bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytoadherence of Plasmodium berghei-Infected Red Blood Cells to Murine Brain and Lung Microvascular Endothelial CellsIn Vitro
Authors: El-Assaad Fatima , Wheway Julie , Mitchell Andrew John , Lou Jinning , Hunt Nicholas Henry , Combes Valery , Grau Georges Emile Raymond 
Published: August 2013

ABSTRACTSequestration of infected red blood cells (iRBC) within the cerebral and pulmonary microvasculature is a hallmark of human cerebral malaria (hCM). The interaction between iRBC and the endothelium in hCM has been studied extensively and is linked to the severity of malaria. Experimental CM (eCM) caused byPlasmodium bergheiANKA reproduces most features of hCM, although the sequestration of RBC infected byP. bergheiANKA (PbA-iRBC) has not been completely delineated. The role of PbA-iRBC sequestration in the severity of eCM is not well characterized. Using static and flow cytoadherence assays, we provide the first directin vitroevidence for the binding of PbA-iRBC to murine brain and lung microvascular endothelial cells (MVEC). We found that basal PbA-iRBC cytoadherence to MVECs was significantly higher than that of normal red blood cells (NRBC) and of RBC infected withP. bergheiK173 (PbK173-iRBC), a strain that causes noncerebral malaria (NCM). MVEC prestimulation with tumor necrosis factor (TNF) failed to promote any further significant increase in mixed-stage iRBC adherence. Interestingly, enrichment of the blood for mature parasites significantly increased PbA-iRBC binding to the MVECs prestimulated with TNF, while blockade of VCAM-1 reduced this adhesion. Our study provides evidence for the firm, flow-resistant binding to endothelial cells of iRBC from strain ANKA-infected mice, which develop CM, and for less binding of iRBC from strain K173-infected mice, which develop NCM. An understanding ofP. bergheicytoadherence may help elucidate the importance of sequestration in the development of CM and aid the development of antibinding therapies to help reduce the burden of this syndrome.
No Holes Barred: Invasion of the Intestinal Mucosa by Mycobacterium avium subsp. paratuberculosis
Authors: Bannantine John P. , Bermudez Luiz E. 
Published: August 2013

ABSTRACT

The infection biology of
Mycobacterium avium
subsp.
paratuberculosis
has recently crystallized, with added details surrounding intestinal invasion. The involvement of pathogen-derived effector proteins such as the major membrane protein, oxidoreductase, and fibronectin attachment proteins have been uncovered. Mutations constructed in this pathogen have also shed light on genes needed for invasion. The host cell types that are susceptible to invasion have been defined, along with their transcriptional response. Recent details have given a new appreciation for the dynamic interplay between the host and bacterium that occurs at the outset of infection. An initial look at the global expression pathways of the host has shown a circumvention of the cell communication pathway by
M. avium
subsp.
paratuberculosis
, which loosens the integrity of the tight junctions. We now know that
M. avium
subsp.
paratuberculosis
activates the epithelial layer and also actively recruits macrophages to the site of infection. These notable findings are summarized along with added mechanistic details of the early infection model. We conclude by proposing critical next steps to further elucidate the process of
M. avium
subsp.
paratuberculosis
invasion.
Along-arc geochemical variations in Quaternary magmas of northern Kyushu Island, Japan
Authors: Shibata Tomoyuki , Yoshikawa Masako , Itoh Jun’ich , Ujike Osamu , Miyoshi Masaya , Takemura Keiji 
Published: August 2013

