bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intragenic Rearrangement and Altered RNA Splicing of the Androgen Receptor in a Cell-Based Model of Prostate Cancer Progression
Authors: Li Yingming , Alsagabi Majid , Fan Danhua , Bova G. Steven , Tewfik Ahmed H. , Dehm Scott M. 
Published: January 2011

AbstractAndrogen depletion for advanced prostate cancer (PCa) targets activity of the androgen receptor (AR), a steroid receptor transcription factor required for PCa growth. The emergence of lethal castration-resistant PCa (CRPCa) is marked by aberrant reactivation of the AR despite ongoing androgen depletion. Recently, alternative splicing has been described as a mechanism giving rise to COOH-terminally truncated, constitutively active AR isoforms that can support the CRPCa phenotype. However, the pathologic origin of these truncated AR isoforms is unknown. The goal of this study was to investigate alterations in AR expression arising in a cell-based model of PCa progression driven by truncated AR isoform activity. We show that stable, high-level expression of truncated AR isoforms in 22Rv1 CRPCa cells is associated with intragenic rearrangement of an approximately 35-kb AR genomic segment harboring a cluster of previously described alternative AR exons. Analysis of genomic data from clinical specimens indicated that related AR intragenic copy number alterations occurred in CRPCa in the context of AR amplification. Cloning of the break fusion junction in 22Rv1 cells revealed long interspersed nuclear elements (LINE-1) flanking the rearranged segment and a DNA repair signature consistent with microhomology-mediated, break-induced replication. This rearrangement served as a marker for the emergence of a rare subpopulation of CRPCa cells expressing high levels of truncated AR isoforms during PCa progression in vitro. Together, these data provide the first report of AR intragenic rearrangements in CRPCa and an association with pathologic expression of truncated AR isoforms in a cell-based model of PCa progression. Cancer Res; 71(6); 2108–17. ©2011 AACR.
Genome-Wide Analysis of Alternative Splicing in Medulloblastoma Identifies Splicing Patterns Characteristic of Normal Cerebellar Development
Authors: Menghi Francesca , Jacques Thomas S. , Barenco Martino , Schwalbe Ed C. , Clifford Steven C. , Hubank Mike , Ham Jonathan 
Published: January 2011

Abstract
Alternative splicing is an important mechanism for the generation of protein diversity at a post-transcriptional level. Modifications in the splicing patterns of several genes have been shown to contribute to the malignant transformation of different tissue types. In this study, we used the Affymetrix Exon arrays to investigate patterns of differential splicing between pediatric medulloblastomas and normal cerebellum on a genome-wide scale. Of the 1,262 genes identified as potentially generating tumor-associated splice forms, we selected 14 examples of differential splicing of known cassette exons and successfully validated 11 of them by reverse transcriptase PCR. The pattern of differential splicing of three validated events was characteristic for the molecular subset of sonic hedgehog (Shh)-driven medulloblastomas, suggesting that their unique gene signature includes the expression of distinctive transcript variants. Generally, we observed that tumor and normal fetal cerebellar samples shared significantly lower exon inclusion rates than normal adult cerebellum. We investigated whether tumor-associated splice forms were expressed in primary cultures of Shh-dependent mouse cerebellar granule cell precursors (GCP) and found that Shh caused a decrease in the cassette exon inclusion rate of five of the seven tested genes. Furthermore, we observed a significant increase in exon inclusion between postnatal days 7 and 14 of mouse cerebellar development, at the time when GCPs mature into postmitotic neurons. We conclude that inappropriate splicing frequently occurs in human medulloblastomas and may be linked to the activation of developmental signaling pathways and a failure of cerebellar precursor cells to differentiate. Cancer Res; 71(6); 2045–55. ©2011 AACR.
Zyxin Is a Critical Regulator of the Apoptotic HIPK2-p53 Signaling Axis
Authors: Crone Johanna , Glas Carolina , Schultheiss Kathrin , Moehlenbrink Jutta , Krieghoff-Henning Eva , Hofmann Thomas G. 
Published: January 2011

