bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of Biomarkers and Association With Clinical Outcomes in Patients With Differentiated Thyroid Cancer: Subanalysis of the Sorafenib Phase III DECISION Trial
Authors: Brose Marcia S. , Schlumbeger Martin , Jeffers Michael , Kappeler Christian , Meinhardt Gerold , Peña Carol E.A. 
Published: September 2019

Abstract

Purpose:
The phase III DECISION trial (NCT00984282; EudraCT:2009-012007-25) established sorafenib efficacy in locally recurrent or metastatic, progressive, differentiated thyroid cancer (DTC) refractory to radioactive iodine. We conducted a retrospective, exploratory biomarker analysis of patients from DECISION.

Experimental Design:
Candidate biomarkers [15 baseline plasma proteins, baseline and during-treatment serum thyroglobulin, and relevant tumor mutations (BRAF, NRAS, HRAS, and KRAS)] were analyzed for correlation with clinical outcomes.

Results:
Plasma biomarker and thyroglobulin data were available for 395 of 417 (94.7%) and 403 of 417 (96.6%) patients, respectively. Elevated baseline VEGFA was independently associated with poor prognosis for progression-free survival [PFS; HR = 1.82; 95% confidence interval (CI), 1.38–2.44; P = 0.0007], overall survival (HR = 2.13; 95% CI, 1.37–3.36; P = 0.013), and disease-control rate (DCR; OR = 0.30; P = 0.009). Elevated baseline thyroglobulin was independently associated with poor PFS (HR = 2.03; 95% CI, 1.52–2.71; P &lt; 0.0001) and DCR (OR = 0.32; P = 0.01). Combined VEGFA/thyroglobulin signatures correlated with poor PFS (HR = 2.12; 95% CI, 1.57–2.87; P &lt; 0.00001). Thyroglobulin decrease ≥30% from baseline was achieved by 76% and 14% of patients receiving sorafenib and placebo, respectively (P &lt; 0.001). Patients with ≥30% thyroglobulin reduction had longer PFS than those without ≥30% reduction [HR (95% CI): sorafenib = 0.61 (0.40–0.94), P = 0.022; placebo = 0.49 (0.29–0.85), P = 0.009]. BRAF mutations were associated with better PFS; RAS mutations were associated with worse PFS, although neither was independently prognostic in multivariate models. No examined biomarker predicted sorafenib benefit.

Conclusions:
We identified biomarkers associated with poor prognosis in DTC, including elevated baseline VEGFA and thyroglobulin and the presence of RAS mutations. Serum thyroglobulin may be a biomarker of tumor response and progression.
A First-in-Human Phase I Study of INVAC-1, an Optimized Human Telomerase DNA Vaccine in Patients with Advanced Solid Tumors
Authors: Teixeira Luis , Medioni Jacques , Garibal Julie , Adotevi Olivier , Doucet Ludovic , Durey Marie-Agnès Dragon , Ghrieb Zineb , Kiladjian Jean-Jacques , Brizard Mara , Laheurte Caroline , Wehbe Maria , Pliquet Elodie , Escande Marie , Defrance Rémy , Culine Stephane , Oudard Stephane , Wain-Hobson Simon , Doppler Valérie , Huet Thierry , Langlade-Demoyen Pierre 
Published: September 2019

AbstractPurpose:Human telomerase reverse transcriptase (hTERT) is highly expressed in &gt;85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors.Patients and Methods:INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system. Safety and tolerability were monitored by clinical and laboratory assessments. Progression-free survival and overall survival were reported using Kaplan–Meier survival analysis. Immunogenicity was studied by ELISpot, Luminex, and Flow Cytometry.Results:Twenty-six patients were treated with INVAC-1 administered at three dose levels (100, 400, and 800 μg). Vaccination was well tolerated and no dose-limiting toxicity was reported. One treatment-related grade 3 SAE was reported. Fifty-eight percent of patients experienced disease stabilization. PFS was 2.7 months, median OS was 15 months, and 1-year survival was reached for 65% of patients. INVAC-1 vaccination stimulated specific anti-hTERT CD4 T-cell response as well as cytotoxic CD8 T-cell response. No evidence of peripheral vaccine-induced immunosuppression was observed.Conclusions:INVAC-1 vaccination was safe, well tolerated, and immunogenic when administered intradermally at the three tested doses in patients with relapsed or refractory cancers. Disease stabilization was observed for the majority of patients (58%) during the treatment period and beyond.See related commentary by Slingluff Jr, p. 529
The first photographic record of the Red Panda Ailurus fulgens (Cuvier, 1825) from Lamjung District outside Annapurna Conservation Area, Nepal
Authors: Ghimire Ganesh , Pearch Malcolm , Baral Badri , Thapa Bishnu , Baral Rishi 
Published: September 2019