Abstract

We analysed major and trace elements and Sr–Nd–Pb isotope ratios of Himeshima, Futagoyama and Aso volcanoes, northern Kyushu, Japan. The purpose of the study was to investigate the petrogenesis of Quaternary arc magmas of the northern Kyushu arc, Japan, through along-strike variations. The northern Kyushu arc is underlain by the Philippine Sea Plate, which is divided by the Kyushu–Palau Ridge into the Palaeogene West Philippine Basin segment (60–40 Ma) and the Miocene Shikoku Basin segment (26–15 Ma). The Sr/Y ratios of the arc lavas decrease from north to south along the volcanic front. Mixing relations in Sr–Nd–Pb isotope space suggest recycling of the subducted slab materials from the Philippine Sea Plate to the arc. The
87
Sr/
86
Sr ratios decrease with increasing Sr/Y and SiO
2
, which argues against a genetic link of fractional crystallization between adakites and basaltic magmas. The observations further suggest that partial melting of the hot and young Shikoku Basin slab produces the high Sr/Y component visible in the arc magmas in the north, whereas dehydration of the older West Philippine Basin slab produces the low Sr/Y arc magmas in the south.
Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged after Progression
Authors: Romano Emanuela , Pradervand Sylvain , Paillusson Alexandra , Weber Johann , Harshman Keith , Muehlethaler Katja , Speiser Daniel , Peters Solange , Rimoldi Donata , Michielin Olivier 
Published: August 2013

Abstract
Purpose: To investigate the mechanism(s) of resistance to the RAF-inhibitor vemurafenib, we conducted a comprehensive analysis of the genetic alterations occurring in metastatic lesions from a patient with a BRAFV600E-mutant cutaneous melanoma who, after a first response, underwent subsequent rechallenge with this drug.
Experimental Design: We obtained blood and tissue samples from a patient diagnosed with a BRAFV600E-mutant cutaneous melanoma that was treated with vemurafenib and achieved a near-complete response. At progression, he received additional lines of chemo/immunotherapy and was successfully rechallenged with vemurafenib. Exome and RNA sequencing were conducted on a pretreatment tumor and two subcutaneous resistant metastases, one that was present at baseline and previously responded to vemurafenib (PV1) and one that occurred de novo after reintroduction of the drug (PV2). A culture established from PV1 was also analyzed.
Results: We identified two NRAS-activating somatic mutations, Q61R and Q61K, affecting two main subpopulations in the metastasis PV1 and a BRAF alternative splicing, involving exons 4–10, in the metastasis PV2. These alterations, known to confer resistance to RAF inhibitors, were tumor-specific, mutually exclusive, and were not detected in pretreatment tumor samples. In addition, the oncogenic PIK3CAH1047R mutation was detected in a subpopulation of PV1, but this mutation did not seem to play a major role in vemurafenib resistance in this metastasis.
Conclusions: This work describes the coexistence within the same patient of different molecular mechanisms of resistance to vemurafenib affecting different metastatic sites. These findings have direct implications for the clinical management of BRAF-mutant melanoma. Clin Cancer Res; 19(20); 5749–57. ©2013 AACR.
Differential Response to Neoadjuvant Chemotherapy Among 7 Triple-Negative Breast Cancer Molecular Subtypes
Authors: Masuda Hiroko , Baggerly Keith A. , Wang Ying , Zhang Ya , Gonzalez-Angulo Ana Maria , Meric-Bernstam Funda , Valero Vicente , Lehmann Brian D. , Pietenpol Jennifer A. , Hortobagyi Gabriel N. , Symmans W. Fraser , Ueno Naoto T. 
Published: August 2013

Abstract
Purpose: The clinical relevancy of the 7-subtype classification of triple-negative breast cancer (TNBC) reported by Lehmann and colleagues is unknown. We investigated the clinical relevancy of TNBC heterogeneity by determining pathologic complete response (pCR) rates after neoadjuvant chemotherapy, based on TNBC subtypes.
Experimental Design: We revalidated the Lehmann and colleagues experiments using Affymetrix CEL files from public datasets. We applied these methods to 146 patients with TNBC with gene expression microarrays obtained from June 2000 to March 2010 at our institution. Of those, 130 had received standard neoadjuvant chemotherapy and had evaluable pathologic response data. We classified the TNBC samples by subtype and then correlated subtype and pCR status using Fisher exact test and a logistic regression model. We also assessed survival and compared the subtypes with PAM50 intrinsic subtypes and residual cancer burden (RCB) index.
Results: TNBC subtype and pCR status were significantly associated (P = 0.04379). The basal-like 1 (BL1) subtype had the highest pCR rate (52%); basal-like 2 (BL2) and luminal androgen receptor had the lowest (0% and 10%, respectively). TNBC subtype was an independent predictor of pCR status (P = 0.022) by a likelihood ratio test. The subtypes better predicted pCR status than did the PAM50 intrinsic subtypes (basal-like vs. non basal-like).
Conclusions: Classifying TNBC by 7 subtypes predicts high versus low pCR rate. We confirm the clinical relevancy of the 7 subtypes of TNBC. We need to prospectively validate whether the pCR rate differences translate into long-term outcome differences. The 7-subtype classification may spur innovative personalized medicine strategies for patients with TNBC. Clin Cancer Res; 19(19); 5533–40. ©2013 AACR.
Prognostic Factors in Patients with Advanced Cancer: A Comparison of Clinicopathological Factors and the Development of an Inflammation-Based Prognostic System
Authors: Laird Barry J. , Kaasa Stein , McMillan Donald C. , Fallon Marie T. , Hjermstad Marianne J. , Fayers Peter , Klepstad Pal 
Published: August 2013

