bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effective Assessment of egfr Mutation Status in Bronchoalveolar Lavage and Pleural Fluids by Next-Generation Sequencing
Authors: Buttitta Fiamma , Felicioni Lara , Del Grammastro Maela , Filice Giampaolo , Di Lorito Alessia , Malatesta Sara , Viola Patrizia , Centi Irene , D'Antuono Tommaso , Zappacosta Roberta , Rosini Sandra , Cuccurullo Franco , Marchetti Antonio 
Published: December 2012

Abstract
Purpose: The therapeutic choice for patients with lung adenocarcinoma depends on the presence of EGF receptor (EGFR) mutations. In many cases, only cytologic samples are available for molecular diagnosis. Bronchoalveolar lavage (BAL) and pleural fluid, which represent a considerable proportion of cytologic specimens, cannot always be used for molecular testing because of low rate of tumor cells.
Experimental Design: We tested the feasibility of EGFR mutation analysis on BAL and pleural fluid samples by next-generation sequencing (NGS), an innovative and extremely sensitive platform. The study was devised to extend the EGFR test to those patients who could not get it due to the paucity of biologic material. A series of 830 lung cytology specimens was used to select 48 samples (BAL and pleural fluid) from patients with EGFR mutations in resected tumors. These samples included 36 cases with 0.3% to 9% of neoplastic cells (series A) and 12 cases without evidence of tumor (series B). All samples were analyzed by Sanger sequencing and NGS on 454 Roche platform. A mean of 21,130 ± 2,370 sequences per sample were obtained by NGS.
Results: In series A, EGFR mutations were detected in 16% of cases by Sanger sequencing and in 81% of cases by NGS. Seventy-seven percent of cases found to be negative by Sanger sequencing showed mutations by NGS. In series B, all samples were negative for EGFR mutation by Sanger sequencing whereas 42% of them were positive by NGS.
Conclusions: The very sensitive EGFR-NGS assay may open up to the possibility of specific treatments for patients otherwise doomed to re-biopsies or nontargeted therapies. Clin Cancer Res; 19(3); 691–8. ©2012 AACR.
Influence of Human OATP1B1, OATP1B3, and OATP1A2 on the Pharmacokinetics of Methotrexate and Paclitaxel in Humanized Transgenic Mice
Authors: van de Steeg Evita , van Esch Anita , Wagenaar Els , Kenworthy Kathryn E. , Schinkel Alfred H. 
Published: December 2012

Abstract
Purpose: Organic anion-transporting polypeptide (OATP) drug uptake transporters are thought to play an important role in drug pharmacokinetics and toxicokinetics. We aimed to determine the influence of the individual human OATP1B1, OATP1B3, and OATP1A2 transporters on the in vivo disposition of the anticancer drugs methotrexate and paclitaxel by using liver-specific humanized OATP1A/1B transgenic mice.
Experimental Design: Wild-type, Slco1a/1b−/− (Oatp1a/1b knockout), Slco1a/1b−/−;1B1tg, Slco1a/1b−/−;1B3tg, and newly generated Slco1a/1b−/−;1A2tg (humanized OATP1B1, OATP1B3, and OATP1A2 transgenic) mice were characterized biochemically and physiologically, and subsequently intravenously dosed with methotrexate or paclitaxel (2 or 10 mg/kg each) for pharmacokinetic analyses.
Results: Humanized OATP1B1, OATP1B3, and OATP1A2 transgenic mice all showed partial or complete rescue of increased plasma bilirubin levels, but also of the increased plasma levels and decreased liver and small intestinal accumulation of methotrexate observed in Slco1a/1b−/− mice. Furthermore, hepatic expression of OATP1B3 and OATP1A2, but not OATP1B1, resulted in increased liver uptake of paclitaxel (2 mg/kg). At 10 mg/kg, a modest effect of only OATP1A2 on paclitaxel liver uptake was observed.
Conclusion: Human OATP1A/1B transporters play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutics methotrexate (organic anion) and paclitaxel (hydrophobic, bulky). Variation in OATP1A/1B activity due to genetic variation and pharmacologic inhibition, or differences in tumor-specific expression levels might therefore affect plasma, tissue, and tumor levels of these drugs in patients, and hence their therapeutic efficacy. Humanized transgenic OATP1A/1B mice will provide excellent tools to further study these aspects in vivo for many (anticancer) drugs. Clin Cancer Res; 19(4); 821–32. ©2012 AACR.
DNA Methylation as an Adjunct to Histopathology to Detect Prevalent, Inconspicuous Dysplasia and Early-Stage Neoplasia in Barrett's Esophagus
Authors: Alvi Muhammad A. , Liu Xinxue , O'Donovan Maria , Newton Richard , Wernisch Lorenz , Shannon Nicholas B. , Shariff Kareem , di Pietro Massimiliano , Bergman Jacques J.G.H.M. , Ragunath Krish , Fitzgerald Rebecca C. 
Published: December 2012