In May and June, 2018, a series of field surveys was undertaken to determine the presence of the Red Panda Ailurus fulgens in Marsyangdi Rural Municipality in Lamjung District, western Nepal. A single, adult, Red Panda was photographed and recorded on video at Nafada Khola while scratch marks and distinctive scats provided evidence of Red Panda activity at eleven further localities at elevations between 3,150 and 3,650 m. Threats to the habitat of A. fulgens within the study area are discussed.
Ornithophony in the soundscape of Anaikatty Hills, Coimbatore, Tamil Nadu, India
Authors: Divyapriya Chandrasekaran , Pramod Padmanabhan 
Published: September 2019

An attempt has been made to understand the extent of ornithophony (vocalization of birds) in the soundscape of Anaikatty Hills. The study was limited to 13 hours of daylight from dawn to dusk (06.00–19.00 h) between January 2015 and October 2016. Six replicates of 5-minute bird call recordings were collected from each hour window in 24 recording spots of the study area. Each 5-minute recording was divided into 150 ‘2-sec’ observation units for the detailed analysis of the soundscape. A total of 78 recordings amounting to 390 minutes of acoustic data allowed a preliminary analysis of the ornithophony of the area. A total of 62 bird species were heard vocalizing during the study period and contributed 8,629 units. A total of 73.75% acoustic space was occupied by birds, among which the eight dominant species alone contributed to 63.65% of ornithophony. The remaining 26% of acoustic space was occupied by other biophonies (12.60%), geophony (5.57%), indistinct sounds (7.66%), and anthropogenic noise (0.41%). Passerines dominated the vocalizations with 7,269 (84.24%) and non-passerines with 1,360 (15.76%) units. Birds vocalized in all 13 observation windows, with a peak in the first three hours of the day (06.00–09.00 h). Vocalizations of non-passerines were prominent in the dusk hours (18.00–19.00 h).
Ethnobotanical survey of indigenous leafy vegetables consumed in rural areas of Terai-Dooars region of West Bengal, India
Authors: Mazumder Mallika , Sarkar Anup Kumar 
Published: September 2019

There is always a need for novel, high quality, functional and inexpensive foods among consumers in the global markets. Leafy vegetables can fulfill such needs. Leafy vegetables are now used worldwide as food for their nutritional and medicinal values. In the present work an ethnobotanical survey was carried out on the utilization of edible plants by local communities of the Terai-Dooars Region of West Bengal. The information has been documented by interviewing traditional farmers, herbalists, various older men and women following different ethnobotanical methods. A total of 103 plant species under 44 families with their short botanical description, use, range of demands and cultivation status have been documented.
Variation in Coronary Atherosclerosis Severity Related to a Distinct LDL (Low-Density Lipoprotein) Profile
Authors: Hoogendoorn Ayla , den Hoedt Sandra , Hartman Eline M.J. , Krabbendam-Peters Ilona , te Lintel Hekkert Maaike , van der Zee Leonie , van Gaalen Kim , Witberg Karen Th. , Dorst Kristien , Ligthart Jurgen M.R. , Drouet Ludovic , Van der Heiden Kim , van Lennep Jeanine Roeters , van der Steen Antonius F.W. , Duncker Dirk J. , Mulder Monique T. , Wentzel Jolanda J. 
Published: September 2019

Objective:
In an adult porcine model of familial hypercholesterolemia (FH), coronary plaque development was characterized. To elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein profiles were determined.

