bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nicotinic Acid Phosphoribosyltransferase Regulates Cancer Cell Metabolism, Susceptibility to NAMPT Inhibitors, and DNA Repair
Authors: Piacente Francesco , Caffa Irene , Ravera Silvia , Sociali Giovanna , Passalacqua Mario , Vellone Valerio G. , Becherini Pamela , Reverberi Daniele , Monacelli Fiammetta , Ballestrero Alberto , Odetti Patrizio , Cagnetta Antonia , Cea Michele , Nahimana Aimable , Duchosal Michel , Bruzzone Santina , Nencioni Alessio 
Published: May 2017

Abstract
In the last decade, substantial efforts have been made to identify NAD+ biosynthesis inhibitors, specifically against nicotinamide phosphoribosyltransferase (NAMPT), as preclinical studies indicate their potential efficacy as cancer drugs. However, the clinical activity of NAMPT inhibitors has proven limited, suggesting that alternative NAD+ production routes exploited by tumors confer resistance. Here, we show the gene encoding nicotinic acid phosphoribosyltransferase (NAPRT), a second NAD+-producing enzyme, is amplified and overexpressed in a subset of common types of cancer, including ovarian cancer, where NAPRT expression correlates with a BRCAness gene expression signature. Both NAPRT and NAMPT increased intracellular NAD+ levels. NAPRT silencing reduced energy status, protein synthesis, and cell size in ovarian and pancreatic cancer cells. NAPRT silencing sensitized cells to NAMPT inhibitors both in vitro and in vivo; similar results were obtained with the NAPRT inhibitor 2-hydroxynicotinic acid. Reducing NAPRT levels in a BRCA2-deficient cancer cell line exacerbated DNA damage in response to chemotherapeutics. In conclusion, NAPRT-dependent NAD+ biosynthesis contributes to cell metabolism and to the DNA repair process in a subset of tumors. This knowledge could be used to increase the efficacy of NAMPT inhibitors and chemotherapy. Cancer Res; 77(14); 3857–69. ©2017 AACR.
Neuregulin 1 Allosterically Enhances the Antitumor Effects of the Noncompeting Anti-HER3 Antibody 9F7-F11 by Increasing Its Binding to HER3
Authors: Le Clorennec Christophe , Bazin Hervé , Dubreuil Olivier , Larbouret Christel , Ogier Charline , Lazrek Yassamine , Garambois Véronique , Poul Marie-Alix , Mondon Philippe , Barret Jean-Marc , Mathis Gérard , Prost Jean-François , Pèlegrin André , Chardès Thierry 
Published: May 2017

AbstractExploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregulin (NRG1; HER3 ligand) expression at tumor sites is a predictive biomarker of anti-HER3 antibody efficacy in cancer. We hypothesized that in NRG1-expressing tumors, where the ligand is present before antibody treatment, anti-HER3 antibodies that do not compete with NRG1 for receptor binding have a higher receptor-neutralizing action than antibodies competing with the ligand for binding to HER3. Using time-resolved–fluorescence energy transfer (TR-FRET), we demonstrated that in the presence of recombinant NRG1, binding of 9F7-F11 (a nonligand-competing anti-HER3 antibody) to HER3 is increased, whereas that of ligand-competing anti-HER3 antibodies (H4B-121, U3-1287, Ab#6, Mab205.10.2, and MOR09825) is decreased. Moreover, 9F7-F11 showed higher efficacy than antibodies that compete with the ligand for binding to HER3. Specifically, 9F7-F11 inhibition of cell proliferation and of HER3/AKT/ERK1/2 phosphorylation as well as 9F7-F11–dependent cell-mediated cytotoxicity were higher in cancer cells preincubated with recombinant NRG1 compared with cells directly exposed to the anti-HER3 antibody. This translated in vivo into enhanced growth inhibition of NRG1-expressing BxPC3 pancreatic, A549 lung, and HCC-1806 breast cell tumor xenografts in mice treated with 9F7-F11 compared with H4B-121. Conversely, both antibodies had similar antitumor effect in NRG1-negative HPAC pancreatic carcinoma cells. In conclusion, the allosteric modulator 9F7-F11 shows increased anticancer effectiveness in the presence of NRG1 and thus represents a novel treatment strategy for NRG1-addicted tumors. Mol Cancer Ther; 16(7); 1312–23. ©2017 AACR.
Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer
Authors: White Mark A. , Lin Chenchu , Rajapakshe Kimal , Dong Jianrong , Shi Yan , Tsouko Efrosini , Mukhopadhyay Ratna , Jasso Diana , Dawood Wajahat , Coarfa Cristian , Frigo Daniel E. 
Published: May 2017