AbstractPurpose: Endoscopic surveillance of Barrett's esophagus is problematic because dysplasia/early-stage neoplasia is frequently invisible and likely to be missed because of sampling bias. Molecular abnormalities may be more diffuse than dysplasia. The aim was therefore to test whether DNA methylation, especially on imprinted and X-chromosome genes, is able to detect dysplasia/early-stage neoplasia.Experimental design: 27K methylation arrays were used to find genes best able to differentiate between 22 Barrett's esophagus and 24 esophageal adenocarcinoma (EAC) samples. These were validated using pyrosequencing on a retrospective cohort (60 Barrett's esophagus, 36 dysplastic, and 90 EAC) and then in a prospective multicenter study (98 Barrett's esophagus patients, including 28 dysplastic and 9 early EAC) designed to utilize biomarkers to stratify patients according to their prevalent dysplasia/EAC status.Results: Genes (23%) on the array, including 7% of X-linked and 69% of imprinted genes, have shown statistically significant changes in methylation in EAC versus Barrett's esophagus (Wilcoxon P &lt; 0.05). 6/7 selected candidate genes were successfully internally (Pearson's P &lt; 0.01) and externally validated (ANOVA P &lt; 0.001). Four genes (SLC22A18, PIGR, GJA12, and RIN2) showed the greatest area under curve (0.988) to distinguish between Barrett's esophagus and dysplasia/EAC in the retrospective cohort. This methylation panel was able to stratify patients from the prospective cohort into three risk groups based on the number of genes methylated (low risk: &lt;2 genes, intermediate: 2, and high: &gt;2).Conclusion: Widespread DNA methylation changes were observed in Barrett's carcinogenesis including ≈70% of known imprinted genes. A four-gene methylation panel stratified patients with Barrett's esophagus into three risk groups with potential clinical utility. Clin Cancer Res; 19(4); 878–88. ©2012 AACR.
Inhibiting EGF Receptor or SRC Family Kinase Signaling Overcomes BRAF Inhibitor Resistance in Melanoma
Authors: Girotti Maria R. , Pedersen Malin , Sanchez-Laorden Berta , Viros Amaya , Turajlic Samra , Niculescu-Duvaz Dan , Zambon Alfonso , Sinclair John , Hayes Andrew , Gore Martin , Lorigan Paul , Springer Caroline , Larkin James , Jorgensen Claus , Marais Richard 
Published: December 2012

Abstract
We generated cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)–SRC family kinase (SFK)–STAT3 signaling pathway was upregulated in these cells. In addition to driving proliferation of resistant cells, this pathway also stimulated invasion and metastasis. EGFR inhibitors cooperated with BRAF inhibitors to block the growth of the resistant cells in vitro and in vivo, and monotherapy with the broad specificity tyrosine kinase inhibitor dasatinib blocked growth and metastasis in vivo. We analyzed tumors from patients with intrinsic or acquired resistance to vemurafenib and observed increased EGFR and SFK activity. Furthermore, dasatinib blocked the growth and metastasis of one of the resistant tumors in immunocompromised mice. Our data show that BRAF inhibitor-mediated activation of EGFR–SFK–STAT3 signaling can mediate resistance in patients with BRAF-mutant melanoma. We describe 2 treatments that seem to overcome this resistance and could deliver therapeutic efficacy in patients with drug-resistant BRAF-mutant melanoma.
Significance: Therapies that target the driver oncogenes in cancer can achieve remarkable responses if patients are stratified for treatment. However, as with conventional therapies, patients often develop acquired resistance to targeted therapies, and a proportion of patients are intrinsically resistant and fail to respond despite the presence of an appropriate driver oncogene mutation. We found that the EGFR/SFK pathway mediated resistance to vemurafenib in BRAF-mutant melanoma and that BRAF and EGFR or SFK inhibition blocked proliferation and invasion of these resistant tumors, providing potentially effective therapeutic options for these patients. Cancer Discov; 3(2); 158–67. ©2012 AACR.
This article is highlighted in the In This Issue feature, p. 125
The mTORC1 Inhibitor Everolimus Prevents and Treats Eμ-Myc Lymphoma by Restoring Oncogene-Induced Senescence
Authors: Wall Meaghan , Poortinga Gretchen , Stanley Kym L. , Lindemann Ralph K. , Bots Michael , Chan Christopher J. , Bywater Megan J. , Kinross Kathryn M. , Astle Megan V. , Waldeck Kelly , Hannan Katherine M. , Shortt Jake , Smyth Mark J. , Lowe Scott W. , Hannan Ross D. , Pearson Richard B. , Johnstone Ricky W. , McArthur Grant A. 
Published: December 2012

