bluuebunny/crossref_metadata_2025_split huggingface dataset:
AMPK Alpha-1 Intrinsically Regulates the Function and Differentiation of Tumor Myeloid-Derived Suppressor Cells
Authors: Trillo-Tinoco Jimena , Sierra Rosa A. , Mohamed Eslam , Cao Yu , de Mingo-Pulido Álvaro , Gilvary Danielle L. , Anadon Carmen M. , Costich Tara Lee , Wei Sheng , Flores Elsa R. , Ruffell Brian , Conejo-Garcia José R. , Rodriguez Paulo C. 
Published: August 2019

AbstractMyeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC is tightly regulated by the tumor microenvironment and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPKα) and the immunoregulatory activity of MDSC in tumors. AMPKα signaling was increased in tumor-MDSC from tumor-bearing mice and patients with ovarian cancer. Transcription of the Ampkα1-coding gene, Prkaa1, in tumor-MDSC was induced by cancer cell–derived granulocyte–monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat5–dependent manner. Conditional deletion of Prkaa1 in myeloid cells, or therapeutic inhibition of Ampkα in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered antitumor CD8+ T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPKα signaling intrinsically promoted MDSC immunoregulatory activity. In addition, Prkaa1 deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages and re-routed M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct antitumor cytotoxic effects through nitric oxide synthase 2-mediated actions. Thus, our results demonstrate the primary role of AMPKα1 in the immunosuppressive effects induced by tumor-MDSC and support the therapeutic use of AMPK inhibitors to overcome MDSC-induced T-cell dysfunction in cancer.Significance:AMPKα1 regulates the immunosuppressive activity and differentiation of tumor-MDSC, suggesting AMPK inhibition as a potential therapeutic strategy to restore protective myelopoiesis in cancer.
Herbal Medicine Containing Aristolochic Acid and the Risk of Primary Liver Cancer in Patients with Hepatitis C Virus Infection
Authors: Chen Chi-Jen , Yang Yao-Hsu , Lin Meng-Hung , Lee Chuan-Pin , Tsan Yu-Tse , Lai Ming-Nan , Yang Hsiao-Yu , Doyle Pat , Ho Wen-Chao , Chen Pau-Chung 
Published: August 2019

Abstract

Background:
We investigated the association between taking herbal medicine (HM) containing aristolochic acid (AA) and the risk of primary liver cancer (PLC) among patients with hepatitis C virus (HCV) infection.

Methods:
This is a prospective study for the long-term follow-up of a nationwide population-based cohort of patients ages 18 years or older diagnosed with HCV infection during 1997 to 2010. A total of 223,467 HCV-infected patients were identified using the National Health Insurance Research Database in Taiwan. The use of HM containing AA was evaluated among patients who had visited traditional Chinese medicine clinics beginning from 1997 to 1 year prior to the diagnosis of PLC or dates censored (2003). We tracked each individual patient from 1997 to 2013 to identify incident cases of PLC since 1999.

Results:
During the follow-up period of 3,052,132 person-years, we identified 25,502 PLC cases; this corresponded to an overall incidence rate of 835.5 PLCs per 100,000 person-years. The adjusted HRs were 1.21 [95% confidence interval (CI), 1.18–1.24], 1.48 (95% CI, 1.37–1.59), 1.50 (95% CI, 1.34–1.68), and 1.88 (95% CI, 1.61–2.19) for estimated AA usage groups: 1 to 250, 251 to 500, 501 to 1,000, and more than 1,000 mg, respectively, relative to no AA exposure (reference group).

Conclusions:
The current findings suggest that among HCV-positive patients, increasing exposure to AA poses an increased risk of acquiring PLC.

Impact:
AA may increase the risk of PLC in HCV-positive populations.
The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition
Authors: Parmar Kalindi , Kochupurakkal Bose S. , Lazaro Jean-Bernard , Wang Zhigang C. , Palakurthi Sangeetha , Kirschmeier Paul T. , Yang Chunyu , Sambel Larissa A. , Färkkilä Anniina , Reznichenko Elizaveta , Reavis Hunter D. , Dunn Connor E. , Zou Lee , Do Khanh T. , Konstantinopoulos Panagiotis A. , Matulonis Ursula A. , Liu Joyce F. , D'Andrea Alan D. , Shapiro Geoffrey I. 
Published: August 2019

AbstractPurpose:PARP inhibitors are approved for the treatment of high-grade serous ovarian cancers (HGSOC). Therapeutic resistance, resulting from restoration of homologous recombination (HR) repair or replication fork stabilization, is a pressing clinical problem. We assessed the activity of prexasertib, a checkpoint kinase 1 (CHK1) inhibitor known to cause replication catastrophe, as monotherapy and in combination with the PARP inhibitor olaparib in preclinical models of HGSOC, including those with acquired PARP inhibitor resistance.Experimental Design:Prexasertib was tested as a single agent or in combination with olaparib in 14 clinically annotated and molecularly characterized luciferized HGSOC patient-derived xenograft (PDX) models and in a panel of ovarian cancer cell lines. The ability of prexasertib to impair HR repair and replication fork stability was also assessed.Results:Prexasertib monotherapy demonstrated antitumor activity across the 14 PDX models. Thirteen models were resistant to olaparib monotherapy, including 4 carrying BRCA1 mutation. The combination of olaparib with prexasertib was synergistic and produced significant tumor growth inhibition in an olaparib-resistant model and further augmented the degree and durability of response in the olaparib-sensitive model. HGSOC cell lines, including those with acquired PARP inhibitor resistance, were also sensitive to prexasertib, associated with induction of DNA damage and replication stress. Prexasertib also sensitized these cell lines to PARP inhibition and compromised both HR repair and replication fork stability.Conclusions:Prexasertib exhibits monotherapy activity in PARP inhibitor–resistant HGSOC PDX and cell line models, reverses restored HR and replication fork stability, and synergizes with PARP inhibition.
Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non–Small Cell Lung Cancer
Authors: Gray Jhanelle E. , Saltos Andreas , Tanvetyanon Tawee , Haura Eric B. , Creelan Ben , Antonia Scott J. , Shafique Michael , Zheng Hong , Dai Wenjie , Saller James J. , Chen Zhihua , Tchekmedyian Nishan , Goas Kristen , Thapa Ram , Boyle Theresa A. , Chen Dung-Tsa , Beg Amer A. 
Published: August 2019