Abstract
Despite the known importance of androgen receptor (AR) signaling in prostate cancer, the processes downstream of AR that drive disease development and progression remain poorly understood. This knowledge gap has thus limited the ability to treat cancer. Here, it is demonstrated that androgens increase the metabolism of glutamine in prostate cancer cells. This metabolism was required for maximal cell growth under conditions of serum starvation. Mechanistically, AR signaling promoted glutamine metabolism by increasing the expression of the glutamine transporters SLC1A4 and SLC1A5, genes commonly overexpressed in prostate cancer. Correspondingly, gene expression signatures of AR activity correlated with SLC1A4 and SLC1A5 mRNA levels in clinical cohorts. Interestingly, MYC, a canonical oncogene in prostate cancer and previously described master regulator of glutamine metabolism, was only a context-dependent regulator of SLC1A4 and SLC1A5 levels, being unable to regulate either transporter in PTEN wild-type cells. In contrast, rapamycin was able to decrease the androgen-mediated expression of SLC1A4 and SLC1A5 independent of PTEN status, indicating that mTOR complex 1 (mTORC1) was needed for maximal AR-mediated glutamine uptake and prostate cancer cell growth. Taken together, these data indicate that three well-established oncogenic drivers (AR, MYC, and mTOR) function by converging to collectively increase the expression of glutamine transporters, thereby promoting glutamine uptake and subsequent prostate cancer cell growth.
Implications: AR, MYC, and mTOR converge to increase glutamine uptake and metabolism in prostate cancer through increasing the levels of glutamine transporters. Mol Cancer Res; 15(8); 1017–28. ©2017 AACR.
Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke)
Authors: Barreto Andrew D. , Ford Gary A. , Shen Loren , Pedroza Claudia , Tyson Jon , Cai Chunyan , Rahbar Mohammad H. , Grotta James C. , Ajani Zahra , Alexandrov Andrei V. , Cherches Igor , Coull Bruce , Dawson Jesse , del Junco Debra , Demchuk Andrew , Devine Joseph , Dickerson Aisha S. , Dixit Anand , Frey James L. , James Martin , Khan Usman , Levine Steven , MacDonald Claire , Malkoff Marc , McColl Elaine , Misra Vivek , Mullen Michael , Perry Richard , Piechowski-Jozwiak Bartlomiej , Roffe Christine , Sangha Navi , Sisson April , Tsivgoulis Georgios , Volpi John J. 
Published: May 2017

Background and Purpose—
We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)–treated ischemic stroke patients.

Methods—
Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 μg/kg bolus) followed by infusion of either 1 (low dose) or 3 μg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0–1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33–3.0).

Results—
Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57–2.37), 1.27 (0.63–2.53), and 1.34 (0.68–2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively.

