bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in non-occupational sedentary behaviours across the retirement transition: the Finnish Retirement and Aging (FIREA) study
Authors: Leskinen Tuija , Pulakka Anna , Heinonen Olli J , Pentti Jaana , Kivimäki Mika , Vahtera Jussi , Stenholm Sari 
Published: April 2018

BackgroundRetirement is a major life transition which may influence health behaviours and time use. Little is known about how sedentary behaviour changes as a result of increased time availability after retirement. The aim of this study was to examine changes in non-occupational sedentary behaviours across the retirement transition. In addition, we examined which preretirement characteristics were associated with these changes.MethodsThe study population consisted of 2011 participants from the Finnish Retirement and Aging Study. Repeated postal survey including questions on sedentary behaviour domains (television viewing, computer use at home, sitting in a vehicle and other sitting) were conducted once a year across the retirement transition, covering on average 3.4 study waves. Linear regression with generalised estimating equations was used for the analyses.ResultsTotal sedentary time increased by 73 (95% CI 66 to 80) min/day during the retirement transition. Of the domain-specific sedentary behaviours, television viewing time increased by 28 (95% CI 25 to 32) min/day, computer use at home by 19 (95% CI 17 to 22) min/day and other sitting time by 37 (95% CI 33 to 41) min/day, while time sitting in a vehicle decreased by 6 (95% CI 4 to 9) min/day. Highest increase in total sedentary time was among women and persons who had high occupational sitting time, low physical activity level, sleep difficulties, mental disorders or poor health before retirement (all p values for interaction <0.03).ConclusionTotal and domain-specific sedentary time, except sitting in a vehicle, increased during the retirement transition.
Standardisation of laboratories engaged in lipid analyses of population health examination surveys
Authors: Alfthan Georg , Sundvall Jouko , Råman Laura , Kuulasmaa Kari , Tolonen Hanna 
Published: April 2018

BackgroundReliable data on clinical biomarkers are necessary in order to assess the health risks of populations and especially in assessing long-term trends related to disease incidence.MethodsTen European laboratories participated in a two-phase quality control exercise of total cholesterol (TC) and high-density lipoprotein-cholesterol (HDL-C) analysis. The European Health Examination Survey Reference Laboratory prepared plasma batches for analysis, and provided target values for them. Two criteria were set for the precision and the systematic error (bias). Three plasma samples were analysed in duplicate on separate days (n=12).ResultsIn Round 1, all laboratories met the acceptable criterion (3%) for precision of TC. The mean bias of all laboratories was 0.99% (95% CI 0.03% to 1.95%). Six laboratories measured samples from Round 2. Five laboratories met the goal criterion of 3%; one failed to meet the acceptable criterion of 5%. The mean bias for HDL-C of the three batches of six laboratories was within goal limits (±5% from target) and that of all 10 within acceptable (±10%). The mean bias of all laboratories was 1.1% (95% CI −0.18 to 2.32). In Round 2 four laboratories met the goal criterion and one the acceptable criterion.ConclusionThe quality control exercise demonstrated that although the majority of the laboratories met the strict criteria for systematic error for TC and HDL-C, standardisation of methods is still needed to improve the accuracy of biomarker measurements of laboratories engaged in population health surveys. A protocol is recommended for obtaining reliable and comparable biomarker data between countries.
Resistance Mechanisms to Targeted Therapies in ROS1+ and ALK+ Non–small Cell Lung Cancer
Authors: McCoach Caroline E. , Le Anh T. , Gowan Katherine , Jones Kenneth , Schubert Laura , Doak Andrea , Estrada-Bernal Adriana , Davies Kurtis D. , Merrick Daniel T. , Bunn Paul A. , Purcell W. Tom , Dziadziuszko Rafal , Varella-Garcia Marileila , Aisner Dara L. , Camidge D. Ross , Doebele Robert C. 
Published: April 2018