Abstract
MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in Eμ-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of Eμ-Myc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established Eμ-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes.
Significance: This work provides novel insights into the requirements for MYC-induced oncogenesis by showing that mTORC1 activity is necessary to bypass senescence during transformation of B lymphocytes. Furthermore, tumor eradication through senescence elicited by targeted inhibition of mTORC1 identifies a previously uncharacterized mechanism responsible for significant anticancer activity of rapamycin analogues and serves as proof-of-concept that senescence can be harnessed for therapeutic benefit. Cancer Discov; 3(1); 82–95. ©2012 AACR.
This article is highlighted in the In This Issue feature, p. 1
A Crucial Role for p90RSK-Mediated Reduction of ERK5 Transcriptional Activity in Endothelial Dysfunction and Atherosclerosis
Authors: Le Nhat-Tu , Heo Kyung-Sun , Takei Yuichiro , Lee Hakjoo , Woo Chang-Hoon , Chang Eugene , McClain Carolyn , Hurley Cheryl , Wang Xin , Li Faqian , Xu Haodong , Morrell Craig , Sullivan Mark A. , Cohen Michael S. , Serafimova Iana M. , Taunton Jack , Fujiwara Keigi , Abe Jun-ichi 
Published: December 2012

Background—
Diabetes mellitus is a major risk factor for cardiovascular mortality by increasing endothelial cell (EC) dysfunction and subsequently accelerating atherosclerosis. Extracellular-signal regulated kinase 5 (ERK5) is activated by steady laminar flow and regulates EC function by increasing endothelial nitric oxide synthase expression and inhibiting EC inflammation. However, the role and regulatory mechanisms of ERK5 in EC dysfunction and atherosclerosis are poorly understood. Here, we report the critical role of the p90 ribosomal S6 kinase (p90RSK)/ERK5 complex in EC dysfunction in diabetes mellitus and atherosclerosis.

Methods and Results—

Inducible EC-specific ERK5 knockout (ERK5-EKO) mice showed increased leukocyte rolling and impaired vessel reactivity. To examine the role of endothelial ERK5 in atherosclerosis, we used inducible ERK5-EKO-LDLR
−/−
mice and observed increased plaque formation. When activated, p90RSK associated with ERK5, and this association inhibited ERK5 transcriptional activity and upregulated vascular cell adhesion molecule 1 expression. In addition, p90RSK directly phosphorylated ERK5 S496 and reduced endothelial nitric oxide synthase expression. p90RSK activity was increased in diabetic mouse vessels, and fluoromethyl ketone-methoxyethylamine, a specific p90RSK inhibitor, ameliorated EC-leukocyte recruitment and diminished vascular reactivity in diabetic mice. Interestingly, in ERK5-EKO mice, increased leukocyte rolling and impaired vessel reactivity were resistant to the beneficial effects of fluoromethyl ketone-methoxyethylamine, suggesting a critical role for endothelial ERK5 in mediating the salutary effects of fluoromethyl ketone-methoxyethylamine on endothelial dysfunction. Fluoromethyl ketone-methoxyethylamine also inhibited atherosclerosis formation in ApoE
−/−
mice.

