bluuebunny/crossref_metadata_2025_split huggingface dataset:
COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms
Authors: Lindemann Antje , Patel Ameeta A. , Silver Natalie L. , Tang Lin , Liu Zhiyi , Wang Li , Tanaka Noriaki , Rao Xiayu , Takahashi Hideaki , Maduka Nakachi K. , Zhao Mei , Chen Tseng-Cheng , Liu WeiWei , Gao Meng , Wang Jing , Frank Steven J. , Hittelman Walter N. , Mills Gordon B. , Myers Jeffrey N. , Osman Abdullah A. 
Published: July 2019

AbstractPurpose:TP53 mutations are highly prevalent in head and neck squamous cell carcinoma (HNSCC) and associated with increased resistance to conventional treatment primarily consisting of chemotherapy and radiation. Restoration of wild-type p53 function in TP53-mutant cancer cells represents an attractive therapeutic approach and has been explored in recent years. In this study, the efficacy of a putative p53 reactivator called COTI-2 was evaluated in HNSCC cell lines with different TP53 status.Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine in vitro and in vivo sensitivity of HNSCC cell lines with either wild-type, null, or mutant TP53 to COTI-2 alone, and in combination with cisplatin and/or radiation. Western blotting, cell cycle, live-cell imaging, RNA sequencing, reverse-phase protein array, chromatin immunoprecipitation, and apoptosis analyses were performed to dissect molecular mechanisms.Results:COTI-2 decreased clonogenic survival of HNSCC cells and potentiated response to cisplatin and/or radiation in vitro and in vivo irrespective of TP53 status. Mechanistically, COTI-2 normalized wild-type p53 target gene expression and restored DNA-binding properties to the p53-mutant protein in HNSCC. In addition, COTI-2 induced DNA damage and replication stress responses leading to apoptosis and/or senescence. Furthermore, COTI-2 lead to activation of AMPK and inhibition of the mTOR pathways in vitro in HNSCC cells.Conclusions:COTI-2 inhibits tumor growth in vitro and in vivo in HNSCC likely through p53-dependent and p53-independent mechanisms. Combination of COTI-2 with cisplatin or radiation may be highly relevant in treating patients with HNSCC harboring TP53 mutations.
Targeting MUC1-C Inhibits TWIST1 Signaling in Triple-Negative Breast Cancer
Authors: Hata Tsuyoshi , Rajabi Hasan , Yamamoto Masaaki , Jin Caining , Ahmad Rehan , Zhang Yan , Kui Ling , Li Wei , Yasumizu Yota , Hong Deli , Miyo Masaaki , Hiraki Masayuki , Maeda Takahiro , Suzuki Yozo , Takahashi Hidekazu , Samur Mehmet , Kufe Donald 
Published: July 2019

Abstract
The oncogenic MUC1-C protein and the TWIST1 epithelial–mesenchymal transition transcription factor (EMT-TF) are aberrantly expressed in triple-negative breast cancer (TNBC) cells. However, there is no known association between MUC1-C and TWIST1 in TNBC or other cancer cells. Here, we show that MUC1-C activates STAT3, and that MUC1-C and pSTAT3 drive induction of the TWIST1 gene. In turn, MUC1-C binds directly to TWIST1, and MUC1-C/TWIST1 complexes activate MUC1-C expression in an autoinductive circuit. The functional significance of the MUC1-C/TWIST1 circuit is supported by the demonstration that this pathway is sufficient for driving (i) the EMT-TFs, ZEB1 and SNAIL, (ii) multiple genes in the EMT program as determined by RNA-seq, and (iii) the capacity for cell invasion. We also demonstrate that the MUC1-C/TWIST1 circuit drives (i) expression of the stem cell markers SOX2, BMI1, ALDH1, and CD44, (ii) self-renewal capacity, and (iii) tumorigenicity. In concert with these results, we show that MUC1-C and TWIST1 also drive EMT and stemness in association with acquired paclitaxel (PTX) resistance. Of potential therapeutic importance, targeting MUC1-C and thereby TWIST1 reverses the PTX refractory phenotype as evidenced by synergistic activity with PTX against drug-resistant cells. These findings uncover a master role for MUC1-C in driving the induction of TWIST1, EMT, stemness, and drug resistance, and support MUC1-C as a highly attractive target for inhibiting TNBC plasticity and progression.
A Randomized Phase II Trial of Pioglitazone for Lung Cancer Chemoprevention in High-Risk Current and Former Smokers
Authors: Keith Robert L. , Blatchford Patrick J. , Merrick Daniel T. , Bunn Paul A. , Bagwell Brandi , Dwyer-Nield Lori D. , Jackson Mary K. , Geraci Mark W. , Miller York E. 
Published: July 2019