Conclusions—
In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique Identifier: NCT01464788.
Unravelling the function of dolphin leaps using the dusky dolphin (Lagenorhynchus obscurus) as a model species
Authors: Pearson Heidi C. 
Published: May 2017

The prevalence of leaping across delphinids indicates it has an adaptive benefit. I examined leaping behaviour in dusky dolphins (Lagenorhynchus obscurus) according to signalling, social facilitation, and prey capture hypotheses. I quantified the effect of leaping on group behaviour and fission-fusion and the behavioural context of leaping. I observed dolphins in Admiralty Bay, New Zealand during 171 focal follows totalling 157 h. Data were analysed using generalized estimating equations. Clean leaping had a positive effect on party fission () and foraging behaviour (). Coordinated leaping caused a short-term wane in foraging behaviour () and had a positive effect on party fusion (). Noisy leaping had a negative effect on perpetuating resting and traveling cessation (both ). The signalling hypothesis was the most strongly supported. The social facilitation and prey capture hypotheses were moderately supported. Leaping may provide adaptive benefits such as reduced scramble competition, increased foraging efficiency, and social bonding.
“Yes, ... but ...”: The Neo-Perennialists
Authors: Martin Craig 
Published: May 2017

AbstractThis essay argues that despite their opposition to perennialism, a number of recent scholars inadvertently repeat some of the problematic gestures of perennialism. These scholars are attempting to push the field forward after poststructuralist critiques of religious studies, particularly regarding the varieties of essentialism that have plagued the field. However, their account of “religion” ends up looking, at least in some respects, little different from the pre-critical, essentialist, and ahistorical accounts of religion that were regnant prior to the wave of poststructuralist critiques of religious studies. To some extent we appear to be back to where we started.
Beyond the Neuro-Realism Fallacy
Authors: Casini Silvia 
Published: May 2017

This article examines visual practices inside the laboratory and in the arts, highlighting a problem of reductionism in the transformation from data to images and in the visual incarnation of the neuro-realism fallacy, that is the extreme images of brain scan. Neurosciences are not inherently reductionist. John R. Mallard’s work around data visualisation problems in the development of biomedical imaging shows how scientists themselves can be attentive to the construction of visual practices and their meaning. If neuro-realism is a fallacy within the neurosciences, are art-neuroscience collaborative projects reproducing this fallacy at visual level? The article analysis how neuroscience-art projects can enable us (or not) to foster and maintain a stereoscopic vision in the way in which we approach the conundrum of what it is like to be both a biological organism made up of molecules, neurons, cells, and an entity equipped with intentionality, desires, thoughts, values.
Fatigue in Younger and Older Drivers: Effectiveness of an Alertness-Maintaining Task
Authors: Song Woojin , Woon Fu L. , Doong Alice , Persad Carol , Tijerina Louis , Pandit Pooja , Cline Carol , Giordani Bruno 
Published: May 2017

Objective: The aim of this study was to examine the effects of an alertness-maintaining task (AMT) in older, fatigued drivers. Background: Fatigue during driving increases crash risk, and previous research suggests that alertness and driving in younger adults may be improved using a secondary AMT during boring, fatigue-eliciting drives. However, the potential impact of an AMT on driving has not been investigated in older drivers whose ability to complete dual tasks has been shown to decline and therefore may be negatively affected with an AMT in driving. Method: Younger ( n = 29) and older drivers ( n = 39) participated in a 50-minute simulated drive designed to induce fatigue, followed by four 10-minute sessions alternating between driving with and without an AMT. Results: Younger drivers were significantly more affected by fatigue on driving performance than were older drivers but benefitted significantly from the AMT. Older drivers did not demonstrate increased driver errors with fatigue, and driving did not deteriorate significantly during participation in the AMT condition, although their speed was significantly more variable with the AMT. Conclusion: Consistent with earlier research, an AMT applied during fatiguing driving is effective in improving alertness and reducing driving errors in younger drivers. Importantly, older drivers were relatively unaffected by fatigue, and use of an AMT did not detrimentally affect their driving performance. Application: These results support the potential use of an AMT as a new automotive technology to improve fatigue and promote driver safety, though the benefits of such technology may differ between different age groups.
Distinct Effects of Growth Hormone and Glutamine on Activation of Intestinal Stem Cells
Authors: Chen Yun , Tseng Sheng‐Hong , Yao Chao‐Ling , Li Chuan , Tsai Ya‐Hui 
Published: May 2017

