bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomised controlled trial of stand-alone tailored emails for smoking cessation
Authors: Westmaas J Lee , Bontemps-Jones Jeuneviette , Hendricks Peter S , Kim Jihye , Abroms Lorien C 
Published: May 2017

IntroductionDigital technology has created opportunities for delivering smoking cessation assistance at the population level. However, the efficacy of sending multiple, automated, tailored emails providing motivation, support and information for quitting is unknown.MethodsSmokers planning to quit (n=1070) were randomly assigned to (1) 27 tailored cessation emails (deluxe email group (DEG)), (2) 3 to 4 tailored emails with links to downloadable booklets (basic email group (BEG)) or (3) a single non-tailored email (single email group (SEG)). All emails included links to quitting resources. Self-reported 7-day point-prevalence abstinence was assessed at 1 month, 3 months and 6 months postenrolment.ResultsAcross follow-ups, abstinence was significantly greater for smokers in the DEG (34%) compared with the SEG (25.8%; OR=1.47, 95% CI 1.07 to 2.02, p=0.02) but there was no difference between the BEG (30.8%) and the SEG (p=0.13). Results were independent of baseline cigarettes per day, interest in quitting, smoker in household, use of nicotine replacement therapy (NRT) or varenicline and gender, themselves associated with abstinence (ps<0.05). Missing=smoking and multiple imputation analyses based on 25 data sets corroborated results. Participants in the DEG were also more likely to use non-medication aids (eg, quit smoking website, cessation class/clinic) compared with the SEG (OR=1.34, p=0.02, CI 1.06 to 1.71), but use of these or NRT by the 4-week follow-up (vs no use) increased abstinence across follow-ups primarily for those in the SEG.ConclusionsStand-alone tailored, multiple emails providing support, motivation and information during a quit attempt are an easily deployable, inexpensive mode of providing effective cessation assistance to large numbers of smokers planning to quit.
Radiative neutrino mass generation: Models, flavour and the LHC
Authors: Volkas Raymond R. 
Published: May 2017

Radiative neutrino mass models and the seesaw models are viewed from the unifying framework of standard model effective operators that explicitly violate lepton number by two units [Formula: see text]. After some comments on naturalness and leptogenesis in the minimal type 1 seesaw model, a full list of minimal renormalisable models that produce mass dimension-7, [Formula: see text] operators at low energies is presented. By way of example, phenomenological bounds from Run 1 LHC and lepton flavour violation data are then placed on one of these models. A possible connection between radiative neutrino mass models and the current flavour anomalies in [Formula: see text] and [Formula: see text] transitions is then described.
Postmeal exercise blunts postprandial glucose excursions in people on metformin monotherapy
Authors: Erickson Melissa L. , Little Jonathan P. , Gay Jennifer L. , McCully Kevin K. , Jenkins Nathan T. 
Published: May 2017

Metformin is used clinically to reduce fasting glucose with minimal effects on postprandial glucose. Postmeal exercise reduces postprandial glucose and may offer additional glucose-lowering benefit beyond that of metformin alone, yet controversy exists surrounding exercise and metformin interactions. It is currently unknown how postmeal exercise and metformin monotherapy in combination will affect postprandial glucose. Thus, we examined the independent and combined effects of postmeal exercise and metformin monotherapy on postprandial glucose. A randomized crossover design was used to assess the influence of postmeal exercise on postprandial glucose excursions in 10 people treated with metformin monotherapy (57 ± 10 yr, HbA1C = 6.3 ± 0.6%). Each participant completed the following four conditions: sedentary and postmeal exercise (5 × 10-min bouts of treadmill walking at 60% V̇o2max) with metformin and sedentary and postmeal exercise without metformin. Peak postprandial glucose within a 2-h time window and 2-h total area under the curve was assessed after a standardized breakfast meal, using continuous glucose monitoring. Postmeal exercise significantly blunted 2-h peak ( P = 0.001) and 2-h area under the curve ( P = 0.006), with the lowest peak postprandial glucose excursion observed with postmeal exercise and metformin combined ( P < 0.05 vs. all other conditions: metformin/sedentary: 12 ± 3.4, metformin/exercise: 9.7 ± 2.3, washout/sedentary: 13.3 ± 3.2, washout/exercise: 11.1 ± 3.4 mmol/l). Postmeal exercise and metformin in combination resulted in the lowest peak postprandial glucose excursion compared with either treatment modality alone. Exercise timed to the postprandial phase may be important for optimizing glucose control during metformin monotherapy. NEW & NOTEWORTHY The interactive effects of metformin and exercise on key physiological outcomes remain an area of controversy. Findings from this study show that the combination of metformin monotherapy and moderate-intensity postmeal exercise led to beneficial reductions in postprandial glucose excursions. Postmeal exercise may be a useful strategy for the management of postprandial glucose in people on metformin.
Aortic arch compliance and idiopathic unilateral vocal fold paralysis
Authors: Behkam Reza , Roberts Kara E. , Bierhals Andrew J. , Jacobs M. Eileen , Edgar Julia D. , Paniello Randal C. , Woodson Gayle , Vande Geest Jonathan P. , Barkmeier-Kraemer Julie M. 
Published: May 2017

