bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prototype MR insertable brain PET using tileable GAPD arrays
Authors: Hong Key Jo , Choi Yong , Jung Jin Ho , Kang Jihoon , Hu Wei , Lim Hyun Keong , Huh Yoonsuk , Kim Sangsu , Jung Ji Woong , Kim Kyu Bom , Song Myung Sung , Park Hyun‐wook 
Published: March 2013

Purpose:The aim of this study was to develop a prototype magnetic resonance (MR)‐compatible positron emission tomography (PET) that can be inserted into a MR imager and that allows simultaneous PET and MR imaging of the human brain. This paper reports the initial results of the authors’ prototype brain PET system operating within a 3‐T magnetic resonance imaging (MRI) system using newly developed Geiger‐mode avalanche photodiode (GAPD)‐based PET detectors, long flexible flat cables, position decoder circuit with high multiplexing ratio, and digital signal processing with field programmable gate array‐based analog to digital converter boards.Methods:A brain PET with 72 detector modules arranged in a ring was constructed and mounted in a 3‐T MRI. Each PET module was composed of cerium‐doped lutetium yttrium orthosilicate (LYSO) crystals coupled to a tileable GAPD. The GAPD output charge signals were transferred to preamplifiers using 3 m long flat cables. The LYSO and GAPD were located inside the MR bore and all electronics were positioned outside the MR bore. The PET detector performance was investigated both outside and inside the MRI, and MR image quality was evaluated with and without the PET system.Results:The performance of the PET detector when operated inside the MRI during MR image acquisition showed no significant change in energy resolution and count rates, except for a slight degradation in timing resolution with an increase from 4.2 to 4.6 ns. Simultaneous PET/MR images of a hot‐rod and Hoffman brain phantom were acquired in a 3‐T MRI. Rods down to a diameter of 3.5 mm were resolved in the hot‐rod PET image. The activity distribution patterns between the white and gray matter in the Hoffman brain phantom were well imaged. The hot‐rod and Hoffman brain phantoms on the simultaneously acquired MR images obtained with standard sequences were observed without any noticeable artifacts, although MR image quality requires some improvement.Conclusions:These results demonstrate that the simultaneous acquisition of PET and MR images is feasible using the MR insertable PET developed in this study.
A gEUD‐based inverse planning technique for HDR prostate brachytherapy: Feasibility study
Authors: Giantsoudi D. , Baltas D. , Karabis A. , Mavroidis P. , Zamboglou N. , Tselis N. , Shi C. , Papanikolaou N. 
Published: March 2013

Purpose:The purpose of this work was to study the feasibility of a new inverse planning technique based on the generalized equivalent uniform dose for image‐guided high dose rate (HDR) prostate cancer brachytherapy in comparison to conventional dose‐volume based optimization.Methods:The quality of 12 clinical HDR brachytherapy implants for prostate utilizing HIPO (Hybrid Inverse Planning Optimization) is compared with alternative plans, which were produced through inverse planning using the generalized equivalent uniform dose (gEUD). All the common dose‐volume indices for the prostate and the organs at risk were considered together with radiobiological measures. The clinical effectiveness of the different dose distributions was investigated by comparing dose volume histogram and gEUD evaluators.Results:Our results demonstrate the feasibility of gEUD‐based inverse planning in HDR brachytherapy implants for prostate. A statistically significant decrease in D10 or/and final gEUD values for the organs at risk (urethra, bladder, and rectum) was found while improving dose homogeneity or dose conformity of the target volume.Conclusions:Following the promising results of gEUD‐based optimization in intensity modulated radiation therapy treatment optimization, as reported in the literature, the implementation of a similar model in HDR brachytherapy treatment plan optimization is suggested by this study. The potential of improved sparing of organs at risk was shown for various gEUD‐based optimization parameter protocols, which indicates the ability of this method to adapt to the user's preferences.
The CRISPR-Associated Genecas2of Legionella pneumophila Is Required for Intracellular Infection of Amoebae
Authors: Gunderson Felizza F. , Cianciotto Nicholas P. 
Published: March 2013