Abstract
Purpose: Despite initial benefit from tyrosine kinase inhibitors (TKIs), patients with advanced non–small cell lung cancer (NSCLC) harboring ALK (ALK+) and ROS1 (ROS1+) gene fusions ultimately progress. Here, we report on the potential resistance mechanisms in a series of patients with ALK+ and ROS1+ NSCLC progressing on different types and/or lines of ROS1/ALK–targeted therapy.
Experimental Design: We used a combination of next-generation sequencing (NGS), multiplex mutation assay, direct DNA sequencing, RT-PCR, and FISH to identify fusion variants/partners and copy-number gain (CNG), kinase domain mutations (KDM), and copy-number variations (CNVs) in other cancer-related genes. We performed testing on 12 ROS1+ and 43 ALK+ patients.
Results: One of 12 ROS1+ (8%) and 15 of 43 (35%) ALK+ patients harbored KDM. In the ROS1+ cohort, we identified KIT and β-catenin mutations and HER2-mediated bypass signaling as non-ROS1–dominant resistance mechanisms. In the ALK+ cohort, we identified a novel NRG1 gene fusion, a RET fusion, 2 EGFR, and 3 KRAS mutations, as well as mutations in IDH1, RIT1, NOTCH, and NF1. In addition, we identified CNV in multiple proto-oncogenes genes including PDGFRA, KIT, KDR, GNAS, K/HRAS, RET, NTRK1, MAP2K1, and others.
Conclusions: We identified a putative TKI resistance mechanism in six of 12 (50%) ROS1+ patients and 37 of 43 (86%) ALK+ patients. Our data suggest that a focus on KDMs will miss most resistance mechanisms; broader gene testing strategies and functional validation is warranted to devise new therapeutic strategies for drug resistance. Clin Cancer Res; 24(14); 3334–47. ©2018 AACR.
A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer
Authors: Bendell Johanna C. , Varghese Anna M. , Hyman David M. , Bauer Todd M. , Pant Shubham , Callies Sophie , Lin Ji , Martinez Ricardo , Wickremsinhe Enaksha , Fink Aaron , Wacheck Volker , Moore Kathleen N. 
Published: April 2018

Abstract
Purpose: The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414.
Patients and Methods: A 3+3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug–drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity.
Results: Forty-seven patients with solid tumors received LY3023414 at once-daily (20–450 mg) or twice-daily dosing (150–250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ≥ 90% target inhibition at doses ≥150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%.
Conclusions: LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data. Clin Cancer Res; 24(14); 3253–62. ©2018 AACR.
Disruption ofNSD1in Head and Neck Cancer Promotes Favorable Chemotherapeutic Responses Linked to Hypomethylation
Authors: Bui Nam , Huang Justin K. , Bojorquez-Gomez Ana , Licon Katherine , Sanchez Kyle S. , Tang Sean N. , Beckett Alex N. , Wang Tina , Zhang Wei , Shen John Paul , Kreisberg Jason F. , Ideker Trey 
Published: April 2018

AbstractHuman papillomavirus (HPV)–negative head and neck squamous cell carcinoma (HNSCC) represents a distinct classification of cancer with worse expected outcomes. Of the 11 genes recurrently mutated in HNSCC, we identify a singular and substantial survival advantage for mutations in the gene encoding Nuclear Set Domain Containing Protein 1 (NSD1), a histone methyltransferase altered in approximately 10% of patients. This effect, a 55% decrease in risk of death in NSD1-mutated versus non-mutated patients, can be validated in an independent cohort. NSD1 alterations are strongly associated with widespread genome hypomethylation in the same tumors, to a degree not observed for any other mutated gene. To address whether NSD1 plays a causal role in these associations, we use CRISPR-Cas9 to disrupt NSD1 in HNSCC cell lines and find that this leads to substantial CpG hypomethylation and sensitivity to cisplatin, a standard chemotherapy in head and neck cancer, with a 40% to 50% decrease in the IC50 value. Such results are reinforced by a survey of 1,001 cancer cell lines, in which loss-of-function NSD1 mutations have an average 23% decrease in cisplatin IC50 value compared with cell lines with wild-type NSD1.Significance: This study identifies a favorable subtype of HPV–negative HNSCC linked to NSD1 mutation, hypomethylation, and cisplatin sensitivity. Mol Cancer Ther; 17(7); 1585–94. ©2018 AACR.
Exosomes Induce Fibroblast Differentiation into Cancer-Associated Fibroblasts through TGFβ Signaling
Authors: Ringuette Goulet Cassandra , Bernard Geneviève , Tremblay Sarah , Chabaud Stéphane , Bolduc Stéphane , Pouliot Frédéric 
Published: April 2018

