bluuebunny/crossref_metadata_2025_split huggingface dataset:
Registration audit of clinical trials given a favourable opinion by UK research ethics committees
Authors: Denneny Carla , Bourne Sue , Kolstoe Simon E 
Published: February 2019

ObjectiveTo determine levels of public registration for a cohort of clinical trials reviewed and given a favourable opinion by research ethics committees in the United Kingdom.Study designAudit of records.SettingClinical trials receiving a favourable ethics opinion between 1 January 2016 and 30 June 2016.Main outcome measuresCorrelation between trials on the UK research ethics committee database and any primary registry entry on the WHO International Clinical Trials Registry Platform or clinicaltrials.gov as of 29 August 2017 (14 to 20 months after the favourable ethics committee opinion).ResultsOver the study period 1014 trials received a favourable ethics opinion, with 397 (39%) registered on the European Union Drug Regulating Authorities Clinical Trials database, and 18 with an agreed clinical trial registration deferral. Excluding these trials, the total number subsequently requiring registration was 599, and of these 405 (40% of total) were found to be registered. Follow-up with the 194 investigators or sponsors of trials not found to be registered produced 121 responses with a further 10 (1%) trials having already registered, 55 commitments to register and a variety of other responses. The overall registration rate was therefore 80%.ConclusionsDespite researchers and sponsors being reminded that registration of clinical trials is a condition of the research ethics committee (REC) favourable opinion, one-fifth of clinical trials either had not been registered, or their registration could not easily be found, 14 to 20 months after receiving the favourable opinion letter. The methodology trialled here proved effective, and although there are positive indications of a culture change towards greater registration, our results show that more still needs to be done to increase trial registration.
Antimicrobial photodynamic therapy against Staphylococcus aureus using zinc phthalocyanine and zinc phthalocyanine-integrated TiO2 nanoparticles
Authors: Tunçel Ayça , Öztürk İsmail , Ince Mine , Ocakoglu Kasim , Hoşgör-Limoncu Mine , Yurt Fatma 
Published: February 2019

Antibiotic resistance is an increasing healthcare problem worldwide. In the present study, the effects of antimicrobial photodynamic therapy (APDT) of ZnPc and ZnPc-integrated TiO2 nanoparticles (ZnPc-TiO[Formula: see text] were investigated against Staphylococcus aureus. A light emitting diode (LED) (630–700 nm, 17.4 mW/cm[Formula: see text] was used on S. aureus at different light doses (8 J/cm2 for 11 min, 16 J/cm2 for 22 min, 24 J/cm2 for 33 min) in the presence of the compounds under the minimum inhibitory concentration values. Both compounds showed similar phototoxicity toward S. aureus when high light doses (16 and 24 J/cm[Formula: see text] were applied. In addition, the success of APDT increased with an increasing light dose.
Parametrized complexity of virtual network embeddings
Authors: Rost Matthias , Döhne Elias , Schmid Stefan 
Published: February 2019

This paper makes the case for a parametrized complexity approach to tackle the fundamental but notoriously hard Virtual Network Embedding Problem. In particular, we show that the structure of the to-be-embedded virtual network requests can be exploited toward fast (i.e.,fixed-parameter tractable) approximation algorithms, using dynamic as well as linear programming algorithms.
Our approach does provide formal guarantees on the runtime and solution quality and can safeguard also latency constraints. Using extensive computational experiments we demonstrate the practical relevance of our novel approach.
Angiotensin II-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways
Authors: Singh Madhu V. , Cicha Michael Z. , Nunez Sarah , Meyerholz David K. , Chapleau Mark W. , Abboud François M. 
Published: February 2019

Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins myeloid differentiation protein 88 (MyD88) and Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF). Previously, we demonstrated that TRIF mediates the signaling of angiotensin II (ANG II)- induced hypertension and cardiac hypertrophy. Since TRIF is activated selectively by TLR3 and TLR4, our goals in this study were to determine the roles of TLR3 and TLR4 in mediating ANG II-induced hypertension and cardiac hypertrophy, and associated changes in proinflammatory gene expression in heart and kidney. In wild-type (WT) mice, ANG II infusion (1,000 ng·kg−1·min−1for 3 wk) increased systolic blood pressure and caused cardiac hypertrophy. In ANG II-infused TLR4-deficient mice ( Tlr4del), hypertrophy was significantly attenuated despite a preserved or enhanced hypertensive response. In contrast, in TLR3-deficient mice ( Tlr3−/−), both ANG II-induced hypertension and hypertrophy were abrogated. In WT mice, ANG II increased the expression of several proinflammatory genes in hearts and kidneys that were attenuated in both TLR4- and TLR3-deficient mice compared with WT. We conclude that ANG II activates both TLR4-TRIF and TLR3-TRIF pathways in a nonredundant manner whereby hypertension is dependent on activation of the TLR3-TRIF pathway and cardiac hypertrophy is dependent on both TLR3-TRIF and TLR4-TRIF pathways.NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension is dependent on the endosomal Toll-like receptor 3 (TLR3)-Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF) pathway of the innate immune system but not on cell membrane localized TLR4. However, ANG II-induced cardiac hypertrophy is regulated by both TLR4-TRIF and TLR3-TRIF pathways. Thus, ANG II-induced rise in systolic blood pressure is independent of TLR4-TRIF effect on cardiac hypertrophy. The TLR3-TRIF pathway may be a potential target of therapeutic intervention.
Reflected hemodynamic waves influence the pattern of Doppler ultrasound waveforms along the umbilical arteries
Authors: Sled John G. , Stortz Greg , Cahill Lindsay S. , Milligan Natasha , Ayyathurai Viji , Serghides Lena , Morgen Eric , Seravalli Viola , Delp Cassandra , McShane Cyrethia , Baschat Ahmet , Kingdom John , Macgowan Christopher K. 
Published: February 2019

The pulsatile pattern of blood motion measured by Doppler ultrasound within the umbilical artery is known to contain useful diagnostic information and is widely used to monitor pregnancies at risk of fetal growth restriction or stillbirth. Animal studies have identified reflected pressure waves traveling counter to the direction of blood flow as an important factor in the shape of these waveforms. In the present study, we establish a method to measure reflected waves in the human umbilical artery and assess their influence on blood velocity pulsation. Ninety-five pregnant women were recruited from a general obstetrics clinic between 26 and 37 wk of gestation and examined by Doppler ultrasound. Blood velocity waveforms were recorded for each umbilical artery at three locations along the umbilical cord. With the use of a computational procedure, a pair of forward and reverse propagating waves was identified to explain the variation in observed Doppler ultrasound waveforms along the cord. Among the data sets that met data quality requirements, waveforms in 93 of the 130 arteries examined agreed with the wave reflection model to within 1.5% and showed reflections ranging in magnitude from 3 to 52% of the forward wave amplitude. Strong reflections were associated with large differences in pulsatility between the fetal and placental ends of the cord. As reflections arise from transitions in the biomechanical properties of blood vessels, these observations provide a plausible mechanism for the link between abnormal waveforms and clinically significant placental pathology and could lead to more precise screening methods for detecting pregnancies complicated by placental disease.NEW & NOTEWORTHY The pulsatile pattern of blood motion measured by Doppler ultrasound within the umbilical artery is known to contain useful diagnostic information and is widely used to monitor pregnancies at risk of fetal growth restriction. We demonstrate based on a study of 95 pregnant women that the shape of these umbilical artery waveforms is explained by the presence of a reflected pressure wave traveling counter to the direction of blood flow.
Overcoming BET Inhibitor Resistance in Malignant Peripheral Nerve Sheath Tumors
Authors: Cooper Jonathan M. , Patel Amish J. , Chen Zhiguo , Liao Chung-Ping , Chen Kun , Mo Juan , Wang Yong , Le Lu Q. 
Published: February 2019

AbstractPurpose:BET bromodomain inhibitors have emerged as a promising therapy for numerous cancer types in preclinical studies, including neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumor (MPNST). However, potential mechanisms underlying resistance to these inhibitors in different cancers are not completely understood. In this study, we explore new strategy to overcome BET inhibitor resistance in MPNST.Experimental Design: Through modeling tumor evolution by studying genetic changes underlying the development of MPNST, a lethal sarcoma with no effective medical treatment, we identified a targetable addiction to BET bromodomain family member BRD4 in MPNST. This served as a controlled model system to delineate mechanisms of sensitivity and resistance to BET bromodomain inhibitors in this disease.Results:Here, we show that a malignant progression–associated increase in BRD4 protein levels corresponds to partial sensitivity to BET inhibition in MPNST. Strikingly, genetic depletion of BRD4 protein levels synergistically sensitized MPNST cells to diverse BET inhibitors in culture and in vivo.Conclusions:Collectively, MPNST sensitivity to combination genetic and pharmacologic inhibition of BRD4 revealed the presence of a unique addiction to BRD4 in MPNST. Our discovery that a synthetic lethality exists between BET inhibition and reduced BRD4 protein levels nominates MPNST for the investigation of emerging therapeutic interventions such as proteolysis-targeting chimeras (PROTACs) that simultaneously target bromodomain activity and BET protein abundance.
A Novel mTORC1/2 Inhibitor (MTI-31) Inhibits Tumor Growth, Epithelial–Mesenchymal Transition, Metastases, and Improves Antitumor Immunity in Preclinical Models of Lung Cancer
Authors: Zhang Qianwen , Zhang Yan , Chen Yaqing , Qian Jianchang , Zhang Xuesai , Yu Ker 
Published: February 2019