AbstractLung cancer chemoprevention, especially in high-risk former smokers, has great potential to reduce lung cancer incidence and mortality. Thiazolidinediones prevent lung cancer in preclinical studies, and diabetics receiving thiazolidinediones have lower lung cancer rates which led to our double-blind, randomized, phase II placebo-controlled trial of oral pioglitazone in high-risk current or former smokers with sputum cytologic atypia or known endobronchial dysplasia. Bronchoscopy was performed at study entry and after completing 6 months of treatment. Biopsies were histologically scored, and primary endpoint analysis tested worst biopsy scores (Max) between groups; Dysplasia index (DI) and average score (Avg) changes were secondary endpoints. Biopsies also received an inflammation score. The trial accrued 92 subjects (47 pioglitazone, 45 placebo), and 76 completed both bronchoscopies (39 pioglitazone, 37 placebo). Baseline dysplasia was significantly worse for current smokers, and 64% of subjects had mild or greater dysplasia at study entry. Subjects receiving pioglitazone did not exhibit improvement in bronchial dysplasia. Former smokers treated with pioglitazone exhibited a slight improvement in Max, while current smokers exhibited slight worsening. While statistically significant changes in Avg and DI were not observed in the treatment group, former smokers exhibited a slight decrease in both Avg and DI. Negligible Avg and DI changes occurred in current smokers. A trend toward decreased Ki-67 labeling index occurred in former smokers with baseline dysplasia receiving pioglitazone. While pioglitazone did not improve endobronchial histology in this high-risk cohort, specific lesions showed histologic improvement, and further study is needed to better characterize responsive dysplasia.
Important Clinical Factors in Sequential Therapy Including Lenvatinib against Unresectable Hepatocellular Carcinoma
Authors: Hiraoka Atsushi , Kumada Takashi , Atsukawa Masanori , Hirooka Masashi , Tsuji Kunihiko , Ishikawa Toru , Takaguchi Koichi , Kariyama Kazuya , Itobayashi Ei , Tajiri Kazuto , Shimada Noritomo , Shibata Hiroshi , Ochi Hironori , Tada Toshifumi , Toyoda Hidenori , Nouso Kazuhiro , Tsutsui Akemi , Nagano Takuya , Itokawa Norio , Hayama Korenobu , Imai Michitaka , Joko Kouji , Tanaka Hironori , Tamai Tsutomu , Koizumi Yohei , Hiasa Yoichi , Michitaka Kojiro , Kudo Masatoshi ,   Real-life Practice Experts for HCC (RELPEC) Study Group,   HCC 48 Group (hepatocellular carcinoma experts from 48 clinics in Japan)
Published: July 2019

