bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thermodynamic modelling of hydrogen migration in argillite for a deep geological radioactive waste repository: IRSN contribution to FORGE
Authors: Dymitrowska M. , Smaï F. , Bourgeat A. 
Published: February 2015

Abstract
The aim of this work is to provide an improved mathematical and physical description of two-phase flow in tight porous media in order to model hydrogen migration within a geological repository for radioactive waste as required to further assess the behaviour in time and space of such facilities. First, we introduce a general physical framework describing multicomponent and two-phase (liquid and gas) flow in porous media with capillary pressure curve and mass exchange between phases. Assuming thermodynamic equilibrium, mass exchange between phases is governed by thermodynamic principles which we briefly describe. This physical modelling is able to describe single-phase flow (only gas mixture or liquid solution) as well as two-phase flow (both liquid and gas phases are present). On the basis of this treatment we obtain a generalized formulation of Henry and Raoult–Kelvin laws. We show that, for a hydrogen–water mixture in repository conditions of pressure and suction, these relationships constitute an adequate mass equilibrium description. Second, we consider the mathematical formulation of the problem, which is mainly determined by the choice of primary variables. Contrary to existing approaches, we are interested in avoiding the need to switch primary variables during calculations. Indeed, such a switch is often proposed as a solution to treat phase appearance or disappearance. We will show that, in our physical framework, taking into account the capillary pressure and mass exchanges between phases, it is possible to work with universal primary variables to correctly describe gas phase appearance or disappearance. Simple numerical simulations are presented for validation as well as an application of this model to the FORGE benchmark on the cell scale together with a sensitivity analysis guided by physical considerations.
Akt–Girdin Signaling in Cancer-Associated Fibroblasts Contributes to Tumor Progression
Authors: Yamamura Yumiko , Asai Naoya , Enomoto Atsushi , Kato Takuya , Mii Shinji , Kondo Yuji , Ushida Kaori , Niimi Kaoru , Tsunoda Nobuyuki , Nagino Masato , Ichihara Shu , Furukawa Koichi , Maeda Kengo , Murohara Toyoaki , Takahashi Masahide 
Published: March 2015

Abstract
PI3K–Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment. Cancer Res; 75(5); 813–23. ©2015 AACR.
RIP1 Kinase Is an Oncogenic Driver in Melanoma
Authors: Liu Xiao Ying , Lai Fritz , Yan Xu Guang , Jiang Chen Chen , Guo Su Tang , Wang Chun Yan , Croft Amanda , Tseng Hsin-Yi , Wilmott James S. , Scolyer Richard A. , Jin Lei , Zhang Xu Dong 
Published: February 2015

Abstract
Although many studies have uncovered an important role for the receptor-binding protein kinase RIP1 in controlling cell death signaling, its possible contributions to cancer pathogenesis have been little explored. Here, we report that RIP1 functions as an oncogenic driver in human melanoma. Although RIP1 was commonly upregulated in melanoma, RIP1 silencing inhibited melanoma cell proliferation in vitro and retarded the growth of melanoma xenografts in vivo. Conversely, while inducing apoptosis in a small proportion of melanoma cells, RIP1 overexpression enhanced proliferation in the remaining cells. Mechanistic investigations revealed that the proliferative effects of RIP1 overexpression were mediated by NF-κB activation. Strikingly, ectopic expression of RIP1 enhanced the proliferation of primary melanocytes, triggering their anchorage-independent cell growth in an NF-κB–dependent manner. We identified DNA copy-number gain and constitutive ubiquitination by a TNFα autocrine loop mechanism as two mechanisms of RIP1 upregulation in human melanomas. Collectively, our findings define RIP1 as an oncogenic driver in melanoma, with potential implications for targeting its NF-κB–dependent activation mechanism as a novel approach to treat this disease. Cancer Res; 75(8); 1736–48. ©2015 AACR.
“(Not) All (Dead) Things Share the Same Breath”: Identification of Cell Death Mechanisms in Anticancer Therapy
Authors: Rello-Varona Santiago , Herrero-Martín David , López-Alemany Roser , Muñoz-Pinedo Cristina , Tirado Oscar M. 
Published: February 2015