Unilateral vocal fold paralysis (UVP) occurs related to recurrent laryngeal nerve (RLN) impairment associated with impaired swallowing, voice production, and breathing functions. The majority of UVP cases occur subsequent to surgical intervention with approximately 12–42% having no known cause for the disease (i.e., idiopathic). Approximately two-thirds of those with UVP exhibit left-sided injury with the average onset at ≥50 yr of age in those diagnosed as idiopathic. Given the association between the RLN and the subclavian and aortic arch vessels, we hypothesized that changes in vascular tissues would result in increased aortic compliance in patients with idiopathic left-sided UVP compared with those without UVP. Gated MRI data enabled aortic arch diameter measures normalized to blood pressure across the cardiac cycles to derive aortic arch compliance. Compliance was compared between individuals with left-sided idiopathic UVP and age- and sex-matched normal controls. Three-way factorial ANOVA test showed that aortic arch compliance ( P = 0.02) and aortic arch diameter change in one cardiac cycle ( P = 0.04) are significantly higher in patients with idiopathic left-sided UVP compared with the controls. As previously demonstrated by other literature, our finding confirmed that compliance decreases with age ( P < 0.0001) in both healthy individuals and patients with idiopathic UVP. Future studies will investigate parameters of aortic compliance change as a potential contributor to the onset of left-sided UVP.NEW & NOTEWORTHY Unilateral vocal fold paralysis results from impaired function of the recurrent laryngeal nerve (RLN) impacting breathing, swallowing, and voice production. A large proportion of adults suffering from this disorder have an idiopathic etiology (i.e., unknown cause). The current study determined that individuals diagnosed with left-sided idiopathic vocal fold paralysis exhibited significantly greater compliance than age- and sex-matched controls. These seminal findings suggest a link between aortic arch compliance levels and RLN function.
Inhibition of Mitochondrial Matrix Chaperones and Antiapoptotic Bcl-2 Family Proteins Empower Antitumor Therapeutic Responses
Authors: Karpel-Massler Georg , Ishida Chiaki Tsuge , Bianchetti Elena , Shu Chang , Perez-Lorenzo Rolando , Horst Basil , Banu Matei , Roth Kevin A. , Bruce Jeffrey N. , Canoll Peter , Altieri Dario C. , Siegelin Markus D. 
Published: May 2017

Abstract
Rational therapeutic approaches based on synthetic lethality may improve cancer management. On the basis of a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL, and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and obatoclax) or selective (ABT199, WEHI-539, and A1210477), along with the established mitochondrial matrix chaperone inhibitor gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer, and patient-derived orthotopic xenografts (PDX) of human glioblastoma. We found that combining BH3 mimetics and gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL, or Mcl-1 recapitulated the effects of BH3 mimetics and enhanced the effects of gamitrinib-TPP. Mechanistic investigations revealed that gamitrinib-TPP activated a PERK-dependent integrated stress response, which activated the proapoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments. Cancer Res; 77(13); 3513–26. ©2017 AACR.
Preclinical Evaluation of MEDI0641, a Pyrrolobenzodiazepine-Conjugated Antibody–Drug Conjugate Targeting 5T4
Authors: Harper Jay , Lloyd Christopher , Dimasi Nazzareno , Toader Dorin , Marwood Rose , Lewis Leeanne , Bannister David , Jovanovic Jelena , Fleming Ryan , D'Hooge Francois , Mao Shenlan , Marrero Allison M. , Korade Martin , Strout Patrick , Xu Linda , Chen Cui , Wetzel Leslie , Breen Shannon , van Vlerken-Ysla Lilian , Jalla Sanjoo , Rebelatto Marlon , Zhong Haihong , Hurt Elaine M. , Hinrichs Mary Jane , Huang Keven , Howard Philip W. , Tice David A. , Hollingsworth Robert E. , Herbst Ronald , Kamal Adeela 
Published: May 2017