Abstract
HIPK2 activates the apoptotic arm of the DNA damage response by phosphorylating tumor suppressor p53 at serine 46. Unstressed cells keep HIPK2 levels low through targeted polyubiquitination and subsequent proteasomal degradation. Here we identify the LIM domain protein Zyxin as a novel regulator of the HIPK2-p53 signaling axis in response to DNA damage. Remarkably, depletion of endogenous Zyxin, which colocalizes with HIPK2 at the cytoskeleton and in the cell nucleus, stimulates proteasome-dependent HIPK2 degradation. In contrast, ectopic expression of Zyxin stabilizes HIPK2, even upon enforced expression of its ubiquitin ligase Siah-1. Consistently, Zyxin physically interacts with Siah-1, and knock-down of Siah-1 rescues HIPK2 expression in Zyxin-depleted cancer cells. Mechanistically, our data suggest that Zyxin regulates Siah-1 activity through interference with Siah-1 dimerization. Furthermore, we show that endogenous Zyxin coaccumulates with HIPK2 in response to DNA damage in cancer cells, and that depletion of endogenous Zyxin results in reduced HIPK2 protein levels and compromises DNA damage-induced p53 Ser46 phosphorylation and caspase activation. These findings suggest an unforeseen role for Zyxin in DNA damage-induced cell fate control through modulating the HIPK2-p53 signaling axis. Cancer Res; 71(6); 2350–9. ©2011 AACR.
Rebiopsy of Lung Cancer Patients with Acquired Resistance to EGFR Inhibitors and Enhanced Detection of the T790M Mutation Using a Locked Nucleic Acid-Based Assay
Authors: Arcila Maria E. , Oxnard Geoffrey R. , Nafa Khedoudja , Riely Gregory J. , Solomon Stephen B. , Zakowski Maureen F. , Kris Mark G. , Pao William , Miller Vincent A. , Ladanyi Marc 
Published: January 2011

Abstract
Background: The epidermal growth factor receptor (EGFR) mutation T790M is reported in approximately 50% of lung cancers with acquired resistance to EGFR inhibitors and is a potential prognostic and predictive biomarker. Its assessment can be challenging due to limited tissue availability and underdetection at low mutant allele levels. Here, we sought to determine the feasibility of tumor rebiopsy and to more accurately assess the prevalence of the T790M using a highly sensitive locked nucleic acid (LNA) PCR/sequencing assay. MET amplification was also analyzed.
Methods: Patients with acquired resistance were rebiopsied and samples were studied for sensitizing EGFR mutations. Positive cases were evaluated for T790M using standard PCR-based methods and a subset were re-evaluated with an LNA-PCR/sequencing method with an analytical sensitivity of approximately 0.1%. MET amplification was assessed by FISH.
Results: Of 121 patients undergoing tissue sampling, 104 (86%) were successfully analyzed for sensitizing EGFR mutations. Most failures were related to low tumor content. All patients (61/61) with matched pretreatment and resistance specimens showed concordance for the original sensitizing EGFR mutation. Standard T790M mutation analysis on 99 patients detected 51(51%) mutants. Retesting of 30 negative patients by the LNA-based method detected 11 additional mutants for an estimated prevalence of 68%. MET was amplified in 11% of cases (4/37).
Conclusions: The re-biopsy of lung cancer patients with acquired resistance is feasible and provides sufficient material for mutation analysis in most patients. Using high sensitivity methods, the T790M is detected in up to 68% of these patients. Clin Cancer Res; 17(5); 1169–80. ©2011 AACR.
Overexpression of miR-200c Induces Chemoresistance in Esophageal Cancers Mediated Through Activation of the Akt Signaling Pathway
Authors: Hamano Rie , Miyata Hiroshi , Yamasaki Makoto , Kurokawa Yukinori , Hara Johji , Moon Jeong ho , Nakajima Kiyokazu , Takiguchi Shuji , Fujiwara Yoshiyuki , Mori Masaki , Doki Yuichiro 
Published: January 2011