Conclusions—
Our study highlights the importance of the p90RSK/ERK5 module as a critical mediator of EC dysfunction in diabetes mellitus and atherosclerosis formation, thus revealing a potential new target for therapeutic intervention.
The personal and interpersonal rewards of communal orientation
Authors: Le Bonnie M. , Impett Emily A. , Kogan Aleksandr , Webster Gregory D. , Cheng Cecilia 
Published: December 2012

People high in communal orientation care for the welfare of others based on others’ needs and desire similar care for themselves. The current study investigates the personal and interpersonal rewards associated with individual differences in communal orientation. We hypothesized that communally oriented people experience rewards from the positive emotion they feel from caring for others. Results from a 4-week daily experience study ( N = 232) indicated that communally oriented people experienced greater self-esteem, greater satisfaction and love in their relationships, and greater love for humanity in daily life. These associations were mediated by greater daily positive emotion and the results were unique to tendencies to give care rather than the desire to receive it. We discuss implications for prosociality and well-being in close relationships and beyond.
Assessing the usefulness of health data linkage in obtaining adverse event data in a randomised controlled trial of oral and implant naltrexone in the treatment of heroin dependence
Authors: Kelty Erin , Ngo Hanh , Hulse Gary 
Published: December 2012

Background The completeness of self-reported serious adverse events (SAEs) in clinical trials can be reduced by inaccuracies in subject reporting and lost to follow-up. Purpose This study assesses the usefulness of a health data linkage system in obtaining SAE data in a randomised controlled study of oral and implant naltrexone. Methods SAEs were collected from 68 heroin-dependent subjects during a randomised controlled trial of oral and implant naltrexone with follow-up to 26 weeks. Patient self-report data were cross-matched against hospital and emergency department (ED) attendances for the same period using a health data linkage system. Results A total of 29 hospital admissions and 74 ED attendances were identified using health data linkage. Of these, 12 (41.4%) hospital admissions and 50 (67.7%) of ED attendances had not been reported as SAE in the randomised controlled trial. In subjects participating in the trial at the time of the event, there was a 1.25-fold increase in the number of hospital admissions and a 2.25-fold increase in the number of ED attendances recorded using data linkage. Overall (including withdrawn subjects or those lost to follow-up), there was a 1.71-fold increase in hospital admission and a 3.09-fold increase in ED attendance recorded. Limitations The use of data linkage should not be used as a replacement for thorough follow-up, as the datasets can take substantial periods to update, making them a poor substitute for real-time follow-up. Additionally, some SAEs such as life-threatening events that do not involve ED or hospital attendance may be overlooked as would SAEs that occurred outside the dataset’s range, for example, interstate or overseas. Conclusions Health data linkage can be used to effectively reduce the extent of missing health data in a clinical trial.
Hygrothermal simulations of foundations: Part 1: Soil material properties
Authors: Pallin Simon , Kehrer Manfred 
Published: December 2012

Deep basements, crawl spaces and slab on grade are typical foundations in residential buildings in North America. The foundation of a house is a somewhat invisible and at sometimes ignored component of the building. Appropriate foundation design and construction practice must not only include thermal performance, but also design for a durable and safe hygrothermal performance. A hygrothermal simulation tool can be used to evaluate and predict the hygrothermal behavior of an insulated foundation constructions, in cooperation with the surrounding soil. Though, further development of the tool might first be needed and validated to fulfill the prerequisites. Transient hygrothermal simulation tools have existed in Building Science for more than 20 years, but are mainly used for building envelope simulation above ground. A lot of knowledge already exists in Soil Science concerning the variation of the soil material properties in relation to soil texture, moisture content etc. However, Soil Science uses these properties for other purpose and with different modeling approaches, hence a conversion is needed. This paper studies the existing knowledge of soil properties, converted to apply for simulation in Building Science. Further, the soil properties are implemented in a transient hygrothermal simulation tool, studying the applicability for modeling soil temperature and moisture flow. Finally the results are compared with measurement and followed by a discussion of further investigations and development needed.
Pharmacologic stabilization of HIF-1α increases hematopoietic stem cell quiescence in vivo and accelerates blood recovery after severe irradiation
Authors: Forristal Catherine E. , Winkler Ingrid G. , Nowlan Bianca , Barbier Valerie , Walkinshaw Gail , Levesque Jean-Pierre 
Published: December 2012

Key PointsHIF-1α protein stabilization increases HSC quiescence in vivo. HIF-1α protein stabilization increases HSC resistance to irradiation and accelerates recovery.
Induction of megakaryocyte differentiation drives nuclear accumulation and transcriptional function of MKL1 via actin polymerization and RhoA activation
Authors: Smith Elenoe C. , Teixeira Alexandra M. , Chen Rachel C. , Wang Lin , Gao Yuan , Hahn Katherine L. , Krause Diane S. 
Published: December 2012