<b><i>Background/Aim:</i></b> We evaluated clinical factors related to improved prognosis of unresectable hepatocellular carcinoma patients (u-HCC), who were treated with tyrosine kinase inhibitor (TKI) sequential therapy, including lenvatinib (LEN). <b><i>Materials/Methods:</i></b> We enrolled 84 u-HCC cases treated with TKIs including LEN from March 2018 to January 2019 (median age 71 years, 63 males, Child-Pugh score (CPS) 5/6/7 = 62/21/1, tumor-node-metastasis stage of Liver Cancer Study Group of Japan 6th (TNM-LCSGJ) II/III/IVa/IVb = 12/30/5/37, Barcelona Clinic Liver Cancer stage B/C = 33:51). Clinical findings at introduction of the initial TKI were retrospectively evaluated. <b><i>Results:</i></b> The median albumin-bilirubin (ALBI) score at introduction of the initial TKI (sorafenib [SOR]/LEN = 80/4) was –2.56, and the past number of transarterial catheter chemoembolization was 3 (IQR: 2–5) (second-line: regorafenib [REG]/LEN/SOR = 31/49/4, third-line: LEN/REG = 31:1). The total period of administration with TKIs showed a good relationship with overall survival (OS) (<i>r</i> = 0.946, 95% confidence interval [CI]: 0.918–0.965, <i>p</i> &#x3c; 0.001). The prognosis of the entire cohort was good (estimated median survival time: 46.4 months, 1-/2-/3-year OS rate [OSR] = 87.7/63.0/57.2%). A modified-ALBI grade (mALBI) of 2b (ALBI score &#x3e;–2.27) was the only significant factor at the start of the initial TKI for poor prognosis (hazard ratio 2.319, 95% CI: 1.064–5.052, <i>p</i> = 0.034), while CPS (≥6) was not. Although there was no significant difference in TNM-LCSGJ (<i>p</i> = 0.213), the prognosis of patients with mALBI 1/2a (<i>n</i> = 66) showed better prognosis as compared to those with mALBI 2b (<i>n</i> = 18) (1-year/2-year/3-year OSR = 89.1/69.8/66% vs. 82.4/47.1/23.5%, <i>p</i> = 0.029). <b><i>Conclusion:</i></b> Good hepatic function (mALBI 1/2a) at introduction of the initial TKI is a requirement for improved prognosis of u-HCC undergoing TKI sequential therapy.
Subtype Specificity of Genetic Loci Associated With Stroke in 16 664 Cases and 32 792 Controls
Authors: Traylor Matthew , Anderson Christopher D. , Rutten-Jacobs Loes C.A. , Falcone Guido J. , Comeau Mary E. , Ay Hakan , Sudlow Cathie L.M. , Xu Huichun , Mitchell Braxton D. , Cole John W. , Rexrode Kathryn , Jimenez-Conde Jordi , Schmidt Reinhold , Grewal Raji P. , Sacco Ralph , Ribases Marta , Rundek Tatjana , Rosand Jonathan , Dichgans Martin , Lee Jin-Moo , Langefeld Carl D. , Kittner Steven J. , Markus Hugh S. , Woo Daniel , Malik Rainer ,   on behalf of the NINDS Stroke Genetics Network (SiGN) and International Stroke Genetics Consortium (ISGC)
Published: July 2019

Background:
Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes.

Methods:
We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel.

Results:

Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An
EDNRA
locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes.

Conclusions:
Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.
Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease
Authors: Rodionov Roman N. , Begmatov Hoshimjon , Jarzebska Natalia , Patel Ketul , Mills Matthew T. , Ghani Zulaikha , Khakshour Doreen , Tamboli Pankti , Patel Mitul N. , Abdalla Mirette , Assaf Maryann , Bornstein Stefan R. , Millan Jose Luis , Bode‐Böger Stefanie M. , Martens‐Lobenhoffer Jens , Weiss Norbert , Savinova Olga V. 
Published: July 2019

Background

Homoarginine (
hA
rg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown.
hA
rg can inhibit tissue‐nonspecific alkaline phosphatase (
TNAP
), an enzyme that promotes vascular calcification. We hypothesized that
hA
rg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with
TNAP
overexpression and hypercholesterolemia.

Methods and Results

TNAP
was overexpressed in the endothelium in mice homozygous for a low‐density lipoprotein receptor mutation (wicked high cholesterol [
WHC
] allele).
WHC
and
WHC
–endothelial
TNAP
mice received placebo or
hA
rg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected,
WHC
–endothelial
TNAP
mice on the placebo had increased mortality (median survival 27 days,
P
<0.0001), increased coronary calcium and lipids (
P
<0.01), increased left ventricular end‐diastolic diameter (
P
<0.0001), reduced ejection fraction (
P
<0.05), and increased myocardial fibrosis (
P
<0.0001) compared with
WHC
mice. Contrary to our hypothesis,
hA
rg neither inhibited
TNAP
activity in vivo nor reduced coronary artery calcification and atherosclerosis in
WHC
–endothelial
TNAP
mice; however, compared with the placebo,
hA
rg prevented left ventricular dilatation (
P
<0.01), preserved ejection fraction (
P
<0.05), and reduced myocardial fibrosis (
P
<0.001).