ABSTRACTRecent studies have shown that the clustered regularly interspaced palindromic repeats (CRISPR) array and its associated (cas) genes can play a key role in bacterial immunity against phage and plasmids. Upon analysis of theLegionella pneumophilastrain 130b chromosome, we detected a subtype II-B CRISPR-Cas locus that containscas9,cas1,cas2,cas4, and an array with 60 repeats and 58 unique spacers. Reverse transcription (RT)-PCR analysis demonstrated that the entire CRISPR-Cas locus is expressed during 130b extracellular growth in both rich and minimal media as well as during intracellular infection of macrophages and aquatic amoebae. Quantitative reverse transcription-PCR (RT-PCR) further showed that the levels ofcastranscripts, especially those ofcas1andcas2, are elevated during intracellular growth relative to exponential-phase growth in broth. Mutants lacking components of the CRISPR-Cas locus were made and found to grow normally in broth and on agar media.cas9,cas1,cas4, and CRISPR array mutants also grew normally in macrophages and amoebae. However,cas2mutants, although they grew typically in macrophages, were significantly impaired for infection of bothHartmannellaandAcanthamoebaspecies. A complementedcas2mutant infected the amoebae at wild-type levels, confirming thatcas2is required for intracellular infection of these host cells.IMPORTANCEGiven that infection of amoebae is critical forL. pneumophilapersistence in water systems, our data indicate thatcas2has a role in the transmission of Legionnaires’ disease. Because our experiments were done in the absence of added phage, plasmid, or nucleic acid, the event that is facilitated by Cas2 is uniquely distinct from current dogma concerning CRISPR-Cas function.
The reach and adoption of a coach-led exercise training programme in community football
Authors: Finch Caroline F , Diamantopoulou Kathy , Twomey Dara M , Doyle Tim L A , Lloyd David G , Young Warren , Elliott Bruce C 
Published: March 2013

ObjectiveTo determine the reach and adoption of a coach-led exercise training programme for lower limb injury prevention.DesignSecondary analysis of data from a group-clustered randomised controlled trial.SettingA periodised exercise training warm-up programme was delivered to players during training sessions over an 8-week preseason (weeks 1–8) and 18-week playing season.Participants1564 community Australian football players.Main outcome measurementsReach, measured weekly, was the number of players who attended training sessions. Adoption was the number of attending players who completed the programme in full, partially or not at all. Reasons for partial or non-participation were recorded.ResultsIn week 1, 599 players entered the programme; 55% attended 1 training session and 45% attended > 1 session. By week 12, 1540 players were recruited but training attendance (reach) decreased to <50%. When players attended training, the majority adopted the full programme—ranging from 96% (week 1) to above 80% until week 20. The most common reasons for low adoption were players being injured, too sore, being late for training or choosing their own warm-up.ConclusionsThe training programme's reach was highest preseason and halved at the playing season's end. However, when players attended training sessions, their adoption was high and remained close to 70% by season end. For sports injury prevention programmes to be fully effective across a season, attention also needs to be given to (1) encouraging players to attend formal training sessions and (2) considering the possibility of some form of programme delivery outside of formal training.
Abstract A11: STRADα regulates cell polarity and invasion through PAK1 signaling in LKB1 null cells
Authors: Eggers Carrie M. , Kline Erik R. , Zhong Diansheng , Zhou Wei , Marcus Adam I. 
Published: March 2013

Abstract
The kinase LKB1 is mutated in multiple tumor types with a high mutation rate in non-small cell lung cancer. LKB1 activity is regulated by the pseudokinase, STE20-related adaptor alpha (STRADα), and the STRADα-LKB1 pathway plays critical roles in cell polarity and metastasis. Though much attention is given to the STRADα-LKB1 pathway, the function of STRADα itself, including a role outside of the LKB1 pathway, has not been well-studied. Data in C. elegans suggest that STRADα has an LKB1-independent role in regulating cell polarity, and therefore we tested the hypothesis that STRADα regulates cancer cell polarity and motility when wild-type LKB1 is absent. These results show that STRADα protein is reduced in LKB1-null cell lines (mutation or homozygous deletion) and this partial degradation occurs through the Hsp90-dependent proteasome pathway. The remaining STRADα participates in cell polarity and invasion, such that STRADα depletion results in misaligned lamellipodia, improper Golgi positioning, and reduced invasion. To probe the molecular basis of this defect, we show that STRADα associates in a complex with PAK1, and STRADα loss disrupts PAK1 activity via thr423 PAK1 phosphorylation. When STRADα is depleted, PAK1-induced invasion could not occur, suggesting that STRADα is necessary for PAK1 to drive motility. Based upon these data, we conclude that STRADα regulates PAK1 in LKB1-null cells to oversee cancer cell polarity and invasion.
Abstract A23: Detection of K ras mutations in Korean non small cell lung cancer patients
Authors: Kim Hee Joung , Kim Sun Jong , Yoo Gwang Ha , Kim Won Dong , Oh Seo Young , Kim Wan Seop , Lee Kye Young 
Published: March 2013