Abstract
Purpose: In advanced cancer, oncological treatment is influenced by performance status (PS); however, this has limitations. Biomarkers of systemic inflammation may have prognostic value in advanced cancer. The study compares key factors in prognosis (performance status, patient-reported outcomes; PRO) with an inflammation-based score (Glasgow Prognostic Score, mGPS). A new method of prognosis in advanced cancer (combining performance status and mGPS) is tested and then validated.
Experimental Design: Two international biobanks of patients with advanced cancer were analyzed. Key prognostic factors [performance status, PROs (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30), and mGPS (using C-reactive protein and albumin concentrations)] were examined. The relationship between these and survival was examined using Kaplan–Meier and Cox regression methods, in a test sample before independent validation.
Results: Data were available on 1,825 patients (test) and 631 patients (validation). Median survival ranged from 3.2 months (test) to 7.03 months (validation). On multivariate analysis, performance status (HR 1.62–2.77) and mGPS (HR 1.51–2.27) were independently associated with, and were the strongest predictors of survival (P &lt; 0.01). Survival at 3 months varied from 82% (mGPS 0) to 39% (mGPS 2) and from 75% (performance status 0–1) to 14% (performance status 4). When used together, survival ranged from 88% (mGPS 0, PS 0–1) to 10% (mGPS 2, performance status 4), P &lt; 0.001.
Conclusion: A systemic inflammation-based score, mGPS, and performance status predict survival in advanced cancer. The mGPS is similar to performance status in terms of prognostic power. Used together, performance status and mGPS act synergistically improving prognostic accuracy. This new method may be of considerable value in the management of patients with advanced cancer. Clin Cancer Res; 19(19); 5456–64. ©2013 AACR.
EGFR Inhibition Promotes an Aggressive Invasion Pattern Mediated by Mesenchymal-like Tumor Cells within Squamous Cell Carcinomas
Authors: Basu Devraj , Bewley Arnaud F. , Sperry Steven M. , Montone Kathleen T. , Gimotty Phyllis A. , Rasanen Kati , Facompre Nicole D. , Weinstein Gregory S. , Nakagawa Hiroshi , Diehl J. Alan , Rustgi Anil K. , Herlyn Meenhard 
Published: August 2013

Abstract
Squamous cell carcinomas (SCC) with an infiltrative invasion pattern carry a higher risk of treatment failure. Such infiltrative invasion may be mediated by a mesenchymal-like subpopulation of malignant cells that we have previously shown to arise from epithelial–mesenchymal transition (EMT) and resist epidermal growth factor receptor (EGFR) targeting. Here, we show that SCCs with infiltrative, high-risk invasion patterns contain abundant mesenchymal-like cells, which are rare in tumors with low-risk patterns. This cellular heterogeneity was modeled accurately in three-dimensional culture using collagen-embedded SCC spheroids, which revealed distinct invasive fronts created by collective migration of E-cadherin–positive cells versus infiltrative migration of individual mesenchymal-like cells. Because EGFR expression by mesenchymal-like cells was diminished in the spheroid model and in human SCCs, we hypothesized that SCCs shift toward infiltrative invasion mediated by this subpopulation during anti-EGFR therapy. Anti-EGFR treatment of spheroids using erlotinib or cetuximab enhanced infiltrative invasion by targeting collective migration by E-cadherin–positive cells while sparing mesenchymal-like cells; by contrast, spheroid invasion in absence of mesenchymal-like cells was abrogated by erlotinib. Similarly, cetuximab treatment of xenografts containing mesenchymal-like cells created an infiltrative invasive front composed of this subpopulation, whereas no such shift was observed upon treating xenografts lacking these cells. These results implicate mesenchymal-like SCC cells as key mediators of the infiltrative invasion seen in tumors with locally aggressive behavior. They further show that EGFR inhibition can promote an infiltrative invasion front composed of mesenchymal-like cells preferentially in tumors where they are abundant before therapy. Mol Cancer Ther; 12(10); 2176–86. ©2013 AACR.
Histone Deacetylase Regulation of ATM-Mediated DNA Damage Signaling
Authors: Thurn K. Ted , Thomas Scott , Raha Paromita , Qureshi Ian , Munster Pamela N. 
Published: August 2013