Abstract

Purpose:
We aimed to investigate efficacy and mechanism of MTI-31 (LXI-15029), a novel mTORC1/mTORC2 inhibitor currently in human trial (NCT03125746), in non–small cell lung cancer (NSCLC) models of multiple driver mutations and tyrosine kinase inhibitor (TKI)-resistance.

Experimental Design:
Gene depletion, inhibitor treatment, immunological, flow cytometry, cellular, and animal studies were performed to determine in vitro and in vivo efficacy in NSCLC models of driver mutations and elucidate roles by mTOR complexes in regulating migration, epithelial–mesenchymal transition (EMT), metastasis, intracranial tumor growth, and immune-escape.

Results:
MTI-31 potently inhibited cell proliferation (IC50 &lt;1 μmol/L) and in vivo tumor growth in multiple NSCLC models of EGFR/T790M, EML4-ALK, c-Met, or KRAS (MED &lt;10 mg/kg). In EGFR-mutant and/or EML4-ALK-driven NSCLC, MTI-31 or disruption of mTORC2 reduced cell migration, hematogenous metastasis to the lung, and abrogated morphological and functional traits of EMT. Disruption of mTORC2 inhibited EGFR/T790M-positive tumor growth in mouse brain and prolonged animal survival correlating a diminished tumor angiogenesis and recruitment of IBA1+ microglia/macrophages in tumor microenvironment. MTI-31 also suppressed programmed death ligand 1 (PD-L1) in EGFR- and ALK-driven NSCLC, mediated in part by mTORC2/AKT/GSK3β-dependent proteasomal degradation. Depletion of mTOR protein or disruption of mTOR complexes profoundly downregulated PD-L1 and alleviated apoptosis in Jurkat T and primary human T cells in a tumor-T cell coculture system.

Conclusions:
Our results highlight mTOR as a multifaceted regulator of tumor growth, metastasis, and immune-escape in EGFR/ALK-mutant and TKI-resistant NSCLC cells. The newly characterized mechanisms mediated by the rapamycin-resistant mTORC2 warrant clinical investigation of mTORC1/mTORC2 inhibitors in patients with lung cancer.
Multiplexed (18-Plex) Measurement of Signaling Targets and Cytotoxic T Cells in Trastuzumab-Treated Patients using Imaging Mass Cytometry
Authors: Carvajal-Hausdorf Daniel E. , Patsenker Jonathan , Stanton Kelly P. , Villarroel-Espindola Franz , Esch Amanda , Montgomery Ruth R. , Psyrri Amanda , Kalogeras Konstantine T. , Kotoula Vassiliki , Foutzilas George , Schalper Kurt A. , Kluger Yuval , Rimm David L. 
Published: February 2019

Abstract

Purpose:
Imaging mass cytometry (IMC) uses metal-conjugated antibodies to provide multidimensional, objective measurement of protein targets. We used this high-throughput platform to perform an 18-plex assessment of HER2 ICD/ECD, cytotoxic T-cell infiltration and other structural and signaling proteins in a cohort of patients treated with trastuzumab to discover associations with trastuzumab benefit.

Experimental Design:
An antibody panel for detection of 18 targets (pan-cytokeratin, HER2 ICD, HER2 ECD, CD8, vimentin, cytokeratin 7, β-catenin, HER3, MET, EGFR, ERK 1–2, MEK 1–2, PTEN, PI3K p110 α, Akt, mTOR, Ki67, and Histone H3) was used with a selection of trastuzumab-treated patients from the Hellenic Cooperative Oncology Group 10/05 trial (n = 180), and identified a case–control series.

Results:
Patients that recurred after adjuvant treatment with trastuzumab trended toward a decreased fraction of HER2 ECD pixels over threshold compared with cases without recurrence (P = 0.057). After exclusion of the lowest HER2 expressers, 5-year recurrence events were associated with reduced total extracellular domain (ECD)/intracellular domain (ICD) ratio intensity in tumor (P = 0.044). These observations are consistent with our previous work using quantitative immunofluorescence, but represent the proof on identical cell content. We also describe the association of the ECD of HER2 with CD8 T-cell infiltration on the same slide.