Abstract
A particularly important tumor microenvironment relationship exists between cancer cells and surrounding stromal cells. Fibroblasts, in response to cancer cells, become activated and exhibit myofibroblastic characteristics that favor invasive growth and metastasis. However, the mechanism by which cancer cells promote activation of healthy fibroblasts into cancer-associated fibroblasts (CAF) is still not well understood. Exosomes are nanometer-sized vesicles that shuttle proteins and nucleic acids between cells to establish intercellular communication. Here, bladder cancer–derived exosomes were investigated to determine their role in the activation of healthy primary vesical fibroblasts. Exosomes released by bladder cancer cells are internalized by fibroblasts and promoted the proliferation and expression of CAF markers. In addition, cancer cell–derived exosomes contain TGFβ and in exosome-induced CAFs SMAD-dependent signaling is activated. Furthermore, TGFβ inhibitors attenuated CAF marker expression in healthy fibroblasts. Therefore, these data demonstrate that bladder cancer cells trigger the differentiation of fibroblasts to CAFs by exosomes-mediated TGFβ transfer and SMAD pathway activation. Finally, exosomal TGFβ localized inside the vesicle and contributes 53.4% to 86.3% of the total TGFβ present in the cancer cell supernatant. This study highlights a new function for bladder cancer exosomes as novel modulators of stromal cell differentiation.
Implication: This study identifies exosomal TGFβ as new molecular mechanism involved in cancer-associated fibroblast activation. Mol Cancer Res; 16(7); 1196–204. ©2018 AACR.
Ultraviolet Radiation Inhibits Mammary Carcinogenesis in an ER-Negative Murine Model by a Mechanism Independent of Vitamin D3
Authors: Makarova Anastasia M. , Frascari Flora , Davari Parastoo , Gorouhi Farzam , Dutt Philip , Wang Lynn , Dhawan Akash , Wang Grace , Green Jeffrey E. , Epstein Ervin H. 
Published: April 2018

Abstract
Three decades ago, the Garlands postulated that vitamin D3 produced in the skin by ultraviolet radiation (UVR)-induced conversion of 7-dehydrocholesterol to pre-D3 has anticancer effects, thus triggering more than 9,500 publications on D3 and cancer. Here, we report that UVR treatment of transgenic mice of the well-established C3(1)/SV40 Tag mammary cancer model significantly inhibits both autochthonous carcinogenesis and allograft tumor growth, but in contrast neither dietary nor topical D3 influences mammary carcinogenesis in this specific mouse model. Furthermore, UVR's inhibitory effects occur irrespective of whether or not the treatment increases circulating D3 in the mice. The inhibitory effect of UVR on autochthonous tumors occurs at or before the stage of ductal carcinoma in situ. Our studies indicate clearly that UVR can exert D3-independent anticancer effects in C3(1)/SV40 Tag mice. Therefore, supplemental D3 may not mimic all possible beneficial effects of UVR, and uncovering non–D3-mediated mechanisms of UVR tumor inhibition may lead to novel strategies for cancer prevention. Cancer Prev Res; 11(7); 383–92. ©2018 AACR.
Growth Hormone Improves Cognitive Function After Experimental Stroke
Authors: Ong Lin Kooi , Chow Wei Zhen , TeBay Clifford , Kluge Murielle , Pietrogrande Giovanni , Zalewska Katarzyna , Crock Patricia , Åberg N. David , Bivard Andrew , Johnson Sarah J. , Walker Frederick R. , Nilsson Michael , Isgaard Jörgen 
Published: April 2018

Background and Purpose—
Cognitive impairment is a common outcome for stroke survivors. Growth hormone (GH) could represent a potential therapeutic option as this peptide hormone has been shown to improve cognition in various clinical conditions. In this study, we evaluated the effects of peripheral administration of GH at 48 hours poststroke for 28 days on cognitive function and the underlying mechanisms.

Methods—
Experimental stroke was induced by photothrombotic occlusion in young adult mice. We assessed the associative memory cognitive domain using mouse touchscreen platform for paired-associate learning task. We also evaluated neural tissue loss, neurotrophic factors, and markers of neuroplasticity and cerebrovascular remodeling using biochemical and histology analyses.

Results—
Our results show that GH-treated stroked mice made a significant improvement on the paired-associate learning task relative to non–GH-treated mice at the end of the study. Furthermore, we observed reduction of neural tissue loss in GH-treated stroked mice. We identified that GH treatment resulted in significantly higher levels of neurotrophic factors (IGF-1 [insulin-like growth factor-1] and VEGF [vascular endothelial growth factor]) in both the circulatory and peri-infarct regions. GH treatment in stroked mice not only promoted protein levels and density of presynaptic marker (SYN-1 [synapsin-1]) and marker of myelination (MBP [myelin basic protein]) but also increased the density and area coverage of 2 major vasculature markers (CD31 and collagen-IV), within the peri-infarct region.

