.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01110538.
Risk Factors for Multiple Malignancies in the Head and Neck
Authors: Deganello Alberto , Gitti Gianni , Mannelli Giuditta , Meccariello Giuseppe , Gallo Oreste 
Published: March 2013

ObjectiveTo define the prognostic role of multiple epidemiological, clinical, and biological factors for the development of multiple malignancies (MM) in patients with head and neck cancer (HNC).Study DesignHistorical cohort study. p53 gene status, microsatellite instability (MSI) of the index tumor, and inherited chromosome fragility (CF) were studied.SettingNinety‐six consecutive patients affected by primary HNC, between January 1987 and October 1991, who were eligible for curative radiation therapy were followed up.Subjects and Methodsp53 gene status, MSI, and CF in 96 curative radiotherapy‐treated patients were correlated with the risk for MM.ResultsMultiple malignancies occurred in 28.9%. Microsatellite instability (P = 0.05), CF (P < 0.01), and smoking after treatment of the index tumor (P = 0.02) were correlated with an increased risk of MM.ConclusionGenetic susceptibility may play a central role for MM development in patients with HNC.
Considerations for Initial Dosing of Botulinum Toxin in Treatment of Adductor Spasmodic Dysphonia
Authors: Rosow David E. , Parikh Punam , Vivero Richard J. , Casiano Roy R. , Lundy Donna S. 
Published: March 2013

ObjectivesTo assess the effect on voice improvement and duration of breathiness based on initial dose of onabotulinum toxin A (BTX‐A) in the management of adductor spasmodic dysphonia (SD) and to compare voice outcomes for initial bilaterally injected doses of 1.25 units (group A) vs 2.5 units (group B) of BTX‐A.Study DesignCase series with chart review of patients with adductor SD treated at a tertiary care facility from 1990 to 2011.SettingAcademic subspecialty laryngology practice.MethodsDemographic data (age and sex), voice rating, duration of voice improvement, and breathiness were evaluated and compared between groups A and B using the Student t test and χ2 analysis.ResultsOf 478 patients identified, 305 (223 in group A, 82 in group B) patients met inclusion criteria. The average age was 56.2 years in group A and 57.4 years in group B (P =. 5). The female to male ratio was 2.91 for group A vs 3.56 for group B (P =. 61). Good voice outcomes (grade 3 or 4) were reported by 91% of group A patients vs 94% of group B (P =. 75). The average duration of voice improvement was 99.7 days for group A and 108.3 days for group B (P =. 54). The average duration of breathiness was 10.88 days for group A vs 15.42 days for group B (P =. 02).ConclusionPatients injected with 1.25 units bilaterally had a statistically significant shorter duration of breathiness without a statistically significant difference in clinical effectiveness or voice outcome. It is therefore recommended that a relatively low initial BTX‐A dose be used with subsequent titration to achieve improved voice outcomes.
Perception of Pure Tones and Iterated Rippled Noise for Normal Hearing and Cochlear Implant Users
Authors: Penninger Richard T. , Chien Wade W. , Jiradejvong Patpong , Boeke Emily , Carver Courtney L. , Limb Charles J. 
Published: March 2013

Cochlear Implant (CI) users typically perform poorly on musical tasks, especially those based on pitch ranking and melody recognition. It was hypothesized that CI users would demonstrate deterioration in performance for a pitch ranking and a melody recognition task presented with iterated rippled noise (IRN) in comparison to pure tones (PT). In Addition, it was hypothesized that normal hearing (NH) listeners would show fewer differences in performance between IRN and PT for these two tasks. In this study, the ability of CI users and NH subjects to rank pitches and to identify melodies created with IRN and PT was assessed in free field in a sound-isolated room. CI subjects scored significantly above chance level with PT stimuli in both tasks. With IRN stimuli their performance was around chance level. NH subjects scored significantly above chance level in both tasks and with all stimuli. NH subjects performed significantly better than CI subjects in both tasks. These results illustrate the difficulties of CI subjects to rank pitches and to identify melodies.
CD133 expression is not an independent prognostic factor in stage II and III colorectal cancer but may predict the better outcome in patients with adjuvant therapy
Authors: Mia-Jan Khalilullah , Jung So Young , Kim Ik-Yong , Oh Sung Soo , Choi EunHee , Chang Sei Jin , Kang Tae Young , Cho Mee-Yon 
Published: March 2013