AbstractBackground: For patients with short bowel syndrome under parenteral nutrition support, growth hormone (GH) and glutamine (GLN) have been found to help the growth of intestinal mucosa. In this research, we studied the effects of GH and GLN on intestinal stem cells (ISCs). Methods: The in vitro and in vivo effects of GH and/or GLN on ISCs were evaluated by observing the ability of ISCs to form organoids in a Matrigel culture system. The expression levels of stemness and differentiation markers in ISCs and organoids were assessed using quantitative real‐time polymerase chain reaction, immunofluorescence assay, and immunohistochemistry staining. Results: In vitro administration of GH activated the stemness of ISCs, whereas GLN enhanced the expression of chromogranin A and Muc2, which are differentiation markers in enteroendocrine and goblet cells, respectively. Administration of GH or GLN in mice showed that GH, but not GLN, upregulated the proliferative activity of ISCs with increased formation of crypt organoids. In addition, GH increased the expression of Lgr5 and GLN enhanced expression of Muc2 in the crypt fractions of the intestines in mice. Conclusion: These results suggest that GH mainly enhances proliferative activities, whereas GLN promotes the differentiation potential of ISCs.
Changing Rates of Morbidity and Mortality in Obstructive Sleep Apnea Surgery
Authors: Friedman Jacob J. , Salapatas Anna M. , Bonzelaar Lauren B. , Hwang Michelle S. , Friedman Michael 
Published: May 2017

ObjectiveWhereas uvulopalatopharyngoplasty (UPPP) was the standard surgical procedure for obstructive sleep apnea prior to 2007, multilevel surgery has become the standard since that time. This study compares morbidity and mortality rates of the stand‐alone UPPP with those of multilevel sleep surgery that includes UPPP.MethodsPatients undergoing UPPP between 2007 and 2014 were identified in the American College of Surgeons National Surgical Quality Improvement Program database. UPPP was defined by Current Procedural Terminology codes 42145 and 42950. Primary outcomes were incidence of morbidity and mortality. Rates were compared between a control group with UPPP only and a group with multilevel surgery.ResultsA total of 2674 cases were analyzed. The incidence of complications in the UPPP‐only group was 1.6% (0.09% fatal); in the multilevel surgery group, 4.63% (0.19% fatal). The difference in overall and nonfatal complications is statistically significant (P <. 01); however, values for fatal complications are too low for comparison. There is a statistically significant (P <. 01) positive correlation (R2 = 0.92) between year of operation and rate of complications, with increased incidence of complications in more recent years.DiscussionComplication rates for multilevel sleep surgery are higher than those of stand‐alone UPPP, and overall complication rates have been increasing in recent years. As UPPP supplemented with multilevel surgery is now the standard surgical treatment for most cases of obstructive sleep apnea‐hypopnea syndrome, historical complication rates based predominantly on patients undergoing UPPP only underestimate complication rates of modern sleep surgery.Implications for PracticeIt is reasonable to inform patients that multilevel procedures bring an increased risk of complications, and patient selection should be guided accordingly.
Respiratory motion during 90Yttrium PET contributes to underestimation of tumor dose and overestimation of normal liver tissue dose
Authors: Ausland Line , Revheim Mona-Elisabeth , Skretting Arne , Stokke Caroline 
Published: May 2017