AbstractPurpose: To determine the relationship between resistance to chemotherapy and microRNA (miRNA) expression in esophageal cancer, we focused on miRNAs known to be associated with maintenance of stem cell function.Experimental Design: Using 98 formalin-fixed, paraffin-embedded samples obtained from patients with esophageal cancer who had received preoperative chemotherapy followed by surgery, we measured expression levels of several miRNAs that are considered to be involved in the regulation of stem cell function (e.g., let-7a, let-7g, miR-21, miR-134, miR-145, miR-155, miR-200c, miR-203, and miR-296) by real-time reverse transcriptase PCR. Then, we examined the relationship between miRNA expression and prognosis or response to chemotherapy. To investigate the mechanism of miRNA-induced chemoresistance, in vitro assays were carried out using esophageal cancer cells.Results: Analyses of the 9 miRNAs expression showed that overexpression of miR-200c (P = 0.037), underexpression of miR-145 (P = 0.023), and overexpression of miR-21 (P = 0.048) correlated significantly with shortened overall duration of survival. In particular, miR-200c expression correlated significantly with response to chemotherapy (P = 0.009 for clinical response; P = 0.007 for pathologic response). In vitro assay showed significantly increased miR-200c expression in cisplatin-resistant cells compared with their parent cells (∼1.7-fold). In anti-miR-200c–transfected cells, chemosensitivity to cisplatin and apoptosis after exposure to cisplatin was found to increase as compared with the negative control. Western blotting showed that knockdown of miR-200c expression was associated with increased expression of PPP2R1B, a subunit of protein phosphatase 2A, which resulted in reduced expression of phospho-Akt.Conclusions: Results of this study emphasized the involvement of miR-200c in resistance to chemotherapy among esophageal cancers and that this effect was mediated through the Akt pathway. Clin Cancer Res; 17(9); 3029–38. ©2011 AACR.
Modulators of Arginine Metabolism Do Not Impact on Peripheral T-Cell Tolerance and Disease Progression in a Model of Spontaneous Prostate Cancer
Authors: Rigamonti Nicolò , Capuano Giusy , Ricupito Alessia , Jachetti Elena , Grioni Matteo , Generoso Luca , Freschi Massimo , Bellone Matteo 
Published: January 2011

AbstractPurpose: Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b+Gr1+ cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-l-arginine methyl ester (l-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity.Experimental Design: Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, l-NAME or sildenafil, and evaluated for CD11b+ cells accumulation in the blood, several organs, and the tumor mass and for disease progression.Results: CD11b+Gr1high, CD11b+Gr1int, and CD11b+Gr1− cells differently accumulated in different organs and especially in the tumor of the two mouse models. l-NAME and sildenafil impaired the immunosuppressive function of CD11b+ cells in both models and restrained TRAMP-C1 growth, but they neither break tumor-specific immune tolerance nor limit tumor progression in TRAMP mice.Conclusions: Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance. Clin Cancer Res; 17(5); 1012–23. ©2011 AACR.
Assessment of Catheter Tip Contact Force Resulting in Cardiac Perforation in Swine Atria Using Force Sensing Technology
Authors: Perna Francesco , Heist E. Kevin , Danik Stephan B. , Barrett Conor D. , Ruskin Jeremy N. , Mansour Moussa 
Published: January 2011

Background—
Force sensing is a recently developed technology that allows the determination of the contact force (CF) at the tip of the catheter during electrophysiology procedures. Previous studies suggested that the optimal CF for adequate catheter contact ranges between 10 and 40 g. The aim of this study was to determine the CF needed to cause perforation in the swine atria.

Methods and Results—

Pericardial access was obtained at the beginning of the study in a swine model to drain pericardial effusions. Electroanatomic maps of the right atrium (RA) and left atrium (LA) were constructed. Ablation was performed using an irrigated-tip radiofrequency catheter equipped with force-sensing technology (30 W, 30 mL/min, for 30 seconds). Perforations of the LA and RA wall were intentionally performed in different locations with and without radiofrequency ablation. CF values preceding each perforation were recorded. A total of 111 cardiac perforations were achieved in 7 pigs. The overall average CF resulting in perforation was 175.8±60.4 g (range, 77 to 376 g). This was significantly lower after 30 seconds of radiofrequency delivery: 151.8±49.9 g versus 197±61.3 g (
P
=0.00005). The average value of CF resulting in perforation was not statistically different between the RA and the LA (169.6±61.6 g versus 181.7±59.3 g) (
P
=0.29).