AbstractBackgroundCancer stem cells (CSCs) are notorious for their capacity of tumor progression, metastasis or resistance to chemo-radiotherapy. However, the undisputed role of cancer stem marker, CD133, in colorectal cancers (CRCs) is not clear yet.MethodsWe assessed 271 surgically-resected stage II and III primary CRCs with (171) and without (100) adjuvant therapy after surgery. CD133 expression was analyzed by immunohistochemical (IHC) staining and real-time RT-PCR. CD133 promoter methylation was quantified by pyrosequencing.ResultsThe CD133 IHC expression was significantly correlated with mRNA expression (p=0.0257) and inversely correlated with the promoter methylation (p=0.0001). CD133 was expressed more frequently in rectal cancer (p=0.0035), and in moderately differentiated tumors (p=0.0378). In survival analysis, CD133 expression was not significantly correlated with overall survival (OS) (p=0.9689) as well as disease-free survival (DFS) (p=0.2103). However, CD133+ tumors were significantly associated with better OS in patients with adjuvant therapy compared to those without adjuvant therapy (p<0.0001, HR 0.125, 95% CI 0.052-0.299). But the patients with CD133- tumors did not show any significant difference of survival according to adjuvant therapy (p=0.055, HR 0.500, 95% CI 0.247-1.015).ConclusionsIn stage II and III CRCs, CD133 IHC expression may signify the benefit for adjuvant therapy although it is not an independent prognostic factor.
Low-dose endotoxin inhalation in healthy volunteers - a challenge model for early clinical drug development
Authors: Janssen Ole , Schaumann Frank , Holz Olaf , Lavae-Mokhtari Bianca , Welker Lutz , Winkler Carla , Biller Heike , Krug Norbert , Hohlfeld Jens M 
Published: March 2013

Abstract

Background
Inhalation of endotoxin (LPS) induces a predominantly neutrophilic airway inflammation and has been used as model to test the anti-inflammatory activity of novel drugs. In the past, a dose exceeding 15–50 μg was generally needed to induce a sufficient inflammatory response. For human studies, regulatory authorities in some countries now request the use of GMP-grade LPS, which is of limited availability. It was therefore the aim of this study to test the effect and reproducibility of a low-dose LPS challenge (20,000 E.U.; 2 μg) using a flow- and volume-controlled inhalation technique to increase LPS deposition.

Methods
Two to four weeks after a baseline sputum induction, 12 non-smoking healthy volunteers inhaled LPS on three occasions, separated by at least 4 weeks. To modulate the inflammatory effect of LPS, a 5-day PDE4 inhibitor (Roflumilast) treatment preceded the last challenge. Six hours after each LPS inhalation, sputum induction was performed.

Results
The low-dose LPS inhalation was well tolerated and increased the mean percentage of sputum neutrophils from 25% to 72%. After the second LPS challenge, 62% neutrophils and an increased percentage of monocytes were observed. The LPS induced influx of neutrophils and the cumulative inflammatory response compared with baseline were reproducible. Treatment with Roflumilast for 5 days did not have a significant effect on sputum composition.

Conclusion
The controlled inhalation of 2 μg GMP-grade LPS is sufficient to induce a significant neutrophilic airway inflammation in healthy volunteers. Repeated low-dose LPS challenges potentially result in a small shift of the neutrophil/monocyte ratio; however, the cumulative response is reproducible, enabling the use of this model for “proof-of-concept” studies for anti-inflammatory compounds during early drug development.

Trial registration
Clinicaltrials.gov: NCT01400568