Conclusions—
These findings provide compelling preclinical evidence for the usage of GH as a potential therapeutic tool in the recovery phase of patients after stroke.
In Support of Whitehead’s Time
Authors: Lestienne Rémy 
Published: April 2018

Abstract
In 1911, Alfred North Whitehead has a brainstorm: if we deny the reality of the instant, many problems of the philosophy of nature seem solved. His metaphysics, however, will wait until his moving to Harvard, in 1924, to mature. Besides his denial of the instants of time and the replacement of the concept of time by that of “process,” Whitehead articulates new concepts (concrescence, prehension) to account for the crystallization of successive empirical realities, the solidarity between events, the permanence of objects, and their deterministic behavior altogether. His views of nature fit well with both quantum mechanics and relativity theories, although not in the details of the latter. But one of his largely unnoticed merits, in my view, is to reopen the question of free will in the mind-body problem.
Dust Impacts on the 2012 Hurricane Nadine Track during the NASA HS3 Field Campaign
Authors: Nowottnick E. P. , Colarco P. R. , Braun S. A. , Barahona D. O. , da Silva A. , Hlavka D. L. , McGill M. J. , Spackman J. R. 
Published: April 2018

Abstract
During the 2012 deployment of the NASA Hurricane and Severe Storm Sentinel (HS3) field campaign, several flights were dedicated to investigating Hurricane Nadine. Hurricane Nadine developed in close proximity to the dust-laden Saharan air layer and is the fourth-longest-lived Atlantic hurricane on record, experiencing two strengthening and weakening periods during its 22-day total life cycle as a tropical cyclone. In this study, the NASA GEOS-5 atmospheric general circulation model and data assimilation system was used to simulate the impacts of dust during the first intensification and weakening phases of Hurricane Nadine using a series of GEOS-5 forecasts initialized during Nadine’s intensification phase (12 September 2012). The forecasts explore a hierarchy of aerosol interactions within the model: no aerosol interaction, aerosol–radiation interactions, and aerosol–radiation and aerosol–cloud interactions simultaneously, as well as variations in assumed dust optical properties. When only aerosol–radiation interactions are included, Nadine’s track exhibits sensitivity to dust shortwave absorption, as a more absorbing dust introduces a shortwave temperature perturbation that impacts Nadine’s structure and steering flow, leading to a northward track divergence after 5 days of simulation time. When aerosol–cloud interactions are added, the track exhibits little sensitivity to dust optical properties. This result is attributed to enhanced longwave atmospheric cooling from clouds that counters shortwave atmospheric warming by dust surrounding Nadine, suggesting that aerosol–cloud interactions are a more significant influence on Nadine’s track than aerosol–radiation interactions. These findings demonstrate that tropical systems, specifically their track, can be impacted by dust interaction with the atmosphere.
Watch Peripheral Arterial Tonometry in the Diagnosis of Pediatric Obstructive Sleep Apnea
Authors: Tanphaichitr Archwin , Thianboonsong Arathaya , Banhiran Wish , Vathanophas Vannipa , Ungkanont Kitirat 
Published: April 2018

ObjectiveTo assess the accuracy and clinical reliability of watch peripheral arterial tonometry (PAT) compared with polysomnography (PSG) for the diagnosis of pediatric obstructive sleep apnea (OSA).Study DesignProspective, diagnostic test study.SettingNational tertiary referral hospital.Subjects and MethodsPatients aged 8 to 15 years with clinically suspected OSA were recruited. All participants underwent PSG and PAT simultaneously in the sleep laboratory.ResultsThirty‐six patients were included, with a mean age of 10.2 ± 1.8 years. Median (interquartile range) of the apnea hypopnea index (AHI) was 8.0 (5.5‐12) and 2.9 (0.5‐7.5) events/h, median oxygen desaturation index (ODI) was 2.5 (1.4‐8.3) and 1.3 (0.2‐3.8) events/h, mean ± standard deviation total sleep time was 398.4 ± 38.3 and 401.9 ± 36.1 minutes, and mean minimum oxygen saturation was 87.1% ± 8.1% and 89.4% ± 7.1% for PSG and PAT sleep parameter results, respectively. Agreement between methods was excellent for the AHI (intraclass correlation coefficient [ICC]: 0.89; 95% CI, 0.40‐0.96; P <. 001) and ODI (ICC: 0.87; 95% CI, 0.69‐0.94; P <. 001). Correlation between methods was very good for the ODI (r = 0.83; 95% CI, 0.67‐0.90; P <. 001) and moderate for the AHI (r = 0.64; 95% CI, 0.30‐0.85; P <. 001). From the receiver operating characteristic curve constructed to assess PAT diagnostic capability, AHI of PAT (W‐AHI) at a cutoff of 3.5 events/h provided the highest accuracy (76.9% sensitivity, 78.3% specificity), while W‐AHI at 10 events/h yielded 91.3% specificity for diagnosing severe OSA.ConclusionPAT correlated well and had good agreement with PSG. Children with W‐AHI ≥10 had high specificity for the diagnosis of severe OSA. Larger studies with PAT designed for children across all age ranges and with a normal control group are still needed.
Reducing the Time from Surgery to Adjuvant Radiation Therapy: An Institutional Quality Improvement Project
Authors: Divi Vasu , Chen Michelle M. , Hara Wendy , Shah Deepa , Narvasa Kristina , Segura Smith Andrea , Kelley Jennifer , Rosenthal Eben L. , Porter Julie 
Published: April 2018