Conclusions

The beneficial effect of
hA
rg supplementation in the setting of calcified coronary artery disease is likely due to its direct protective actions on the myocardial response to the ischemic injury and not to the inhibition of
TNAP
activity and calcification.
Outcome in Direct Versus Transfer Patients in the DAWN Controlled Trial
Authors: Aghaebrahim Amin , Jadhav Ashutosh P. , Hanel Ricardo , Sauvageau Eric , Granja Manuel F. , Zhang Yanchang , Haussen Diogo C. , Budzik Ronald F. , Bonafe Alain , Bhuva Parita , Ribo Marc , Cognard Christophe , Sila Cathy , Yavagal Dileep , Hassan Ameer E. , Smith Wade S. , Saver Jeffrey , Liebeskind David S. , Nogueira Raul G. , Jovin Tudor G. ,   for the DAWN Investigators
Published: July 2019

Background and Purpose—
The impact of transfer status on clinical outcomes in the DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo) population is unknown. We analyzed workflow and clinical outcome differences between direct versus transfer patients in the DAWN population.

Methods—
The following time metrics were analyzed for each group: (1) last known well to hospital arrival, (2) hospital arrival to eligibility imaging, (3) hospital arrival to arterial puncture, (4) qualifying imaging to arterial puncture, (5) last known well to arterial puncture, (6) last known well to reperfusion. The primary end point was the rate of functional independence (90-day modified Rankin Scale [mRS] score, 0–2). Using univariate unconditional logistic regression, we calculated odds ratios and 95% CIs for the association between clinically relevant time metrics, transfer status, and functional independence (mRS 0–2).

Results—

A total of 206 patients were enrolled. Among these, 121 (59%) patients were transferred, and 85 (41%) patients presented directly to a thrombectomy capable center. Median time last seen well to hospital arrival time was similar between the 2 groups (678 versus 696 minutes). The time from hospital arrival to groin puncture was significantly longer in direct patients compared with transferred patients 140 minutes (interquartile range, 105.5–177.5 minutes) and 88 minutes (interquartile range, 55–125 minutes), respectively (
P
<0.001). Differences in treatment effect or differences in rates of mRS 0–2 in the thrombectomy treated patients were not statistically significant in direct versus transfer patients (odds ratios for mRS 0–2, thrombectomy versus control, were 5.62 in direct and 6.63 in transfer patients, respectively, Breslow-Day
P
=0.817).

Conclusions—
Although transfer patients had a faster door to puncture time, benefits of thrombectomy, and rates of mRS 0 to 2 in the treatment group were similar between direct and transferred patients in the DAWN population. These results may inform prehospital and primary stroke centers triage protocols in patients presenting in the late time window.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02142283.
Prevention of Stroke in Atrial Fibrillation After Coronary Stenting
Authors: Knijnik Leonardo , Rivera Manuel , Blumer Vanessa , Cardoso Rhanderson , Fernandes Amanda , Fernandes Gilson , Ferreira Tanira , Romano Jose G. , Lambrakos Litsa K. , Cohen Mauricio G. 
Published: July 2019

Background and Purpose—
The optimal antithrombotic strategy to balance thromboembolic and bleeding events, especially acute stroke, for patients with atrial fibrillation following coronary stenting remains a matter of debate. We conducted a network meta-analysis to identify the antithrombotic regimen associated with the lowest rate of bleeding and thromboembolic events in atrial fibrillation after coronary stenting.

Methods—
PubMed, Scopus, and Cochrane Central were searched for randomized controlled trials and observational studies of patients with atrial fibrillation after coronary stenting. The outcomes of interest were stroke, myocardial infarction, major adverse cardiac events, mortality, and major bleeding. A network meta-analysis was performed comparing the available antithrombotic regimens in the literature.

Results—
Three randomized and 15 observational studies were included, with a total of 23 478 participants. Median follow-up was 2 years. Network meta-analysis demonstrated that vitamin K antagonist plus single antiplatelet therapy or direct-acting oral anticoagulant plus single antiplatelet therapy were the most effective regimens in preventing stroke. Direct-acting oral anticoagulant regimens were associated with lower major bleeding rates than vitamin K antagonist regimens. Regimens with dual antiplatelet therapy were associated with lower rates of myocardial infarction. Vitamin K antagonist plus dual antiplatelet therapy was associated with a lower mortality and low-dose direct-acting oral anticoagulants with decreased major cardiovascular adverse events.