Abstract
Background: Point mutation of the K ras gene is known to be a poor prognostic marker of an adenocarcinoma of the lung. This study aims to define frequency of K ras mutations and evaluate clinical features of patients with Non small cell lung cancer (NSCLC) who harbor K ras mutation.
Methods: NSCLC patient who were diagnosed from Sep. 2005 to Aug. 2011 at Konkuk University Hospital were included in this retrospective study. K ras mutation was assessed by pyrosequencing on biopsy or cytology specimen. Medial chart review was performed and clinical characteristics were compared according to K ras mutation status of their tumors.
Results: K ras mutation was found in 25 (9.0%) of 277 patients and which was similar to those in East Asian countries, but lower than those in western countries. Fifteen mutations (60.0%) were point mutation at codon 12 (GGT), 7 mutations (28.0%) were point mutation at codon 61 (CAA), and 3 mutations (12.0%) were found at codon 13 (GGC) in exon 2. Median age of 25 patients with KRAS mutation was 6 years (range 43–85 years). There were 20 males (80.0%) and 3 never-smokers (12.0%). The majority of histological diagnoses were adenocarcinomas (21 cases; 84.0%) and squamous cell carcinomas were followed (3 cases; 12.0%). Interestingly, 2 patients had both mutations of EGFR and KRAS unlike previous studies, they showed favorable response to EGFRTKIs.
Conclusions: The data indicate that KRAS mutation is less frequent in Korean than Caucasian patients. Although it is suggested that EGFR and KRAS mutations occur in mutually exclusive, very few of the patients with KRAS mutation showed also EGFR mutation and relatively favorable response to EGFR-TKIs. Additional large scale prospective studies are needed in order to validate the clinical significance of Kras mutation in Asian patients.
Abstract A30: Radiation resistance of human lung cancer stem cells (CSCs)
Authors: Gomez-Casal Roberto , Parikh Simul , Saleet Roje , Basse Per , Gibson Michael K. , Gorelik Elieser , Levina Vera 
Published: March 2013

Abstract
Non-small cell lung cancer (NSCLC), the most common form of lung cancer, is treated with tumor resection and chemotherapy, with ionizing radiation (IR) treatment and chemotherapy used for patients with unresectable tumors. Despite improvements in medical management, 5-year survival rates for NSCLC remain low. Evidence suggests that resistance to radio- and chemotherapy is associated with cancer stem cells (CSCs), which are undifferentiated cells with the capacity to self-renew and differentiate, restoring the tumor cell population following treatment. However, the mechanisms through which lung CSCs evade and resist radiation therapy remain poorly studied.
We previously reported on our ability to isolate, culture, and assay human lung CSCs from cultured cell lines. We found the stem cell factor (SCF) and its receptor c-kit functions in a crucial pathway for the self-renewal and proliferation of human lung CSCs. We discovered that a combination of cisplatin (to eradicate bulk tumor cells) and agents targeting SCF/c-kit signaling in CSCs (e.g., antibody neutralizing SCF and anti-c-kit RTK inhibitors) is an effective therapy against NSCLC in vitro.
Here we extend our work to CSCs derived from primary NSCLC surgical tumor specimens. We analyzed lung CSC resistance to ionizing radiation (IR) and molecular mechanisms associated with CSC radioresistance.
We found that human lung CSC radioresistance is mediated by preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. Tyrosine kinase inhibitors with anti c-kit activity (e.g., imatinib, dovitinib, sunitinib, and axitinib) were compared for their ability to abrogate lung CSC proliferation and potentiate effect of IR on NSCLC. We found that lung CSCs proliferation was abrogated by all of the four c-kit inhibitors; however, axitinib showed the most profound anti-CSC effect.
The combination of IR treatment with SCF/ckit pathway inhibition eliminated bulk NSCLC cells and radiation resistant CSCs.
Abstract A34: Nitric Oxide enhances inflammation, microRNA-21 expression and KRAS-induced lung carcinogenesis
Authors: Okayama Hirokazu , Saito Motonobu , Naohide Oue , Weiss Jonathan M. , Stauffer Jimmy , Takanoshita Seiichi , Wiltrout Robert H. , Hussain S. Perwez , Harris Curtis C. 
Published: March 2013

