bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)
Authors: Shimosako Nana , Kerr Jonathan R 
Published: September 2014

AimsWe have reported gene expression changes in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and the fact that such gene expression data can be used to identify subtypes of CFS/ME with distinct clinical phenotypes. Due to the difficulties in using a comparative gene expression method as an aid to CFS/ME disease and subtype-specific diagnosis, we have attempted to develop such a method based on single-nucleotide polymorphism (SNP) analysis.MethodsTo identify SNP allele associations with CFS/ME and CFS/ME subtypes, we tested genomic DNA of patients with CFS/ME (n=108), patients with endogenous depression (n=17) and normal blood donors (n=68) for 504 human SNP alleles located within 88 CFS-associated human genes using the SNP Genotyping GoldenGate Assay (Illumina, San Diego, California, USA). 360 ancestry informative markers (AIM) were also examined.Results21 SNPs were significantly associated with CFS/ME compared with depression and normal groups. 148 SNP alleles had a significant association with one or more CFS/ME subtypes. For each subtype, associated SNPs tended to be grouped together within particular genes. AIM SNPs indicated that 4 subjects were of Asian origin while the remainder were Caucasian. Hierarchical clustering of AIM data revealed the relatedness between 2 couples of patients with CFS only and confirmed the overall heterogeneity of all subjects.ConclusionsThis study provides evidence that human SNPs located within CFS/ME associated genes are associated with particular genomic subtypes of CFS/ME. Further work is required to develop this into a clinically useful subtype-specific diagnostic test.
Impact of the Great East Japan earthquake on out-of-hospital cardiac arrest with cardiac origin in non-disaster reas
Authors: Kiyohara Kosuke , Kitamura Tetsuhisa , Iwami Taku , Nishiyama Chika , Kawamura Takashi 
Published: September 2014

BackgroundTo examine changes in the incidence of out-of-hospital cardiac arrest (OHCA) with cardiac origin in the non-disaster areas of Japan before and after the Great East Japan Earthquake of 11 March 2011.MethodsThe 35 prefectures in Japan with no dead or missing caused directly by the earthquake were defined as the non-disaster areas. Data of adult OHCA patients in the non-disaster areas from March 4 to 24 each year from 2005 to 2011 were obtained from the All-Japan Utstein Registry. Risk ratios (RRs) of OHCA incidence and 95% CIs were estimated for three specific weeks in 2011 (1 week before and 2 weeks after the earthquake) by applying multivariable Poisson regression model. Incidence in the corresponding periods of March 4–24 from 2005 to 2010 was set as the baseline risk.ResultsIn the analyses from a total of 17 353 OHCA patients, the incidence statistically significantly increased in the first week after the earthquake in all adults (adjusted-RR=1.13, 95% CI=1.05 to 1.22, p=0.001) and in elderly women (adjusted-RR=1.23, 95% CI=1.11 to 1.37, p<0.001).ConclusionsThe Great East Japan Earthquake caused the increase of OHCA among elderly women even in the non-disaster areas.
Chapter 18 East Antarctic continental shelf: Prydz Bay and the Mac.Robertson Land Shelf
Authors: O'Brien P. E. , Harris P. T. , Post A. L. , Young N. 
Published: September 2014

Abstract
Prydz Bay and the Mac.Robertson Land Shelf exhibit many of the variations seen on Antarctic continental shelves. The Mac.Robertson shelf is relatively narrow with rugged, inner-shelf topography and shallow outer-shelf banks swept by the west-flowing Antarctic Coastal Current. U-shaped valleys cut across the shelf. It has thin sedimentary cover, deposited and eroded by cycles of glacial advance and retreat through the Neogene and Quaternary. Modern sedimentation is diatom-rich siliceous, muddy ooze in shelf deeps, while, on the banks, phytodetritus, calcareous bioclasts and terrigenous material are mixed by iceberg ploughing. Prydz Bay is a large embayment fed by the Amery Ice Shelf. It has a broad inner-shelf deep area and outer bank, with depths ranging from 2400 m beneath the ice shelf to 100 m on the outer banks. A clockwise gyre flows through the bay. Fine mud and siliceous ooze drape the seafloor; however, banks are scoured by icebergs to depths as great as 500 m. The Mac.Robertson shelf has seen advances to the shelf edge during glacial episodes and retreat during warming and rising sea level. Prydz Bay shows more complexity, with parts of the bay showing partial advance of the ice-grounding zone.
To the islands born: the research potential of submerged landscapes and human habitation sites from the islands of NW Australia
Authors: Ward I. , Veth P. , Manne T. 
Published: September 2014