Conclusions—
Direct-acting oral anticoagulant regimens were associated with less major bleeding and major cardiovascular adverse events, but vitamin K antagonists were associated with decreased mortality and stroke. These results suggest that the decision of antithrombotic therapy in patients with atrial fibrillation after percutaneous coronary intervention needs to be individualized.
<strong>Species occurrence and distribution of Trichoptera (caddisflies) in California</strong>
Authors: MENDEZ PATINA K. , MYERS MARILYN J. , DAMEROW JOAN E. , LEW CHRISTINA , RESH VINCENT H. 
Published: July 2019

A formal list of the caddisflies of California has not been published since 1956, at which time just over 170 species were included. Since then, the estimate of Trichoptera richness in the state has doubled. We used just under 7,000 digital records from online repositories and museum databases to compile a preliminary faunal list. To gain a broader view of the distribution of caddisflies in California, we augmented this dataset with almost 46,000 larval biomonitoring records for Trichoptera from the California Digital Exchange Network. We compared this digital species list derived from collection records to three existing literature resources: Donald Denning’s original species list from 1956, a list by Donald Burdick in 2010, and the published records documented in the Distributional Checklist of Nearctic Trichoptera by Rasmussen & Morse in 2018. The California species richness for Trichoptera based on these resources is 333 species, with another 69 taxa occurring in collections that require expert review of the material before adding to these totals. Monitoring data, although extensive, did not contribute to the species list, but highlighted differences in collection location emphasis. Digital records can be powerful tools for compiling preliminary taxa and distribution lists, but oftentimes only partial verbatim label information (i.e. not containing full localities) limits further spatial analysis.
Description of the tadpoles of Phyllodytes brevirostris (Anura: Hylidae)
Authors: VIEIRA WASHINGTON L. S. , SANTANA GINDOMAR G. , DA NÓBREGA CARNEIRO DOS SANTOS SÔNIA CRISTINA , ALVES RÔMULO R. N. , PEREIRA-FILHO GENTIL A. 
Published: July 2019

The genus Phyllodytes, comprises twelve species (Frost 2008), and only the tadpoles of Phyllodytes auratus, P. melanomystax, P. gyrinaethes e P. edelmoi were described until now. The present work describes the tadpoles of P. brevirostris, using external morphological features and internal oral characteristics, and compares them to other tadpoles of species belonging to the genus.
Characteristics of Recent Vehicle-Related Fatalities during Active Precipitation in the United States
Authors: Tobin Dana M. , Kumjian Matthew R. , Black Alan W. 
Published: July 2019

Abstract
Data from the National Highway Traffic Safety Administration’s (NHTSA) Fatality Analysis Reporting System (FARS) database were used to identify vehicle-related fatalities that occurred during active precipitation from 2013 to 2017. Changes to FARS for 2013–present allow the identification of freezing rain, in addition to rain, snow, sleet, and precipitation mixtures as prevailing precrash atmospheric conditions. The characteristics of vehicle-related fatalities for each precipitation type identified in FARS were assessed in terms of total numbers, roadway surface conditions, location, and annual and diurnal variability. Vehicle-related fatalities were also matched to nearby Automated Surface Observing System (ASOS) and Automated Weather Observing System (AWOS) precipitation-type reports to determine their agreement with precipitation types documented in FARS. Of the vehicle-related fatalities examined, 8.6% occurred during precipitation, with these fatalities further divided by precipitation type of approximately 81% rain, 14% snow, and 5% sleet, freezing rain, and mixtures of precipitation. Unexpected discrepancies between the numbers of sleet- versus freezing-rain-related fatalities reveal that caution should be taken when using FARS to identify these precipitation types. ASOS/AWOS precipitation-type reports have moderate agreement with FARS at 20 mi (32.2 km), and are capable of distinguishing precipitation and nonprecipitation indicated in FARS. Rain and snow have good agreement between the databases, whereas sleet, freezing rain, and precipitation mixtures have significantly reduced agreement due to a combination of ASOS/AWOS limitations and suspected FARS limitations. To provide a more accurate account of precipitation types for fatal crashes, the use of crashes where FARS-identified precipitation types are confirmed by nearby ASOS/AWOS reports is suggested.