Conclusions:
The proximity of CD8 cells as a function of the expression of the ECD of HER2 provides further evidence for the role of the immune system in the mechanism of action of trastuzumab.
Comparison of Biomarker Assays for EGFR: Implications for Precision Medicine in Patients with Glioblastoma
Authors: Lassman Andrew B. , Roberts-Rapp Lisa , Sokolova Irina , Song Minghao , Pestova Ekaterina , Kular Rupinder , Mullen Carolyn , Zha Zheng , Lu Xin , Gomez Erica , Bhathena Anahita , Maag David , Kumthekar Priya , Gan Hui K. , Scott Andrew M. , Guseva Maria , Holen Kyle D. , Ansell Peter J. , van den Bent Martin J. 
Published: February 2019

Abstract

Purpose:
Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing EGFR amplification by multiple assays. Specifically, we evaluated correlation among fluorescence in situ hybridization (FISH), a standard assay for detecting EGFR amplification, with other methods.
Experimental Design: Formalin-fixed, paraffin-embedded tumor samples were used for all assays. EGFR amplification was detected using FISH (N = 206) and whole-exome sequencing (WES, N = 74). EGFR mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, N = 206) and transcriptome profiling (RNAseq, N = 64). EGFR protein expression was determined by immunohistochemistry (IHC, N = 34). Significant correlations among various methods were determined using Cohen's kappa (κ = 0.61–0.80 defines substantial agreement) or R2 statistics.

Results:
EGFR mRNA expression levels by RNA sequencing (RNAseq) and RT-PCR were highly correlated with EGFR amplification assessed by FISH (κ = 0.702). High concordance was also observed when comparing FISH to WES (κ = 0.739). RNA expression was superior to protein expression in delineating EGFR amplification.

Conclusions:
Methods for assessing EGFR mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for EGFR amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapeutic approaches.
Comparison of Outcomes After Percutaneous Coronary Intervention in Elderly Patients, Including 10 628 Nonagenarians: Insights From a Japanese Nationwide Registry (J‐PCI Registry)
Authors: Numasawa Yohei , Inohara Taku , Ishii Hideki , Yamaji Kyohei , Kohsaka Shun , Sawano Mitsuaki , Kodaira Masaki , Uemura Shiro , Kadota Kazushige , Amano Tetsuya , Nakamura Masato ,   on behalf of the J‐PCI Registry Investigators, Kadota Kazushige , Shiode Nobuo , Tanaka Nobuhiro , Amano Tetsuya , Uemura Shiro , Akasaka Takashi , Morino Yoshihiro , Fujii Kenshi , Hikichi Hiroshi , Kohsaka Shun , Ishii Hideki , Tanabe Kengo , Ozaki Yukio , Sumitsuji Satoru , Iida Osamu , Hara Hidehiko , Takashima Hiroaki , Shirai Shinichi , Nanasato Mamoru , Inohara Taku , Ueda Yasunori , Numasawa Yohei , Noma Shigetaka 
Published: February 2019

Background

Scarce data exist about the outcomes after percutaneous coronary intervention (
PCI
) in old patients. This study sought to provide an overview of
PCI
in elderly patients, especially nonagenarians, in a Japanese large prospective nationwide registry.

Methods and Results

We analyzed 562 640 patients undergoing PCI (≥60 years of age) from 1018 Japanese hospitals between 2014 and 2016 in the J‐PCI (Japanese percutaneous coronary intervention) registry. Among them, 10 628 patients (1.9%), including 6780 (1.2%) with acute coronary syndrome (
ACS
) and 3848 (0.7%) with stable coronary artery disease, were ≥90 years of age. We investigated differences in characteristics and in‐hospital outcomes among sexagenarians, septuagenarians, octogenarians, and nonagenarians. Older patients were more frequently women and had a greater frequency of heart failure and chronic kidney disease than younger patients. In addition, older patients had a higher rate of in‐hospital mortality, cardiac tamponade, cardiogenic shock after
PCI
, and bleeding complications requiring blood transfusion. Nonagenarians had the highest risk of in‐hospital mortality (odds ratio, 3.60; 95%
CI
, 3.10–4.18 in
ACS
; odds ratio
,
6.24; 95%
CI,
3.82–10.20 in non‐
ACS
) and bleeding complications (
odds ratio,
1.79; 95%
CI,
1.35–2.36 in
ACS
; odds ratio
,
2.70; 95%
CI,
1.68–4.35 in non‐
ACS
) when referenced to sexagenarians. More important, transradial intervention was an inverse independent predictor of both in‐hospital mortality and bleeding complications.