Abstract
This paper focuses on the continental shelf of NW Australia, and on models for change in littoral and offshore environments of relevance to human occupation over the last 50 kyr. Major island groups occur on the shelf including the Montebello and Barrow islands, and those of the Dampier Archipelago. At lowest sea level around 22 ka, these would have been uplands that then became progressively isolated by subsequent sea-level rise. By integrating archaeological and zooarchaeological records from excavations on these islands with the geology and geomorphology, we interpret palaeoeconomic resource potential in relation to changing sea level and coastline morphology. The preservation potential for submerged archaeological sites and features is also assessed. Current archaeological evidence from these offshore islands indicates that the submerged coastal landscape is likely to have been a potentially rich environment for resources and human occupation, even at times of lowest sea level and regional aridity. Should any exploration of submerged archaeology be carried out in this region, it is likely to be rewarding, offering unique insights into Late Pleistocene coastal occupation.
Marine geological and archaeological evidence of a possible pre-Neolithic site in Pantelleria Island, Central Mediterranean Sea
Authors: Abelli Leonardo , Agosto Maria Vittoria , Casalbore Daniele , Romagnoli Claudia , Bosman Alessandro , Antonioli Fabrizio , Pierdomenico Martina , Sposato Andrea , Chiocci Francesco Latino 
Published: September 2014

Abstract
Recent underwater archaeological surveys recovered hundreds of flint artefacts between depths of 18 and 21 m at Cala Tramontana, a small bay located in the eastern part of Pantelleria Island. Most of the flint artefacts indicate debitage, and are characterized by cores and flakes without any specific morphology. Different lithic tools were also identified, such as fragments of blades, truncations, end-scrapers, points and crested blades. An initial hypothesis is that this lithic industry represents the oldest traces of human visitation to the island, possibly related to the exploitation of the nearby obsidian source, and favoured because of the sheltered coastal configuration of Cala Tramontana and Cala Levante with respect to the dominant winds and related storms. However, the present-day coastal setting in the bay is rather inhospitable, with high cliffs and difficult marine access. In contrast, palaeo-landscape reconstructions by means of high-resolution multibeam bathymetry reveal the possible presence of a small palaeo-beach in the inner part of the bay when the sea level was 15 m lower than at present. By comparing this palaeo-sea level with the eustatic curve (and by excluding possible vertical movements), we roughly estimate an age of the lithic industry of 9.6–7.7 cal ka BP.
BRCA1 Suppresses Epithelial-to-Mesenchymal Transition and Stem Cell Dedifferentiation during Mammary and Tumor Development
Authors: Bai Feng , Chan Ho Lam , Scott Alexandria , Smith Matthew D. , Fan Cheng , Herschkowitz Jason I. , Perou Charles M. , Livingstone Alan S. , Robbins David J. , Capobianco Anthony J. , Pei Xin-Hai 
Published: September 2014

Abstract
BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18Ink4c (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis. Cancer Res; 74(21); 6161–72. ©2014 AACR.
Validation of Biomarkers That Complement CA19.9 in Detecting Early Pancreatic Cancer
Authors: Chan Alison , Prassas Ioannis , Dimitromanolakis Apostolos , Brand Randall E. , Serra Stefano , Diamandis Eleftherios P. , Blasutig Ivan M. 
Published: September 2014