Abstract
Ataxia–telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A, and RRM2B that promote cell-cycle arrest and DNA repair. The upregulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here, we show that histone deacetylases (HDAC) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors. Mol Cancer Ther; 12(10); 2078–87. ©2013 AACR.
Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance
Authors: Haider Christine , Grubinger Markus , Řezníčková Eva , Weiss Thomas S. , Rotheneder Hans , Miklos Walter , Berger Walter , Jorda Radek , Zatloukal Marek , Gucký Tomáš , Strnad Miroslav , Kryštof Vladimír , Mikulits Wolfgang 
Published: August 2013

Abstract
Treatment options for hepatocellular carcinoma using chemotherapeutics at intermediate and advanced stages of disease are limited as patients most rapidly escape from therapy and succumb to disease progression. Mechanisms of the hepatic xenobiotic metabolism are mostly involved in providing chemoresistance to therapeutic compounds. Given the fact that the aberrant activation of cyclin-dependent kinases (CDK) is frequently observed in hepatocellular carcinomas, we focused on the efficacy of the novel compounds BA-12 and BP-14 that antagonize CDK1/2/5/7 and CDK9. Inhibition of those CDKs in human hepatocellular carcinoma cell lines reduced the clonogenicity by arresting cells in S–G2 and G2–M phase of the cell cycle and inducing apoptosis. In contrast, primary human hepatocytes failed to show cytotoxicity and apoptosis. No loss of chemosensitivity was observed in hepatocellular carcinoma cells after long-term exposure to inhibitors. In vivo, treatment of xenografted human hepatocellular carcinomas with BA-12 or BP-14 effectively repressed tumor formation. Moreover, BA-12 or BP-14 significantly diminished diethylnitrosamine (DEN)-induced hepatoma development in mice. These data show that BA-12 or BP-14 exhibit strong antitumorigenic effects in the absence of chemoresistance, resulting in a superior efficacy compared with currently used chemotherapeutics in hepatocellular carcinomas. Mol Cancer Ther; 12(10); 1947–57. ©2013 AACR.
Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis
Authors: Kovářová Denisa , Plachý Jiří , Kosla Jan , Trejbalová Kateřina , Čermák Vladimír , Hejnar Jiří 
Published: August 2013

Abstract
Comparing the gene expression profiles of metastatic and nonmetastatic cells has the power to reveal candidate metastasis-associated genes, whose involvement in metastasis can be experimentally tested. In this study, differentially expressed genes were explored in the v-src-transformed metastatic cell line PR9692 and its nonmetastatic subclone PR9692-E9. First, the contribution of homeodomain only protein X (HOPX) in metastasis formation and development was assessed. HOPX-specific knockdown decreased HOPX expression in the nonmetastatic subclone and displayed reduced cell motility in vitro. Critically, HOPX knockdown decreased the in vivo metastatic capacity in a syngeneic animal model system. Genomic analyses identified a cadre of genes affected by HOPX knockdown that intersected significantly with genes previously found to be differentially expressed in metastatic versus nonmetastatic cells. Furthermore, 232 genes were found in both screens with at least a two-fold change in gene expression, and a number of high-confidence targets were validated for differential expression. Importantly, significant changes were demonstrated in the protein expression level of three metastatic-associated genes (NCAM, FOXG1, and ITGA4), and knockdown of one of the identified HOPX-regulated metastatic genes, ITGA4, showed marked inhibition of cell motility and metastasis formation. These data demonstrate that HOPX is a metastasis-associated gene and that its knockdown decreases the metastatic activity of v-src-transformed cells through altered gene expression patterns.
Implications: This study provides new mechanistic insight into a HOPX-regulated metastatic dissemination signature. Mol Cancer Res; 11(10); 1235–47. ©2013 AACR.
Population Pharmacokinetics of Enoxaparin During the Antenatal Period
Authors: Patel Jignesh P. , Green Bruce , Patel Raj K. , Marsh Michael S. , Davies J. Graham , Arya Roopen 
Published: August 2013