Abstract
Mutant KRAS in lung cancers induce molecular pathways that regulate cellular proliferation, survival and inflammation, which enhance tumorigenesis. Inducible nitric oxide synthese (NOS2) up-regulation and sustained nitric oxide (NO•) generation are induced during the inflammatory response and correlate positively with lung tumorigenesis. To explore the mechanistic contribution of NOS2 to KRAS-induced lung tumorigenesis and inflammation, we used a genetic strategy of crossing NOS2 knockout (NOS2KO) C57BL6 inbred mice with a KRASG12D-driven mouse lung cancer model. KRASG12D/NOS2KO mice exhibited delayed lung tumorigenesis, resulting in a longer overall survival time compared with that of KRASG12D/NOS2WT (wildtype) controls. Correspondingly, tumors in KRASG12D/NOS2KO mice had reduced tumor cell proliferation in adenomas and carcinomas. NOS2-deficiency also led to dramatically suppressed inflammatory response by attenuation of macrophage recruitment into alveoli and within tumor foci. In contrast, FOXP3+ regulatory T cells were increased in tumors from KRASG12D/NOS2KO mice. We further analyzed the expression of microRNA-21 (miR-21), an oncogenic non-coding RNA involved in oncogenic Ras signaling, by quantitative reverse transcription PCR and in situ hybridization. Lung carcinomas dissected from KRASG12D/NOS2KO mice showed a significantly reduced miR-21 expression along with decreased tumor cell proliferation, suggesting that NOS2-deficiency could attenuate RAS signaling pathways that transactivate miR-21 expression. Therefore, deletion of NOS2 decreases lung tumor growth as well as inflammatory responses initiated by oncogenic KRAS, suggesting that both KRAS and NOS2 cooperate in driving lung tumorigenesis and inflammation. Inhibition of NOS2 may have a therapeutic value in lung cancers with oncogenic KRAS mutations.
Abstract A35: The role of Mdm2 cleavage in p53 function and chemotherapy response
Authors: Oliver Trudy G. 
Published: March 2013

Abstract
Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of resistance to specific therapies have been largely unexplored in vivo. Employing genetic, genomic, and imaging approaches, we have examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple mouse models of human non-small cell lung cancer (NSCLC). We show that lung tumors initially respond to cisplatin and exhibit a significant reduction in tumor burden. Prolonged cisplatin treatment promotes the emergence of resistant tumors with enhanced repair capacity that are cross-resistant to platinum analogs, exhibit advanced histopathology, and possess an increased frequency of genomic alterations. Cisplatin-resistant tumors express elevated levels of multiple DNA damage repair and cell cycle arrest-related genes, including p53-inducible protein with a death domain (Pidd).
We show that PIDD expression promotes growth arrest and chemotherapy resistance by a mechanism that depends on Caspase-2 and wild-type p53. PIDD-induced Caspase-2 directly cleaves the E3 ubiquitin ligase Mdm2 at Asp 367, leading to loss of the C-terminal RING domain responsible for p53 ubiquitination. As a consequence, N-terminally truncated Mdm2 binds p53 and promotes its stability. Upon DNA damage, p53 induction of the Caspase-2-PIDDosome creates a positive feedback loop that inhibits Mdm2 and reinforces p53 stability and activity, contributing to cell survival and drug resistance. These data establish Mdm2 as a novel cleavage target of Caspase-2 and provide insight into a mechanism of Mdm2 inhibition that impacts p53 dynamics upon genotoxic stress. Our current goals are to: 1) elucidate how cleaved Mdm2 dictates p53 function and 2) create mouse models to manipulate Mdm2 cleavage in vivo in order to interrogate the role of Mdm2 cleavage in lung tumorigenesis and drug response.
Abstract A44: K-homology splicing regulatory protein modulates tumor suppressor miRNA 29b through the noncanonical Wnt 7a signaling pathway
Authors: Wilson Lora A. , Winn Robert A. 
Published: March 2013