Abstract
During the last decades, the knowledge of cell death mechanisms involved in anticancer therapy has grown exponentially. However, in many studies, cell death is still described in an incomplete manner. The frequent use of indirect proliferation assays, unspecific probes, or bulk analyses leads too often to misunderstandings regarding cell death events. There is a trend to focus on molecular or genetic regulations of cell demise without a proper characterization of the phenotype that is the object of this study. Sometimes, cancer researchers can feel overwhelmed or confused when faced with such a corpus of detailed insights, nomenclature rules, and debates about the accuracy of a particular probe or assay. On the basis of the information available, we propose a simple guide to distinguish forms of cell death in experimental settings using cancer cell lines. Cancer Res; 75(6); 913–7. ©2015 AACR.
PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients
Authors: de la Rochefordiere Anne , Kamal Maud , Floquet Anne , Thomas Laurence , Petrow Peter , Petit Thierry , Pop Marius , Fabbro Michel , Kerr Christine , Joly Florence , Sevin Emmanuel , Maillard Sophie , Curé Hervé , Weber Béatrice , Brunaud Claire , Minsat Mathieu , Gonzague Laurence , Berton-Rigaud Dominique , Aumont Maud , Gladieff Laurence , Peignaux Karine , Bernard Virginie , Leroy Quentin , Bieche Ivan , Margogne Audrey , Nadan AnaTereza , Fourchotte Virginie , Diallo Alhassane , Asselain Benard , Plancher Corine , Armanet Sébastien , Beuzeboc Philippe , Scholl Suzy M. 
Published: February 2015

Abstract
Purpose: EGFR is frequently overexpressed in cervical cancer, suggesting EGFR blockade as a promising treatment approach. Cetuximab, an anti EGFR antibody, used conjointly with radiochemotherapy, was feasible in first-line treatment of cervix carcinoma limited to the pelvis.
Experimental Design: This randomized phase II trial enrolled 78 FIGO stage IB2–IIIB cervical cancer patients to either cisplatin-based radiochemotherapy alone (arm B, n = 38) or conjointly with a 6-week course of weekly cetuximab (arm A, n = 40). Brachytherapy was given to the pelvic mass. Primary endpoint was disease-free survival (DFS) at 2 years. EGFR expression and targeted sequencing were performed in 54 of 78 patients.
Results: Cetuximab over a 6-week period did not improve DFS at 24 months. At 31 months median follow-up, DFS was not significantly different (P = 0.18). Complete response at 4 to 6 months was strongly predictive for excellent DFS (log-rank test; P &lt; 0.001). PIK3CA, KRAS, and STK11 mutations were observed in 22%, 4%, and 2% of patients, respectively. No tumor with a PI3K pathway mutation showed complete response (0/8 in arm A and 0/6 in arm B), whereas 14 of 52 (27%) tumors without mutations did (P = 0.021). PI3K pathway-mutated tumors showed a trend toward poorer DFS (P = 0.06) following cetuximab (8/22) as compared with those following standard treatment only (6/18).
Conclusions: Similar to patients with head and neck cancer, patients with cervical cancer showed no gain in DFS at 2 years following a combined treatment of cetuximab with radiochemotherapy. Although treatment tolerance and compliance were satisfactory, it remains to be demonstrated whether maintenance therapy with cetuximab could be beneficial in selected patient groups. Clin Cancer Res; 21(11); 2530–7. ©2015 AACR.
Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib
Authors: Gainor Justin F. , Tan Daniel S.W. , De Pas Tomasso , Solomon Benjamin J. , Ahmad Aziah , Lazzari Chiara , de Marinis Filippo , Spitaleri Gianluca , Schultz Katherine , Friboulet Luc , Yeap Beow Y. , Engelman Jeffrey A. , Shaw Alice T. 
Published: February 2015

Abstract
Purpose: Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non–small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents.
Experimental Design: We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and ceritinib.
Results: Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4–10.6]. The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1–694). The mPFS on ceritinib was 7.8 months (6.5–9.1). Among 53 patients with no interval therapies between crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4–9.8). The median combined PFS for sequential treatment with crizotinib and ceritinib was 17.4 months (15.5–19.4). Among 23 patients who underwent post-crizotinib/pre-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5–63.1).
Conclusions: Ceritinib has significant antitumor activity in ALK-positive NSCLC—even when crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib. Clin Cancer Res; 21(12); 2745–52. ©2015 AACR.
Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus
Authors: Huynh Hung , Hao Huai-Xiang , Chan Stephen L. , Chen David , Ong Richard , Soo Khee Chee , Pochanard Panisa , Yang David , Ruddy David , Liu Manway , Derti Adnan , Balak Marissa N. , Palmer Michael R. , Wang Yan , Lee Benjamin H. , Sellami Dalila , Zhu Andrew X. , Schlegel Robert , Huang Alan 
Published: February 2015

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV+ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224–35. ©2015 AACR.
Detection of Tumor Suppressor Genes in Cancer Development by a Novel shRNA-Based Method
Authors: von Burstin Johannes , Diersch Sandra , Schneider Günter , Reichert Maximilian , Rustgi Anil K. , Schmid Roland M. 
Published: February 2015