Conclusions—
Perforation of the atrial wall in a swine model can occur over a wide range of CF values. Perforation can occur with a CF as low as 77 g. Ablation reduces the perforating force by 23%.
The comfort, energy and health implications of London’s urban heat island
Authors: Mavrogianni A. , Davies M. , Batty M. , Belcher SE , Bohnenstengel SI , Carruthers D. , Chalabi Z. , Croxford B. , Demanuele C. , Evans S. , Giridharan R. , Hacker JN , Hamilton I. , Hogg C. , Hunt J. , Kolokotroni M. , Martin C. , Milner J. , Rajapaksha I. , Ridley I. , Steadman JP , Stocker J. , Wilkinson P. , Ye Z. 
Published: January 2011

The urban heat island (UHI) is a well-known effect of urbanisation and is particularly important in world megacities. Overheating in such cities is expected to be exacerbated in the future as a result of further urban growth and climate change. Demonstrating and quantifying the impact of individual design interventions on the UHI is currently difficult using available software tools. The tools developed in the LUCID (‘The Development of a Local Urban Climate Model and its Application to the Intelligent Design of Cities’) research project will enable the related impacts to be better understood, quantified and addressed. This article summarises the relevant literature and reports on the ongoing work of the project. Practical applications: There is a complex relationship between built form, urban processes, local temperature, comfort, energy use and health. The UHI effect is significant and there is a growing recognition of this issue. Developers and planners are seeking advice on design decisions at a variety of scales based on scientifically robust, quantitative methods. The LUCID project has thus developed a series of tools that (1) quantify the effect of urbanisation processes on local environmental conditions, and (2) quantify the impact of such conditions on comfort, energy use and health. The use of such tools is vital, both to inform policy but also to be able to demonstrate compliance with it.
Spontaneous retrograde dissection of ascending aorta from descending thoracic aorta - a case review
Authors: Kaul Pankaj 
Published: January 2011

A 56-year-old man with sudden onset chest pain, absent right lower limb pulses and ECG changes suggestive of inferior ST elevation MI underwent coronary angiogram through the right radial artery with a view to primary percutaneous coronary intervention (PCI). The left coronary angiogram demonstrated severe proximal stenotic disease in the left anterior descending and circumflex coronary arteries, but the right coronary artery could not be selectively cannulated. An ascending aortogram to visualise the right coronary artery not only failed to demonstrate it, but revealed, instead, a dissection flap in the ascending aorta, arch and descending thoracic aorta, with moderately severe aortic regurgitation. At operation, the patient was found to have an acute dissection of the ascending aorta, arch and descending aorta with an entry tear in the descending aorta below the left subclavian artery origin. Triple coronary artery bypass grafting with re-suspension of the aortic valve, supracoronary replacement of the ascending aorta and hemiarch and transaortic repair of the descending aortic tear was performed. The patient made an uncomplicated recovery, with the re-appearance of right limb pulses. A postoperative magnetic resonance (MR) scan revealed complete thrombosis of the false channel in the residual arch and a considerably shrunken false channel in the descending aorta and no aortic regurgitation. Retrograde dissection of the ascending aorta from the descending aorta has been reported infrequently in the past. We believe the scale of the problem has been underestimated because of the failure to adopt open distal anastomosis routinely in the past and, hence, failure to inspect the arch and the descending aorta routinely, particularly when the intimal tear was not identified in the ascending aorta. Retrograde dissection of the ascending aorta from an intimal tear in the descending aorta, when identified as such, has been managed, either on the principle of exclusion of the tear in the descending aorta by various elephant trunk procedures and their variants or, alternatively, on the principle of excision of the tear by extended one-stage aortic replacement, usually combined with an elephant trunk procedure. Neither of these procedures is widely adopted, owing to procedural, institutional and outcome considerations. We describe a transaortic repair of the intimal tear in the descending aorta with supracoronary interposition graft replacement of the ascending aorta and hemiarch with excellent clinical and radiological result. We also review the diagnostic and therapeutic approaches to this incompletely understood lethal disease.
Evaluation of two pediatric polymethyl pentene membrane oxygenators with pulsatile and non-pulsatile perfusion
Authors: Feng Qiu  , Khan Sameer , Talor Jonathan , Kunselman Allan , Ündar Akif 
Published: January 2011