ObjectiveThe National Comprehensive Cancer Network guidelines recommend an interval between surgery and adjuvant radiation therapy of less than 6 weeks, but only 44% of patients meet this metric nationally. We sought to identify key components of an improvement process focused on starting adjuvant radiation therapy within 6 weeks of surgery.MethodsThis project used an A3 model to improve a defined process measure. We studied a consecutive sample of 56 patients with oral cavity carcinoma who were treated at our institution with upfront surgical resection followed by adjuvant radiation therapy. Twelve proposed interventions tested during the study period focused on 3 key drivers of delays: delayed dental evaluation and teeth extraction, delayed radiation oncology consults, and inadequate patient engagement. The primary outcome measure was the number of days from surgery to the start of radiation therapy.ResultsPrior to the intervention, 62% of patients received adjuvant radiation within 6 weeks of surgery. Following the intervention, 73% of patients achieved this metric. The percentage of patients with avoidable delays decreased from 24% to 9%. The percentage of patients with unavoidable delays was relatively constant before and after the intervention (15% and 18%, respectively).DiscussionDefining disease‐specific metrics is critical to improving care in our head and neck cancer patient population. We demonstrate several key components to develop and improve self‐defined metrics.Implications for PracticeAs we transition to a system of value‐based care, structured quality improvement projects can have a measurable impact on cancer patient process measures.
Sudden Sensorineural Hearing Loss in the Department of Defense
Authors: Hughes Charlotte K. , Fischer Jakob , Esquivel Carlos R. , Laury Adrienne M. 
Published: April 2018

ObjectiveThe American Academy of Otolaryngology—Head and Neck Surgery Foundation clinical practice guideline (CPG) proposes recommendations regarding sudden sensorineural hearing loss (SSNHL). SSNHL is managed by primary care, emergency medicine, and otolaryngology providers in the Department of Defense (DoD). However, their adherence to this CPG is unknown. We sought to determine provider compliance and identify areas for improvement.Study DesignCase series with chart review.SettingDoD's electronic medical record.Subjects and MethodsPatients with SSNHL (N = 204) were treated between March 1, 2012, and September 30, 2015. Time from onset of symptoms to evaluation by primary care, emergency department, audiology, and otolaryngology providers and treatments were analyzed.ResultsThe average interval from onset of symptoms to evaluation by a primary care or emergency department provider was 4.86 days (95% CI, 3.46‐6.26). Time from presentation to ear, nose, and throat and audiologic evaluation was 15.26 days (95% CI, 12.34‐18.20) and 14.16 days (95% CI, 11.31‐17.01), respectively. Diagnostic workup included magnetic resonance imaging (n = 150, 73.5%), computed tomography (n = 28, 13.7%), and laboratory testing (n = 50, 24.5%). Oral steroids were used in 137 (67.2%) patients, with 78.8% treated with the recommended dose. Intratympanic steroids were utilized in 65 (31.9%) patients, with variable dosing.ConclusionThe DoD is uniquely positioned to evaluate adherence to CPGs on national and international levels given the robust and standardized electronic medical record. Areas of improvement include timely identification of SSNHL with rapid referral to ear, nose, and throat and audiology providers; minimizing unnecessary imaging, laboratory testing, and medications; and correct dosing of oral and intratympanic steroids.