Approach and Results:

FH pigs (3 years old, homozygous
LDLR
R84C mutation) received an atherogenic diet for 12 months. Coronary atherosclerosis development was monitored using serial invasive imaging and histology. A pronounced difference was observed between mildly diseased pigs which exclusively developed early lesions (maximal plaque burden, 25% [23%–34%]; n=5) and advanced-diseased pigs (n=5) which developed human-like, lumen intruding plaques (maximal plaque burden, 69% [57%–77%]) with large necrotic cores, intraplaque hemorrhage, and calcifications. Advanced-diseased pigs and mildly diseased pigs displayed no differences in conventional risk factors. Additional plasma lipoprotein profiling by size-exclusion chromatography revealed 2 different LDL (low-density lipoprotein) subtypes: regular and larger LDL. Cholesterol, sphingosine-1-phosphate, ceramide, and sphingomyelin levels were determined in these LDL-subfractions using standard laboratory techniques and high-pressure liquid chromatography mass-spectrometry analyses, respectively. At 3 months of diet, regular LDL of advanced-diseased pigs contained relatively more cholesterol (LDL-C; regular/larger LDL-C ratio 1.7 [1.3–1.9] versus 0.8 [0.6–0.9];
P
=0.008) than mildly diseased pigs, while larger LDL contained more sphingosine-1-phosphate, ceramides, and sphingomyelins. Larger and regular LDL was also found in plasma of 3 patients with homozygous FH with varying LDL-C ratios.

Conclusions:
In our adult FH pig model, inter-individual differences in atherosclerotic disease severity were directly related to the distribution of cholesterol and sphingolipids over a distinct LDL profile with regular and larger LDL shortly after the diet start. A similar LDL profile was detected in patients with homozygous FH.
ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure
Authors: Omura Junichi , Satoh Kimio , Kikuchi Nobuhiro , Satoh Taijyu , Kurosawa Ryo , Nogi Masamichi , Ohtsuki Tomohiro , Al-Mamun Md Elias , Siddique Mohammad Abdul Hai , Yaoita Nobuhiro , Sunamura Shinichiro , Miyata Satoshi , Hoshikawa Yasushi , Okada Yoshinori , Shimokawa Hiroaki 
Published: September 2019

Rationale:
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling.

Objective:
Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure.

Methods and Results:

We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a ADAMTS8 (disintegrin and metalloproteinase with thrombospondin motifs 8), a secreted protein specifically expressed in the lung and the heart, was upregulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTS
ΔSM22
). Hypoxia-induced PH was attenuated in ADAMTS
ΔSM22
mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMPK (AMP-activated protein kinase). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTS
ΔSM22
mice demonstrated that phosphorylated DRP-1 (dynamin-related protein 1) at Ser637 was significantly upregulated with higher expression of profusion genes (Mfn1 and Mfn2) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8
ΔαMHC
). ADAMTS8
ΔαMHC
mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8
ΔαMHC
mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models.

Conclusions:
These results indicate that ADAMTS8 is a novel therapeutic target in PAH.
Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development
Authors: Aung Nay , Vargas Jose D. , Yang Chaojie , Cabrera Claudia P. , Warren Helen R. , Fung Kenneth , Tzanis Evan , Barnes Michael R. , Rotter Jerome I. , Taylor Kent D. , Manichaikul Ani W. , Lima Joao A.C. , Bluemke David A. , Piechnik Stefan K. , Neubauer Stefan , Munroe Patricia B. , Petersen Steffen E. 
Published: September 2019

Background:
The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear at present.

Methods:
The LV parameters were measured from the cardiovascular magnetic resonance studies of the UK Biobank. Genotyping was done using Affymetrix arrays, augmented by imputation. We performed genome-wide association studies of 6 LV traits—LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, LV mass, and LV mass to end-diastolic volume ratio. The replication analysis was performed in the MESA study (Multi-Ethnic Study of Atherosclerosis). We identified the candidate genes at genome-wide significant loci based on the evidence from extensive bioinformatic analyses. Polygenic risk scores were constructed from the summary statistics of LV genome-wide association studies to predict the heart failure events.