AbstractAntibody–drug conjugates (ADC) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSC), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation. ADCs targeting 5T4 were constructed by site-specifically conjugating the antibody with payloads that possess different mechanisms of action, either a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer or a microtubule-destabilizing tubulysin, so that each ADC had a drug:antibody ratio of 2. The resulting ADCs demonstrated significant target-dependent activity in vitro and in vivo; however, the ADC conjugated with a PBD payload (5T4-PBD) elicited more durable antitumor responses in vivo than the tubulysin conjugate in xenograft models. Likewise, the 5T4-PBD more potently inhibited the growth of 5T4-positive CSCs in vivo, which likely contributed to its superior antitumor activity. Given that the 5T4-PBD possessed both potent antitumor activity as well as anti-CSC activity, and thus could potentially target bulk tumor cells and CSCs in target-positive indications, it was further evaluated in non-GLP rat toxicology studies that demonstrated excellent in vivo stability with an acceptable safety profile. Taken together, these preclinical data support further development of 5T4-PBD, also known as MEDI0641, against 5T4+ cancer indications. Mol Cancer Ther; 16(8); 1576–87. ©2017 AACR.
Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs
Authors: Currier Mark A. , Stehn Justine R. , Swain Ashleigh , Chen Duo , Hook Jeff , Eiffe Eleanor , Heaton Andrew , Brown David , Nartker Brooke A. , Eaves David W. , Kloss Nina , Treutlein Herbert , Zeng Jun , Alieva Irina B. , Dugina Vera B. , Hardeman Edna C. , Gunning Peter W. , Cripe Timothy P. 
Published: May 2017

Abstract
Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While antimicrotubule drugs are well-established, antiactin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other antitropomyosin analogues for anticancer and on-target activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1-containing filaments, its cytotoxicity potency, and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with antimicrotubule agents against neuroblastoma models in vitro and in vivo. Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane antimicrotubule agents. In vivo, combination-treated animals bearing human neuroblastoma xenografts treated with antitropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared with control and either drug alone. Antitropomyosin combined with vincristine resulted in G2–M phase arrest, disruption of mitotic spindle formation, and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to antimicrotubule agents and are tolerated together in vivo. This combination warrants further study. Mol Cancer Ther; 16(8); 1555–65. ©2017 AACR.
Sensitization of EGFR Wild-Type Non–Small Cell Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitor Erlotinib
Authors: Raimbourg Judith , Joalland Marie-Pierre , Cabart Mathilde , de Plater Ludmilla , Bouquet Fanny , Savina Ariel , Decaudin Didier , Bennouna Jaafar , Vallette François M. , Lalier Lisenn 
Published: May 2017

Abstract
The benefit of EGFR–TKI in non–small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non–small cell lung cancer and the functional consequences in vitro and in in vivo animal models of patient-derived xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR-expressing cells to erlotinib, contrary to what happens in mutant EGFR cells and with a blocking EGFR antibody, both in vitro and in vivo. The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation. We propose a combination of markers that enable to discriminate between the tumors sensitized to erlotinib or not in PDX models, which should be worth testing in patients. These markers might be useful for the selection of patients who would benefit from erlotinib as a maintenance therapy. Mol Cancer Ther; 16(8); 1634–44. ©2017 AACR.
Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade
Authors: Zhou Jun , Mahoney Kathleen M. , Giobbie-Hurder Anita , Zhao Fengmin , Lee Sandra , Liao Xiaoyun , Rodig Scott , Li Jingjing , Wu Xinqi , Butterfield Lisa H. , Piesche Matthias , Manos Michael P. , Eastman Lauren M. , Dranoff Glenn , Freeman Gordon J. , Hodi F. Stephen 
Published: May 2017

Abstract
Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury, and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared with healthy donors. High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors. Cancer Immunol Res; 5(6); 480–92. ©2017 AACR.
Prognostic Value of Urinary Neutrophil Gelatinase‐Associated Lipocalin on the First Day of Admission for Adverse Events in Patients With Acute Decompensated Heart Failure
Authors: Nakada Yasuki , Kawakami Rika , Matsui Masaru , Ueda Tomoya , Nakano Tomoya , Takitsume Akihiro , Nakagawa Hitoshi , Nishida Taku , Onoue Kenji , Soeda Tsunenari , Okayama Satoshi , Watanabe Makoto , Kawata Hiroyuki , Okura Hiroyuki , Saito Yoshihiko 
Published: May 2017

Background

Urinary neutrophil gelatinase‐associated lipocalin (U‐
NGAL
) is an early predictor of acute kidney injury and adverse events in various diseases; however, in acute decompensated heart failure patients, its significance remains poorly understood. This study aimed to investigate the prognostic value of U‐
NGAL
on the first day of admission for the occurrence of acute kidney injury and long‐term outcomes in acute decompensated heart failure patients.