Background—
The optimal dosing strategy of low-molecular-weight heparins for the treatment of antenatal venous thromboembolism is not known. The physiological changes associated with pregnancy alter the pharmacokinetic profile of low-molecular-weight heparins, which has led to controversy and subsequent variation in practice, when pregnant women with venous thromboembolism are treated with low-molecular-weight heparins. Our objective was to develop a robust pharmacokinetic model of enoxaparin during the antenatal period to address this problem.

Method and Results—
Women prescribed antenatal enoxaparin were eligible to enroll in the study. Recruited women were reviewed monthly and had up to 3 anti-Xa activities (trough and 1 and 3 hours after dose) drawn at each clinic attendance. Compartmental pharmacokinetic modeling was conducted using nonlinear mixed-effects modeling. One hundred twenty-three patients contributed 795 anti-Xa activities for pharmacokinetic modeling purposes. Both enoxaparin clearance and volume of distribution were increased during pregnancy. Simulations of once- versus twice-daily enoxaparin administration demonstrated that both dosing regimens would reach target 3-hour plasma concentrations throughout the duration of the pregnancy. When trough anti-Xa activity was simulated, both once- and twice-daily regimens exhibited an increase in trough anti-Xa activity with the progression of pregnancy. This is explained by the significant increase in volume of distribution observed during pregnancy.

Conclusions—
The half-life of enoxaparin is prolonged with the progression of pregnancy, and our work provides compelling evidence for prescribing once-daily enoxaparin for the treatment of antenatal venous thromboembolism. National and international guideline recommendations should be reconsidered.
Simple Integer Risk Score to Determine Prognosis of Patients With Hypertension and Chronic Stable Coronary Artery Disease
Authors: Bavry Anthony A. , Kumbhani Dharam J. , Gong Yan , Handberg Eileen M. , Cooper‐DeHoff Rhonda M. , Pepine Carl J. 
Published: August 2013

Background

It is difficult to accurately determine prognosis of patients with hypertension and chronic stable coronary artery disease (
CAD
). Our aim was to construct a risk score for predicting important adverse events in this population.

Methods and Results

Patients with hypertension and chronic stable
CAD
enrolled in the
IN
ternational
VE
rapamil‐
SR
/Trandolapril
ST
udy (
INVEST
) comprised the study cohort. Candidate predictor variables were obtained from patients with at least 1 postbaseline visit. Patients were divided into development (n=18 484) and validation cohorts (n=2054). Cox regression model identified predictors of the primary outcome: all‐cause mortality, myocardial infarction, or stroke at a mean follow‐up of 2.3 years. The hazard ratio of each variable was rounded to the nearest integer to construct score weights. A score 0 to 4 defined low‐risk, 5 to 6 intermediate‐risk and ≥7 high‐risk. The following variables were retained in the final model: age, residence, body mass index, on‐treatment heart rate and BP, prior myocardial infarction, heart failure, stroke/transient ischemic attack, smoking, diabetes, peripheral arterial disease, and chronic kidney disease. The primary outcome occurred in 2.9% of the low‐risk group, 6.5% of the intermediate‐risk group, and 18.0% of the high‐risk group (
P
for trend <0.0001). The model was good at discriminating those who had an event versus those who did not (C‐statistic=0.75). The model performed well in a validation cohort (C‐statistic=0.77).

Conclusion

Readily available clinical variables can rapidly stratify patients with hypertension and chronic stable
CAD
into useful risk categories.