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer mortality. Carbohydrate antigen 19.9 (CA19.9), the only tumor marker available to detect and monitor PDAC, is not sufficiently sensitive and specific to consistently differentiate early cancer from benign disease. In this study, we aimed to validate recently discovered serum protein biomarkers for the early detection of PDAC and ultimately develop a biomarker panel that could discriminate PDAC from other benign disease better than the existing marker CA19.9.
Patients and Methods: We performed a retrospective blinded evaluation of 400 serum samples collected from individuals recruited on a consecutive basis. The sample population consisted of 250 individuals with PDAC at various stages, 130 individuals with benign conditions and 20 healthy individuals. The serum levels of each biomarker were determined by ELISAs or automated immunoassay.
Results: By randomly splitting matched samples into a training (n = 186) and validation (n = 214) set, we were able to develop and validate a biomarker panel consisting of CA19.9, CA125, and LAMC2 that significantly improved the performance of CA19.9 alone. Improved discrimination was observed in the validation set between all PDAC and benign conditions (AUCCA19.9 = 0.80 vs. AUCCA19.9+CA125+LAMC2 = 0.87; P &lt; 0.005) as well as between early-stage PDAC and benign conditions (AUCCA19.9 = 0.69 vs. AUCCA19.9+CA125+LAMC2 = 0.76; P &lt; 0.05) and between early-stage PDAC and chronic pancreatitis (CP; AUCCA19.9 = 0.59 vs. AUCCA19.9+CA125+LAMC2 = 0.74; P &lt; 0.05).
Conclusions: The data demonstrate that a serum protein biomarker panel consisting of CA125, CA19.9, and LAMC2 is able to significantly improve upon the performance of CA19.9 alone in detecting PDAC. Clin Cancer Res; 20(22); 5787–95. ©2014 AACR.
Phase II Study of Perifosine and Sorafenib Dual-Targeted Therapy in Patients with Relapsed or Refractory Lymphoproliferative Diseases
Authors: Guidetti Anna , Carlo-Stella Carmelo , Locatelli Silvia L. , Malorni Walter , Mortarini Roberta , Viviani Simonetta , Russo Domenico , Marchianò Alfonso , Sorasio Roberto , Dodero Anna , Farina Lucia , Giordano Laura , Di Nicola Massimo , Anichini Andrea , Corradini Paolo , Gianni Alessandro M. 
Published: September 2014

AbstractPurpose: To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases.Experimental Design: Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response.Results: Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4–21). The most common drug-related toxicities were grade 1–2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand–foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response.Conclusions: Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort. Clin Cancer Res; 20(22); 5641–51. ©2014 AACR.
Interrogating Two Schedules of the AKT Inhibitor MK-2206 in Patients with Advanced Solid Tumors Incorporating Novel Pharmacodynamic and Functional Imaging Biomarkers
Authors: Yap Timothy A. , Yan Li , Patnaik Amita , Tunariu Nina , Biondo Andrea , Fearen Ivy , Papadopoulos Kyriakos P. , Olmos David , Baird Richard , Delgado Liliana , Tetteh Ernestina , Beckman Robert A. , Lupinacci Lisa , Riisnaes Ruth , Decordova Shaun , Heaton Simon P. , Swales Karen , deSouza Nandita M. , Leach Martin O. , Garrett Michelle D. , Sullivan Daniel M. , de Bono Johann S. , Tolcher Anthony W. 
Published: September 2014

Abstract
Purpose: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60–80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing.
Experimental Design: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic–pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI.
Results: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial.
Conclusions: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488). Clin Cancer Res; 20(22); 5672–85. ©2014 AACR.
Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients
Authors: Garner Andrew P. , Gozgit Joseph M. , Anjum Rana , Vodala Sadanand , Schrock Alexa , Zhou Tianjun , Serrano Cesar , Eilers Grant , Zhu Meijun , Ketzer Julia , Wardwell Scott , Ning Yaoyu , Song Youngchul , Kohlmann Anna , Wang Frank , Clackson Tim , Heinrich Michael C. , Fletcher Jonathan A. , Bauer Sebastian , Rivera Victor M. 
Published: September 2014

Abstract
Purpose: KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST.
Experimental Design: The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib–KIT costructure was also determined. The clinical activity of ponatinib was examined in three patients with GIST previously treated with all three FDA-approved agents.
Results: In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three patients with GIST.
Conclusion:Ponatinib possesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in patients with GIST. Clin Cancer Res; 20(22); 5745–55. ©2014 AACR.
In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells
Authors: Dasmahapatra Girija , Patel Hiral , Friedberg Johnathan , Quayle Steven N. , Jones Simon S. , Grant Steven 
Published: September 2014