Results:

The study comprised 16 923 European UK Biobank participants (mean age 62.5 years; 45.8% men) without prevalent myocardial infarction or heart failure. We discovered 14 genome-wide significant loci (3 loci each for LV end-diastolic volume, LV end-systolic volume, and LV mass to end-diastolic volume ratio; 4 loci for LV ejection fraction, and 1 locus for LV mass) at a stringent
P
<1×10
−8
. Three loci were replicated at Bonferroni significance and 7 loci at nominal significance (
P
<0.05 with concordant direction of effect) in the MESA study (n=4383). Follow-up bioinformatic analyses identified 28 candidate genes that were enriched in the cardiac developmental pathways and regulation of the LV contractile mechanism. Eight genes (
TTN, BAG3, GRK5, HSPB7, MTSS1, ALPK3, NMB
, and
MMP11
) supported by at least 2 independent lines of in silico evidence were implicated in the cardiac morphogenesis and heart failure development. The polygenic risk scores of LV phenotypes were predictive of heart failure in a holdout UK Biobank sample of 3106 cases and 224 134 controls (odds ratio 1.41, 95% CI 1.26 – 1.58, for the top quintile versus the bottom quintile of the LV end-systolic volume risk score).

Conclusions:
We report 14 genetic loci and indicate several candidate genes that not only enhance our understanding of the genetic architecture of prognostically important LV phenotypes but also shed light on potential novel therapeutic targets for LV remodeling.
Occurrence Rate of Delirium in Acute Stroke Settings
Authors: Shaw Robert C. , Walker Graham , Elliott Emma , Quinn Terence J. 
Published: September 2019

Background and Purpose—
Delirium is associated with increased mortality, length of stay, and poor functional outcome following critical illness. The epidemiology of delirium in stroke is poorly described. We sought to collate evidence around occurrence (incidence or prevalence) of delirium in acute stroke.

Methods—
We searched multiple cross-disciplinary electronic databases using a prespecified search strategy, complemented by hand searching. Eligible studies described delirium in acute (first 6 weeks) stroke. We compared delirium occurrence using random-effects models to describe summary estimates. We assessed risk of bias using the Newcastle-Ottawa tool, incorporating this in sensitivity analyses. We performed subgroup analyses for delirium diagnostic method (confusion assessment method scoring, clinical diagnosis, other), duration and timing of delirium assessment (>1 or <1 week), and performed meta-regression based on the year of publication.

Results—

Of 8822 titles, we included 32 papers (6718 participants) in the quantitative analysis. Summary estimate for occurrence of delirium was 25% (95% CI, 20%–30%; moderate quality evidence). Limiting to studies at low risk of bias (22 studies, 4422 participants), the occurrence rate was 23% (95% CI, 17%–28%). Subgroup summary estimates suggest that delirium occurrence may vary with assessment method: confusion assessment method, 21% (95% CI, 16%–27%); clinical diagnosis, 27% (95% CI, 19%–38%); other, 32% (95% CI, 22%–43%) but not with duration and timing of assessment. Meta-regression suggested decline in occurrence of delirium comparing historical to more recent studies (slope, 0.03 [SE, 0.004];
P
<0.0001).

Conclusions—
Delirium is common, affecting 1 in 4 acute stroke patients. Reported rates of delirium may be dependent on assessment method. Our estimate of delirium occurrence could be used for audit, to plan intervention studies, and inform clinical practice.

Clinical Trial Registration—

URL:
http://www.crd.york.ac.uk/PROSPERO/
. Unique identifier: CRD42015029251.
Setting the Table Anew: Law and Spirit in a Nineteenth-Century Hasidic Code
Authors: Mayse Ariel Evan 
Published: September 2019

AbstractThis essay interrogates the legal discourse of Shulḥan ha-Tahor, a curious—and curiously understudied—work of Hasidic halakhah written by Rabbi Yitzḥak Ayzik Yehudah Yehiel Safrin of Komarno. The book is, at heart, a systematic reformulation of Jewish law in light of Kabbalah, Hasidism, and the quest for personal mystical experience. Shulḥan ha-Tahor offers a rare case study for the interface of mystical experience, Hasidic devotional values, and kabbalistic doctrine as they explicitly shape the codified forms—and norms—of halakhah. The essay reveals a different side of Jewish modernity through a close reading of an exceptional nineteenth-century legal code.
The efficacy of molecular markers associated with virulence in root-knot nematodes
Authors: Mistanoğlu İbrahim , Özalp Tevfik , Devran Zübeyir 
Published: September 2019