Background Yttrium-90 dosimetry after radioembolization is reliant on accurate quantitative imaging of the microsphere deposition. Previous studies have focused on the correction of geometrical resolution effects. Purpose To uncover additional effects of respiratory motion. Material and Methods Mathematical models describing spherical tumors were formed and two blurring effects, limited geometrical resolution and respiratory motion, were simulated. The virtual images were used as basis for dose volume histogram estimations by convolving the radioactivity representations with a dose point kernel. Results For respiratory motion only, the largest errors were found for the smallest tumors and/or tumors with heterogeneous distribution of yttrium-90 microspheres. The deviations in max dose and dose to 25% and 50% of the tumor volume were estimated at 20–40%, 10–30%, and 0–30%, respectively. Additional blurring from geometrical resolution increased the errors to 55–75%, 50–60%, and 25–60%, respectively. Conclusion Respiratory motion contributes to underestimation of tumor dose and overestimation of normal tissue dose.
Evaluating the Types of Pharmacy Student Interventions Made During an Interprofessional 6-Week Adult Internal Medicine Rotation
Authors: Vinluan Celeste M. , Jabalie Melanie M. , Navarrete Jacquelyn P. , Padilla Margie E. 
Published: May 2017

Introduction: The new standards for pharmacy education require that pharmacy students are involved in direct and interprofessional team-based care in multiple practice settings, which include “real-time” interactions with physician prescribers and medical students. Methods: From April 2014 to December 2015, fourth-year Doctor of Pharmacy (PharmD) students at University Medical Center of El Paso, Texas were assigned to an interprofessional team that was comprised of physician prescribers, medical students, and a pharmacist faculty. They recorded their interventions that were analyzed for type, number, physician acceptance, clinical importance, and time requirements for intervention recommendation. Interventions were divided into 5 main types and further divided into specific categories. Results: Twelve PharmD students contributed 531 interventions, resulting in an average of 44 interventions per student with a physician acceptance rate of 87%. The most common types of interventions performed by PharmD students were under the categories of Therapy Needed (29.8%), Too Low Dose/Frequency (21.1%), Too High Dose/Frequency (8.3%), Therapeutic Level Monitoring (6.8%), and IV to PO Conversion (4.9%). A majority of interventions were of moderate clinical importance (56.1%) and took approximately 15 minutes to complete (92.5%). Conclusion: PharmD students under the supervision of clinical faculty on an interprofessional internal medicine team are valuable collaborators and contributors in decreasing the number of drug-related problems that can negatively impact patient care.
Hemoglobin A1c as a Predictor of Postoperative Infection Following Elective Forefoot Surgery
Authors: Cancienne Jourdan M. , Cooper Minton T. , Laroche Kevin A. , Verheul Dirk W. , Werner Brian C. 
Published: May 2017

Background: There remains little evidence to support a perioperative hemoglobin A1c (HbA1c) level that could serve as a threshold for a significantly increased risk of postoperative surgical site infection (SSI) following forefoot surgery. Methods: A national database was queried for patients who underwent elective forefoot surgery with diabetes. Patients with a perioperative HbA1c level within 3 months of surgery were identified and stratified based on HbA1c level in 0.5 mg/dL increments. The incidence of SSI was determined by either a diagnosis or procedure for SSI within 1 year and a receiver operating characteristic (ROC) curve and area under the curve (AUC) analysis was performed to determine an optimal threshold value of HbA1c. Results: A total of 4630 patients who underwent forefoot surgery with diabetes with a perioperative HbA1c were included. The rate of SSI ranged from 2.3% to 11.8%. The inflection point of the ROC curve corresponded to an HbA1c level above 7.5 mg/dL ( P < .0001; 95% confidence interval [CI] = 0.58-0.67; AUC = 0.631; specificity = 75%; sensitivity = 46%). After multivariate analysis, patients with an HbA1c level of 7.5 mg/dL or greater had a significantly higher risk for postoperative wound infection compared to patients below this threshold (OR = 1.92; 95% CI = 1.5-2.4; P < .0001). Conclusions: The risk of postoperative SSI following forefoot surgery increased as the perioperative HbA1c increased. ROC analysis determined that a perioperative HbA1c above 7.5 mg/dL could serve as a threshold for a significantly increased risk of postoperative SSI following forefoot surgery. Level of Evidence: Level III, comparative series.