Abstract
Precedent has established the role of the Wnt/β-catenin pathway in oncogenesis. Several members of the Wnt family are known to be tumor promoting in non-small cell lung cancer, NSCLC. In this pathway β-catenin, a downstream component, accumulates and serves as a T-cell transcription/lymphoid enhancer factor. We previously identified the Wnt ligand in the lung, Wnt 7a, as a member of the non-canonical pathway/β-catenin independent pathway, which inhibits transformed cell growth. K-homology splicing regulatory protein (KSRP) is a member of the family of AU rich element binding proteins. It possesses four K-homology motifs and causes decay of specific mRNA transcripts and regulation of miRNA. Wnt 7a positively regulates the expression of KSRP. As a result, KSRP upregulates the processing of miRNA 29b. The miRNA 29b family is comprised of 29a, 29b, and 29c. KSRP and miRNA 29b expression are elevated in nontransformed cells and alternatively, lower levels of expression are in NSCLC. The role of KSRP regulating miRNA 29b in the non-canonical Wnt pathway in the lung has previously been unknown. Over expression of KSRP through upregulation of miRNA 29b in NSCLC cells decreases cell proliferation in MTS assays, a measure of proliferation, as well as reducing colony formation in clonogenic assays. We reveal a novel association of p53 and miRNA 29b. We identified that KSRP increases PPARγ activation which in turn positively modulates miRNA 29b, resulting in upregulation of p53. The antitumorigenic effect is specific to Wnt 7a activation through Erk 5 dependent kinases.
Abstract B17: The small RhoGTPase RhoB as a new potential marker of EGFR-TKI resistance
Authors: Marty Claire , Favre Gilles , Mazieres Julien 
Published: March 2013

Abstract
Introduction: EGFR tyrosine kinase inhibitors (EGFR-TKI) are widely used in metastatic non small cell lung cancer (NSCLC). Nevertheless, the majority of patients with wild type EGFR do not respond to these treatments and, in the selected group with EGFR mutations, we some primary resistance and all the patients will ultimately develop acquired resistance.
The small RHO GTPase RhoB is involved in cell proliferation, invasion, apoptosis and can act as a tumor suppressor gene in lung carcinogenesis by controlling survival and invasion through AKT pathway. Furthermore, RhoB participates in the regulation of endocytic trafficking of EGFR. Specifically, activated RhoB is able to delay the transport of internalized EGFR to lysosomes, thus modifying its downstream signaling.
The objective of our study is to know if RhoB is a molecular determinant of the response to the EGFR-TKI erlotinib, and if RhoB could be a marker for erlotinib resistance.
Material and Method: We used various lung cancer cell lines harboring either wild-type or mautated EGFR and K-Ras. RhoB was either overexpressed by adenovirus transfection or inhibited by interfering RNA (siRNA) in these cells. Cell proliferation after 72h of treatment with erlotinib was measured by a colorimetric assay. In the same way, we performed invasion assays and western-blot analyses of downtsream signaling pathways.
Results: (1) RhoB overexpression decreases the sensitivity to erlotinib of cells presenting a wild type or mutated EGFR in a dose-dependent manner whereas the sensitivity to erlotinib of cells bearing KRas mutation was not affected by RhoB overexpression. (2) Erlotinib-induced inhibition of cellular invasion is impaired by overexpression of RhoB in wild type or mutated EGFR cell lines. (3) The phosphorylation of Akt (and not of ERK) is inhibited by erlotinib and is restored upon overexpression of RhoB invasion.
Conclusions: Our results suggest that RhoB is involved in the sensitivity to erlotinib in wild-type K-Ras cells harboring either mutated or wild-type EGFR. RhoB is able to block erlotinib-induced inhibition of cell proliferation and invasion mainly through AKT pathway modulation. We plan to extend our in vitro findings in a cohort of patients treated with erlotinib.