Summary
Root-knot nematodes (Meloidogyne spp.) are major crop pests that cause heavy economic losses. The use of resistant cultivars is one of the most important management methods. The Mi-1 gene in tomato confers effective resistance against several species of Meloidogyne. However, Mi-1-virulent root-knot nematodes restrict the use of resistant cultivars. Molecular markers associated with virulence have been developed in previous studies but not validated in large number of Meloidogyne populations so far. In this study, molecular markers were screened in a total of 69 (a)virulent Meloidogyne incognita and M. javanica isolates. The results showed these markers did not separate virulent and avirulent populations from Turkey. In addition, polymerase chain reaction products obtained from primers HM1.F2/HM1.R2 were digested with 30 restriction enzymes but no differences among populations were found. To the best of our knowledge, this is the first report on screening large root-knot nematode populations with these markers.
Topographic Effects on the Luzon Diurnal Cycle during the BSISO
Authors: Riley Dellaripa Emily M. , Maloney Eric D. , Toms Benjamin A. , Saleeby Stephen M. , van den Heever Susan C. 
Published: September 2019

AbstractCloud-resolving simulations are used to evaluate the importance of topography to the diurnal cycle (DC) of precipitation (DCP) over Luzon, Philippines, and surrounding ocean during the July–August 2016 boreal summer intraseasonal oscillation (BSISO) event. Composites of surface precipitation for each 30-min time increment during the day are made to determine the mean DCP. The mean DCP is computed separately for suppressed and active BSISO conditions and compared across three simulations with varying topography—flat, true, and doubled topographic height. The magnitude of the topographic height helps to dictate the timing, intensity, and location of diurnal precipitation over and near Luzon. For example, the mean DCP in the true topography run peaks 1.5 h later, is broader by 1 h, and has a 9% larger amplitude during active conditions relative to suppressed conditions. By contrast, the flat run mean DCP is earlier and narrower by 0.5 h with a 5% smaller amplitude during active conditions versus suppressed conditions. Within the suppressed or active BSISO conditions, the mean DCP peak and amplitude increase as the topographic height increases. The presence of elevated topography focuses precipitation over the coastal mountains during suppressed conditions, while dictating which side of the domain (i.e., east Luzon and the Philippine Sea vs west Luzon and the South China Sea) more precipitation occurs in during active conditions. These topographic-induced changes are discussed in terms of mechanical and thermodynamic forcing differences between the two large-scale BSISO regimes for the three runs.
Neuroprotective Effect of Huperzine A on d-Galactose-Induced Hearing Dysfunction
Authors: Li Cong , Shi Song 
Published: September 2019

Background: Administration of d-galactose (d-gal) has been used to create animal models of neurodegenerative diseases, and huperzine A has been used to treat the neurodegenerative diseases such as Alzheimer disease. Methods: An animal model of hearing dysfunction was established by administration of d-gal in the rats, and the effect of huperzine A on d-gal-induced abnormal hearing function and cochlear damage was investigated. Senescence of the cochlear tissues was examined by β-galactase staining, and messenger RNA expression of inflammatory cytokines was quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR). Results: It was found that d-gal significantly increased auditory brainstem response (ABR) threshold and cellular senescence and decreased neurofilament in the cochlear tissues. Huperzine A could significantly attenuate d-gal-induced increase of ABR threshold and cellular senescence as well as reduction of neurofilament. Moreover, huperzine A could inhibit d-gal-induced activation of nuclear factor kappa-B (NF-κB) in Schwann cells and significantly blocked d-gal-stimulated gene expression of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. Conclusion: These findings suggested that d-gal causes hearing dysfunction by inflammatory injury of cochlear neurons and that huperzine A could prevent hearing loss by protecting d-gal-induced physical damage of cochlear tissues.