Abstract
Pancreatic cancer is one of the deadliest cancers with poor survival rates and limited therapeutic options. To improve the understanding of this disease's biology, a prerequisite for the generation of novel therapeutics, new platforms for rapid and efficient genetic and therapeutic screening are needed. Therefore, a combined in vitro/in vivo hybrid shRNA assay was developed using isolated murine primary pancreatic ductal cells (PDCs), in which oncogenic KrasG12D could be activated in vitro by genomic recombination through 4OH-tamoxifen–induced nuclear translocation of Cre-ERT2 expressed under control of the ROSA26 promoter. Further genetic manipulation was achieved through selective and stable RNAi against the tumor suppressors p16Ink4a (CDKN2A) or Trp53 (TP53) using lentiviral gene delivery. Treatment of PDCs with 4OH-tamoxifen increased phosphorylation of ERK downstream of KRAS, and subsequent lentiviral transduction resulted in sustained target gene repression. Double-mutant PDCs were then reintroduced into the pancreata of NOD-SCID-gamma (NSG) mice and monitored for tumor growth. Orthotopic implantation of PDCs carrying the activated KrasG12D-allele and shRNA against p16Ink4a or Trp53 resulted in tumor growth, metastasis, and reduced survival of NSG mice. In contrast, KrasG12D alone was not sufficient to induce tumor growth.
Implications: The combinatory in vitro/in vivo approach described in this study allows for rapid and efficient identification of genes involved in carcinogenesis and opens new avenues for the development of therapeutic strategies to improve cancer treatment. Mol Cancer Res; 13(5); 863–9. ©2015 AACR.
Variation in Critical Care Unit Admission Rates and Outcomes for Patients With Acute Coronary Syndromes or Heart Failure Among High‐ and Low‐Volume Cardiac Hospitals
Authors: van Diepen Sean , Bakal Jeffrey A. , Lin Meng , Kaul Padma , McAlister Finlay A. , Ezekowitz Justin A. 
Published: February 2015

Background

Little is known about cross‐hospital differences in critical care units admission rates and related resource utilization and outcomes among patients hospitalized with acute coronary syndromes (
ACS
) or heart failure (
HF
).

Methods and Results

Using a population‐based sample of 16 078 patients admitted to a critical care unit with a primary diagnosis of
ACS
(n=14 610) or
HF
(n=1467) between April 1, 2003 and March 31, 2013 in Alberta, Canada, we stratified hospitals into high (>250), medium (200 to 250), or low (<200) volume based on their annual volume of all
ACS
and
HF
hospitalization. The percentage of hospitalized patients admitted to critical care units varied across low, medium, and high‐volume hospitals for both
ACS
and
HF
as follows: 77.9%, 81.3%, and 76.3% (
P
<0.001), and 18.0%, 16.3%, and 13.0% (
P
<0.001), respectively. Compared to low‐volume units, critical care patients with
ACS
and
HF
admitted to high‐volume hospitals had shorter mean critical care stays (56.6 versus 95.6 hours,
P
<0.001), more critical care procedures (1.9 versus 1.2 per patient, <0.001), and higher resource‐intensive weighting (2.8 versus 1.5,
P
<0.001). No differences in in‐hospital mortality (5.5% versus 6.2%, adjusted odds ratio 0.93; 95%
CI
, 0.61 to 1.41) were observed between high‐ and low‐volume hospitals; however, 30‐day cardiovascular readmissions (4.6% versus 6.8%, odds ratio 0.77; 95%
CI
, 0.60 to 0.99) and cardiovascular emergency‐room visits (6.6% versus 9.5%, odds ratio 0.80; 95%
CI
, 0.69 to 0.94) were lower in high‐volume compared to low‐volume hospitals. Outcomes stratified by
ACS
or
HF
admission diagnosis were similar.

Conclusions

Cardiac patients hospitalized in low‐volume hospitals were more frequently admitted to critical care units and had longer hospitals stays despite lower resource‐intensive weighting. These findings may provide opportunities to standardize critical care utilization for
ACS
and
HF
patients across high‐ and low‐volume hospitals.
Sometimes more competent, but always less warm: Perceptions of biologically oriented mental-health clinicians
Authors: Lebowitz Matthew S , Ahn Woo-kyoung , Oltman Kathleen 
Published: February 2015