Conclusions

Older patients, especially nonagenarians, carried a greater risk of in‐hospital death and bleeding compared with younger patients after
PCI
. Transradial intervention might contribute to risk reduction for periprocedural complications in elderly patients undergoing
PCI
.
A revision of the genus Conocrinus d’Orbigny, 1850 (Echinodermata, Crinoidea, Rhizocrinidae) and its place among extant and fossil crinoids with a xenomorphic stalk
Authors: ROUX MICHEL , ELÉAUME MARC , AMÉZIANE NADIA 
Published: February 2019

The genus Conocrinus d’Orbigny, 1850 (Crinoidea, Bourgueticrinina) was established on the basis of two aboral cups that had previously been described as Bourgueticrinus thorenti d’Archiac, 1846. One of these (now considered lost) came from the “Rocher du Goulet” at the base of the Biarritz section (Bartonian, Côte des Basques, southwest France). D’Archiac figured only the second cup; this belongs to the d’Orbigny Collection and is still housed in the palaeontological collection of the Muséum national d’Histoire naturelle (Paris) as the lectotype of the species, C. thorenti. It appears that it was collected from Priabonian levels exposed near Castellane (Alpes de Haute Provence, southeast France). New observations on this cup, as well as a detailed study of the characters of aboral cups, columnals and proximal brachials in a few extant and fossil species classically attributed to Conocrinus or to closely related genera such as Democrinus, Rhizocrinus and Tormocrinus, have yielded arguments for a revision of the taxonomy and interrelationships of extant and fossil taxa in the family Bourgueticrinidae. Conocrinus (= Tormocrinus), as here interpreted, includes six Eocene species: C. thorenti, C. archiaci, C. cahuzaci n. sp., C. duperrieri, C. cf. suessi and C. veronensis. Numerous extinct species previously attributed to Conocrinus or Democrinus are here transferred to two new genera which first occur in the lower Paleocene: Paraconocrinus n. gen. (type species: P. pyriformis) and Pseudoconocrinus n. gen. (type species: P. doncieuxi). Aboral cups from the “Rocher du Goulet” (Biarritz) are here assigned to Paraconocrinus pellati n. gen., n. sp., while the Danian species Democrinus maximus is transferred to Pseudoconocrinus n. gen. A new genus, Cherbonniericrinus, is created to accommodate a single extant species, Ch. cherbonnieri, previously attributed to Conocrinus, while the extant genus Rhizocrinus, closely related to Democrinus, is resurrected. Conocrinus and closely related genera are derived from a bourgueticrinine lineage the first record of which is from the lower Campanian, with the new genus Carstenicrinus. These are all attributed to the family Rhizocrinidae which is here considered distinct from the family Bourgueticrinidae. Rhizocrinids rapidly diversified immediately after the Cretaceous-Paleogene (K/Pg) event. Cretaceous taxa previously placed within the family Bourgueticrinidae now appear to be polyphyletic. Some of them do not belong to Bourgueticrinina, such as those of the Dunnicrinus lineage. Interrelationships of Rhizocrinidae and other post-Palaeozoic families having a xenomorphic stalk are discussed.
Modulation of the Kara Sea Ice Variation on the Ice Freeze-Up Time in Lake Qinghai
Authors: Liu Yong , Chen Huopo , Wang Huijun , Sun Jianqi , Li Hua , Qiu Yubao 
Published: February 2019

Abstract
Lake ice phenology, as an indicator for climate variability and change, exerts a great influence on regional climate and hydrometeorology. In this study, the changing characteristics of lake ice phenology at Lake Qinghai (LQH) are investigated using retrieved historical datasets during 1979–2016. The results show that the variation of the lake freeze-up date over LQH is characterized by a strong interannual variability. Further analysis has revealed that November sea ice concentration (SIC) variation in the Kara Sea can exert a great impact on the freeze-up date at LQH. During the low sea ice years, the open sea serves as a strong diabatic heating source, largely contributing to the enhanced Arctic Eliassen–Palmer flux, which then results in the deceleration of zonal wind in the middle and high latitudes. In addition to this, accompanied with the decreasing Kara SIC, the enhanced stationary Rossby wave flux propagating along the high-latitude regions may further exert remarkable influences in deepening the East Asian trough, which provides a favorable atmospheric circulation pattern for cold air intrusion from the Arctic and Siberian regions to mainland China. The decreased surface air temperature would thus advance the freezing date over LQH. Furthermore, the close relationship between atmospheric circulation anomalies and Kara SIC variations is validated by a large ensemble of simulations from the Community Earth System Model, and the atmospheric circulation patterns induced by the SIC anomalies are reproduced to some extent. Therefore, the November Kara Sea ice anomaly might be an important predictor for the variation in the freeze-up date at LQH.