Key Points
RhoA-induced actin polymerization promotes nuclear accumulation of MKL1 and transcriptional activation. Thrombopoietin activates nuclear accumulation of MKL1 and transcriptional activation in primary megakarocytes.
Anti-CD22–chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia
Authors: Haso Waleed , Lee Daniel W. , Shah Nirali N. , Stetler-Stevenson Maryalice , Yuan Constance M. , Pastan Ira H. , Dimitrov Dimiter S. , Morgan Richard A. , FitzGerald David J. , Barrett David M. , Wayne Alan S. , Mackall Crystal L. , Orentas Rimas J. 
Published: December 2012

Key Points
We have created a new highly active chimeric antigen receptor (CAR) specific for CD22. The design of new CARs may benefit more from target antigen epitope selection than from optimizing affinity.
Mast cell leukemia
Authors: Georgin-Lavialle Sophie , Lhermitte Ludovic , Dubreuil Patrice , Chandesris Marie-Olivia , Hermine Olivier , Damaj Gandhi 
Published: December 2012

AbstractMast cell leukemia (MCL) is a very rare form of aggressive systemic mastocytosis accounting for < 1% of all mastocytosis. It may appear de novo or secondary to previous mastocytosis and shares more clinicopathologic aspects with systemic mastocytosis than with acute myeloid leukemia. Symptoms of mast cell activation—involvement of the liver, spleen, peritoneum, bones, and marrow—are frequent. Diagnosis is based on the presence of ≥ 20% atypical mast cells in the marrow or ≥ 10% in the blood; however, an aleukemic variant is frequently encountered in which the number of circulating mast cells is < 10%. The common phenotypic features of pathologic mast cells encountered in most forms of mastocytosis are unreliable in MCL. Unexpectedly, non-KIT D816V mutations are frequent and therefore, complete gene sequencing is necessary. Therapy usually fails and the median survival time is < 6 months. The role of combination therapies and bone marrow transplantation needs further investigation.
The myth of the second remission of acute leukemia in the adult
Authors: Forman Stephen J. , Rowe Jacob M. 
Published: December 2012

Abstract
Although the majority of adult patients with both acute lymphoblastic leukemia and acute myelogenous leukemia achieve remission with upfront chemotherapy, many patients still suffer relapse. Often, the strategy is proposed of treating patients with relapsed leukemia into a second remission (CR2) and then proceeding to allogeneic transplantation as the definitive curative approach. However, the long-term outcomes of such a strategy are poor: the 5-year overall survival from first relapse for patients with acute leukemia is only approximately 10%. This Perspective highlights the fact that most patients do not achieve CR2 and therefore never really have an opportunity for a potential curative therapy. Although patients who undergo transplantation after relapse may be cured, those who do not achieve CR2 are rarely candidates for transplantation; therefore, the overall outcome for patients who relapse is dismal. There is therefore an urgent need not only for more effective upfront therapy to prevent relapse, but also for the development of therapies that can serve as effective bridging treatments between relapse and transplantation. We suggest that more optimal use of minimal residual disease detection during first remission may also improve the chances for successful transplantation therapy via earlier reinduction therapy, allowing transplantation before overt relapse.
Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib
Authors: Richardson Paul G. , Siegel David , Baz Rachid , Kelley Susan L. , Munshi Nikhil C. , Laubach Jacob , Sullivan Daniel , Alsina Melissa , Schlossman Robert , Ghobrial Irene M. , Doss Deborah , Loughney Nora , McBride Laura , Bilotti Elizabeth , Anand Palka , Nardelli Lisa , Wear Sandra , Larkins Gail , Chen Min , Zaki Mohamad H. , Jacques Christian , Anderson Kenneth C. 
Published: December 2012

Key PointsPomalidomide with/without dexamethasone has promising activity and manageable toxicity in relapsed and refractory multiple myeloma patients.
Telomere length in mantle cell lymphoma
Authors: Jebaraj Billy Michael Chelliah , Kienle Dirk , Lechel André , Mertens Daniel , Heuberger Maria , Ott German , Rosenwald Andreas , Barth Thomas F. E. , Möller Peter , Zenz Thorsten , Döhner Hartmut , Stilgenbauer Stephan 
Published: December 2012

Key Points
Telomere length in MCL is variable but does not correlate with disease characteristics and survival.