Abstract
Interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor carfilzomib were examined in non-Hodgkin lymphoma (NHL) models, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and double-hit lymphoma cells. Marked in vitro synergism was observed in multiple cell types associated with activation of cellular stress pathways (e.g., JNK1/2, ERK1/2, and p38) accompanied by increases in DNA damage (γH2A.X), G2–M arrest, and the pronounced induction of mitochondrial injury and apoptosis. Combination treatment with carfilzomib and ricolinostat increased reactive oxygen species (ROS), whereas the antioxidant TBAP attenuated DNA damage, JNK activation, and cell death. Similar interactions occurred in bortezomib-resistant and double-hit DLBCL, MCL, and primary DLBCL cells, but not in normal CD34+ cells. However, ricolinostat did not potentiate inhibition of chymotryptic activity by carfilzomib. shRNA knockdown of JNK1 (but not MEK1/2), or pharmacologic inhibition of p38, significantly reduced carfilzomib–ricolinostat lethality, indicating a functional contribution of these stress pathways to apoptosis. Combined exposure to carfilzomib and ricolinostat also markedly downregulated the cargo-loading protein HR23B. Moreover, HR23B knockdown significantly increased carfilzomib- and ricolinostat-mediated lethality, suggesting a role for this event in cell death. Finally, combined in vivo treatment with carfilzomib and ricolinostat was well tolerated and significantly suppressed tumor growth and increased survival in an MCL xenograft model. Collectively, these findings indicate that carfilzomib and ricolinostat interact synergistically in NHL cells through multiple stress-related mechanisms, and suggest that this strategy warrants further consideration in NHL. Mol Cancer Ther; 13(12); 2886–97. ©2014 AACR.
Development of Human Serine Protease-Based Therapeutics Targeting Fn14 and Identification of Fn14 as a New Target Overexpressed in TNBC
Authors: Zhou Hong , Mohamedali Khalid A. , Gonzalez-Angulo Ana Maria , Cao Yu , Migliorini Mary , Cheung Lawrence H. , LoBello Janine , Lei Xiudong , Qi Yuan , Hittelman Walter N. , Winkles Jeffrey A. , Tran Nhan L. , Rosenblum Michael G. 
Published: September 2014

AbstractThe cytokine TWEAK and its receptor, Fn14, have emerged as potentially valuable targets for cancer therapy. Granzyme B (GrB)–containing Fn14-targeted constructs were generated containing either the Fn14 ligand TWEAK (GrB-TWEAK) or an anti-Fn14 humanized single-chain antibody (GrB-Fc-IT4) as the targeting moieties. Both constructs showed high affinity and selective cytotoxicity against a panel of Fn14-expressing human tumor cells including triple-negative breast cancer (TNBC) lines. Cellular expression of the GrB inhibitor PI-9 in target cells had no impact on the cytotoxic effect of either construct. Cellular expression of MDR1 showed no cross-resistance to the fusion constructs. GrB-TWEAK and GrB-Fc-IT4 activated intracellular caspase cascades and cytochrome c–related proapoptotic pathways consistent with the known intracellular functions of GrB in target cells. Treatment of mice bearing established HT-29 xenografts with GrB-TWEAK showed significant tumor growth inhibition compared with vehicle alone (P &lt; 0.05). Both GrB-TWEAK and GrB-Fc-IT4 displayed significant tumor growth inhibition when administered to mice bearing orthotopic MDA-MB-231 (TNBC) tumor xenografts. The Cancer Genome Atlas analysis revealed that Fn14 mRNA expression was significantly higher in TNBC and in HER2-positive disease (P &lt; 0.0001) compared with hormone receptor–positive breast cancer, and in basal-like 2 tumors (P = 0.01) compared with other TNBC molecular subtypes. IHC analysis of a 101 patient TNBC tumor microarray showed that 55 of 101 (54%) of tumors stained positive for Fn14, suggesting that this may be an excellent potential target for precision therapeutic approaches. Targeting Fn14 using fully human, GrB-containing fusion constructs may form the basis for a new class of novel, potent, and highly effective constructs for targeted therapeutic applications. Mol Cancer Ther; 13(11); 2688–705. ©2014 AACR.