Objectives: This experiment sought to compare two polymethyl pentene (PMP) hollow-fiber membrane oxygenators: the Medos HILITE 2400 LT and the Maquet Quadrox-iD Pediatric in terms of transmembrane pressure gradients and hemodynamic energy preservation under both pulsatile and non-pulsatile conditions. Methods: A simulated pediatric extracorporeal life support (ECLS) circuit was used to test these two oxygenators. The circuit consisted of a roller pump, ¼ inch tubing for both arterial and venous lines, an oxygenator, and a venous reservoir served as a pseudo-patient. Three pressure transducers were placed upstream and downstream of the oxygenator and the distal arterial line. The experimental system was primed with lactated Ringer’s solution and packed human red blood cells to maintain a hematocrit of 40%.The total volume was 600 ml, including the 350 ml volume of the pseudo-patient.The tests were performed at six flow rates (250, 500, 750, 1000, 1250, 1500 ml/min) and three distal arterial line pressures (MAP) (60, 80, 100 mmHg), under both pulsatile and non-pulsatile perfusion modes.The temperature was kept constant at 37°C for all tests. Results: Both oxygenators had adequate performances in pressure drop and hemodynamic energy preservation. There were no significant differences between pre- and post-oxygenators for mean pressure (MP), energy equivalent pressure (EEP) and total hemodynamic energy (THE). During the pulsatile perfusion mode, the HILITE 2400 LT retained a greater percentage of surplus hemodynamic energy (SHE) across the oxygenator. Conclusions: Both the Quadrox-iD Pediatric and HILITE 2400LT PMP membrane oxygenators are suitable for pediatric ECLS therapy under both non-pulsatile and pulsatile perfusion. An optimized combination of flow rate and MAP should be achieved in order to deliver the maximal pulsatile energy in the extracorporeal circuit.
Is there a benefit to having a clinical oncology pharmacist on staff at a community oncology clinic?
Authors: Ruder Aimee Danette , Smith Douglas Lamont , Madsen Michael Thornton , Kass Frederic Henry 
Published: January 2011

Background. The John Marsh Cancer Center is an ambulatory oncology clinic located in Hagerstown, MD. In 2004, a clinical oncology pharmacist was hired to help manage therapies and control cost. The objective was to evaluate clinical interventions, consultations and cost savings by the clinical oncology pharmacist. Methods. This was a retrospective descriptive analysis of clinical interventions by the clinical oncology pharmacist from September 4, 2004 to October 27, 2006. Interventions were categorized as either drug-related or consultative. Drug-related interventions included medication reconciliation, dosing, and adverse effect management and prevention. Consultations incorporated drug information questions, patient visits, and patient education sessions. Information was extracted from an online documentation program linked to medical charts. Results. A total of 583 clinical interventions were documented among 199 patients. Average time spent per intervention was 10 minutes. Drug-related and consultative interventions accounted for 35% and 65%, respectively. Included among the drug-related interventions were adverse events (131), medication reconciliation (52) and dosing (22). Consultation services consisted of patient education (143), patient visits (124) and drug information (25). The on-site pharmacist saved $210,000 by admixing chemotherapy. Patient and colleague surveys evaluated pharmacist services with positive ratings of 95% and 98%, respectively. Conclusion. Analysis of clinical interventions, cost-savings, and feedback from patients and colleagues confirmed beneficial services provided by a clinical pharmacist in this outpatient oncology center.
Adult Wilms’ tumor: Review of literature
Authors: Ali Elsayed Mostafa , Elnashar Afaf T 
Published: January 2011

Background. The most common renal tumors in adults is renal cell carcinoma. Wilms’ tumor in subjects older than 16 years is rare; only 3% of Wilms’ tumors are reported in adults, which explain the difficulties in diagnosis and treatment of this tumor entity in this age group. Methods. Patient with stage IV adult nephroblastoma with favorable histology was described, current treatment modalities were discussed, and the literature was reviewed. Results. Nineteen year old female patient is presented with renal mass, abdominal lymphadenopathy, and bilateral pulmonary deposits. Sonar guided biopsy from the renal mass was taken and pathology revealed nephroblastoma. Right nephrectomy was performed and the pathological examination revealed classic histology of nephroblastoma. The case diagnosed as stage IV adult Wilms’ tumor with favorable histology. According to National Wilms’ Tumor Study Group (NWTS-3), multimodal therapy was initiated immediately after surgery. The patient failed to respond to the first line therapy and died due to disease progression. Conclusion. Adult Wilms’ tumor has no specific guidelines and this may lead to improper or incorrect treatment.