Background and aims: Biological conceptualizations of psychopathology are ascendant, including among mental-health clinicians. However, it is unknown how this might affect people’s perceptions of clinicians, which in turn could have considerable public-health implications. The present studies sought to address this issue. Methods: In the present research, participants imagined that they or their loved ones were suffering from a mental disorder and then rated their perceptions of one clinician espousing the view that ‘mental disorders are brain diseases’ and another describing them as ‘disorders of thoughts and emotions’. Results: Biologically oriented clinicians were perceived as more competent and effective only when the disorder in question was judged to be biologically caused. Otherwise, there was no significant difference in perceived competence, and biologically oriented clinicians were rated less effective. Regardless, all participants perceived the biologically oriented clinician as significantly less warm on average than the psychosocially oriented clinician. Conclusion: These findings may have important clinical implications for the crucial therapeutic alliance between therapists and patients.
Race and Referral to Diabetes Education in Primary Care Patients With Prediabetes and Diabetes
Authors: Hooks-Anderson Denise R. , Crannage Erica F. , Salas Joanne , Scherrer Jeffrey F. 
Published: February 2015

Purpose The purpose of the study was to determine whether there are any race-related disparities in the prevalence of provisions for diabetes education in primary care clinics for patients with diabetes and prediabetes. Methods A retrospective cross-sectional study of 3967 patients aged 14 to >89 years with prediabetes and diabetes. Medical record data from patient encounters within primary care clinics at a large academic medical health system between July 1, 2008, and July 31, 2013, were used to determine rates of referral for diabetes education by race. Multivariate logistic regression models were used to assess associations between race and referral to diabetes education. Separate regression models were computed for patients who were prediabetic and diabetic. Adjusted models included age, sex, A1C, health care utilization, smoking, and diagnosis for depression, hyperlipidemia, hypertension, vascular disease, and obesity. Results Compared to that of white patients, a significantly higher prevalence of African American patients with prediabetes were referred to diabetes education, and this association was also observed in patients with diabetes. In fully adjusted models, white patients with prediabetes were significantly less likely to be referred. Conclusions Being African American independently increased the likelihood of referral for diabetes education in patients with prediabetes and patients with diabetes. After adjusting for patient comorbidities and risk factors, this association remained significant for patients with prediabetes. Additional research is needed to determine if provider beliefs and attitudes regarding race and diabetes education account for this association.
The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication
Authors: Basol Nursah , Erbas Oytun 
Published: February 2015

Background and objective: Amitriptyline, a frequently used tricyclic antidepressant agent, has powerful cardiotoxic effects especially in high doses. Serum and urine levels of amitriptyline dosages are not correlated with severity of toxicity; therefore, it increases the importance of electrocardiography (ECG) abnormalities. The prolongation of QTc can be a predictive marker for cardiotoxicity. Hence, in this study, it is aimed to evaluate possible effects of metoprolol and diltiazem in amitriptyline toxicity. Materials and methods: The rats were separated into four groups. First one was control group, the second was the amitriptyline + saline group, third one was the amitriptyline + metoprolol group, and forth one was the amitriptyline + diltiazem group. ECG were recorded on rats under anesthesia. Results: In amitriptyline group, QTc duration was prolonged compared with all other groups. The prolongation of QTc was shorter in amitriptyline + metoprolol group and amitriptyline + diltiazem group than amitriptyline group ( p < 0.01 and p < 0.01, respectively). Conclusion: According to the results, it is possible to report ameliorating effects of both metoprolol and diltiazem on QTc prolongation related with amitriptyline intoxication. With further studies, these agents may be used for amitriptyline toxicity and besides, they may be used for patients in cardiovascular risk groups who take amitriptyline treatment regularly.
Using a Randomized Voucher Experiment to Determine Demand for Carbon Monoxide Alarms in a Social Marketing Program
Authors: Bishai David , Haimann Adria , Perry Elise , Shields Wendy , Gielen Andrea , McDonald Eileen 
Published: March 2015

Background: We report on a social marketing campaign conducted in Baltimore homes to promote carbon monoxide (CO) alarms including the use of community outreach, vouchers, and a mobile van to increase availability. This article focuses on the impact of the vouchers and measures the price sensitivity of individuals in their willingness to obtain a CO alarm. Methods: The study provided all 712 participants a health education message about the importance of CO alarms. Then each received one of five randomly selected vouchers that would make the price of a CO alarm US$0, US$5.50, US$11.00, US$16.50, or US$22.00 and that could be redeemed at mobile van that was parked in their neighborhood. Results: The study found that the more the CO alarm was discounted, the more likely the voucher was to be redeemed. Discounting the price to US$0 had a larger effect than any other price point. Individuals who already owned CO alarms were more influenced by the free price point than individuals who did not have CO alarms at baseline, and some of these individuals appear to have installed more than one CO alarm in their dwelling. Homes with children were less likely and homes with older adults were more likely to redeem the vouchers. Conclusion: Making CO alarms free has the largest impact on the total number of CO alarms distributed. Individuals who already had CO alarms are more attracted to free CO alarms than individuals with no CO alarm.