Methods and Results

We studied 260 acute decompensated heart failure patients admitted to our department between 2011 and 2014 by measuring U‐
NGAL
in 24‐hour urine samples collected on the first day of admission. Primary end points were all‐cause death, cardiovascular death, and heart failure admission. Patients were divided into 2 groups according to their median U‐
NGAL
levels (32.5 μg/gCr). The high‐U‐
NGAL
group had a significantly higher occurrence of acute kidney injury during hospitalization than the low‐U‐
NGAL
group (
P
=0.0012). Kaplan‐Meier analysis revealed that the high‐U‐
NGAL
group exhibited a worse prognosis than the low‐U‐
NGAL
group in all‐cause death (hazard ratio 2.07; 95%
CI
1.38‐3.12,
P
=0.0004), cardiovascular death (hazard ratio 2.29; 95%
CI
1.28‐4.24,
P
=0.0052), and heart failure admission (hazard ratio 1.77; 95%
CI
1.13‐2.77,
P
=0.0119). The addition of U‐
NGAL
to the estimated glomerular filtration rate significantly improved the predictive accuracy of all‐cause mortality (
P
=0.0083).

Conclusions

In acute decompensated heart failure patients, an elevated U‐
NGAL
level on the first day of admission was related to the development of clinical acute kidney injury and independently associated with poor prognosis.
Cigarette Smoking‐Associated Alterations in Serotonin/Adrenalin Signaling Pathways of Platelets
Authors: Lowery Curtis Lee , Elliott Clay , Cooper Anthonya , Hadden Coedy , Sonon Roberto N. , Azadi Parastoo , Williams D. Keith , Marsh James D. , Woulfe Donna S. , Kilic Fusun 
Published: May 2017

Background

Cigarette smoking plays a major role in cardiovascular diseases. The acute effects of cigarette smoking produce central nervous system–mediated activation of the sympathetic nervous system. The overactive sympathetic nervous system stimulates the secretion of serotonin (5‐
HT
) and catecholamine into blood at supraphysiological levels. The correlation between these pathological conditions induced by smoking and the increased risk of thrombosis has not been thoroughly investigated. The goal of our study was to explore cigarette smoking–associated changes in platelet biology mediated by elevated 5‐
HT
and catecholamine levels in blood plasma.

Methods and Results

Using blood samples collected from healthy nonsmokers and smokers (15 minutes after smoking), we determined that cigarette smoking increased the plasma 5‐
HT
/catecholamine concentration by several fold and the percent aggregation of platelets 2‐fold. Liquid chromatography–tandem mass spectrometry analysis of proteins eluted from platelet plasma membranes of smokers and nonsmokers demonstrated that
GTP
ase‐activating proteins and proteins participating in the actin cytoskeletal network were differentially and significantly elevated in smokers' platelet membranes compared with those of nonsmokers. Interestingly, Matrix‐assisted laser desorption/ionization–mass spectrometry analyses of the glycans eluted from platelet plasma membranes of the smokers demonstrated that the level and structures of glycans are different from the nonsmokers' platelet surface glycans. Pharmacological blockade of 5‐
HT
or catecholamine receptors counteracted the 5‐
HT
/catecholamine‐mediated aggregation and altered the level and composition of glycan on platelet surfaces.

Conclusions

Based on our findings, we propose that smoking‐associated 5‐
HT
/catecholamine signaling accelerates the trafficking dynamics of platelets, and this remodels the surface proteins and glycans and predisposes platelets to hyperactive levels. Smokers' platelets also had correspondingly higher resting concentrations of intracellular calcium and transglutaminase activity. These findings suggest a link among smoking, platelet 5‐
HT
, catecholamine signaling, and their downstream effectors—including phospholipase C and inositol‐1,4,5‐triphosphate pathways—resulting in an increased tonic level of platelet activation in smokers.