Abstract

Purpose:
Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non–small cell lung cancer.

Patients and Methods:
Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens.

Results:
Thirty-three patients were treated (13 in phase I, 20 in phase Ib). In phase I, both ICI-naïve and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLT). No DLTs were observed, and the recommended phase I dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of six ICI-naïve and 24 ICI-pretreated patients evaluable for response, four (13%) had partial response [two confirmed, one unconfirmed with subsequent prolonged stable disease (SD), one unconfirmed with subsequent progressive disease (PD)], 16 (53%) had SD, and 10 (33%) had PD for a DCR of 67%. In the ICI-pretreated cohort, three patients (one confirmed, two unconfirmed) had partial response and 10 had SD. Pretreatment CD8+ T-cell presence in tumor stromal regions was associated with treatment benefit.

Conclusions:
Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment.
FGF401, A First-In-Class Highly Selective and Potent FGFR4 Inhibitor for the Treatment of FGF19-Driven Hepatocellular Cancer
Authors: Weiss Andreas , Adler Flavia , Buhles Alexandra , Stamm Christelle , Fairhurst Robin A. , Kiffe Michael , Sterker Dario , Centeleghe Mario , Wartmann Markus , Kinyamu-Akunda Jacqueline , Schadt Heiko S. , Couttet Philippe , Wolf Armin , Wang Youzhen , Barzaghi-Rinaudo Patrizia , Murakami Masato , Kauffmann Audrey , Knoepfel Thomas , Buschmann Nicole , Leblanc Catherine , Mah Robert , Furet Pascal , Blank Jutta , Hofmann Francesco , Sellers William R. , Graus Porta Diana 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC90 value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.
Eccentric Activation Patterns in the Left Ventricular Outflow Tract during Idiopathic Ventricular Arrhythmias Originating From the Left Ventricular Summit
Authors: Yamada Takumi , Kumar Vineet , Yoshida Naoki , Doppalapudi Harish 
Published: August 2019

Background:
Idiopathic ventricular arrhythmias (VAs) originating from the left ventricular summit (LVS) can be ablated from the great cardiac vein and remote endocardial sites. The ablation sites are determined by mapping in the great cardiac vein and left ventricular outflow tract. This study investigated whether that mapping could accurately predict the sites of LVS-VA origins.

Methods:
We studied 26 consecutive patients with idiopathic LVS-VA origins that were identified in the basal and apical LVS in 15 and 11 patients, respectively.

Results:
Radiofrequency catheter ablation of the apical LVS-VAs was successful in the great cardiac vein in 9 patients and in the apical LV outflow tract in 2. That of the basal LVS-VAs was successful in the aortomitral continuity in 9 patients, at the junction of the left and right coronary cusps in 4, and in the left coronary cusp in 2. Three apical LVS-VAs exhibited an eccentric endocardial activation pattern that was from the basal to apical LV outflow tract. In 11 basal LVS-VAs, the activation pattern was eccentric because the ventricular activation within the great cardiac vein in the apical LVS was earlier than that in the basal LV outflow tract. In 2 basal LVS-VAs, the activation pattern was eccentric because a relatively early ventricular activation was recorded at multiple sites away from the successful ablation site.

Conclusions:
Eccentric activation patterns often occurred during idiopathic LVS-VAs, which could mislead the catheter ablation of those VAs. Understanding such eccentric activation patterns was suggested to be able to improve the outcomes of the catheter ablation of those VAs by the anatomic approach.
Impact of Cumulative Smoking Exposure on Subclinical Degenerative Aortic Valve Disease in Apparently Healthy Male Workers
Authors: Yamaura Yasuko , Watanabe Nozomi , Shimaya Maki , Tomita Yasuhiko , Fukaya Takashi , Yoshida Kiyoshi 
Published: August 2019

Background:
Little is known regarding the impact of cumulative smoking exposure and smoking cessation on subclinical degenerative aortic valve (DAV) disease.

Methods:
We examined associations of smoking status, cigarette-years of smoking, and years since quitting smoking with subclinical DAV disease defined by echocardiography.

Results:

Of 756 apparently healthy male workers, 154 had DAV including 63 with DAV with ≥2 leaflets calcification (DAV ≥2 cal). Compared with never smokers, ever smokers had higher risk of DAV and DAV ≥2 cal; odds ratios (95% CI) were 2.883 (1.800–4.618) (
p
<0.001) and 5.281 (2.297–12.138) (
p
<0.001), respectively. Both current and former smokers had dose-dependent relationships of cigarette-years on DAV and DAV ≥2 cal (
P
for trend, <0.001 for both DAV, in both smokers). In current smokers with >400–≤800 and with >800 cigarette-years, odds ratios (95%CIs) were 3.201 (1.690–6.063) (
p
<0.001) and 5.326 (2.800–10.053) (
p
<0.001) for DAV, 7.460 (2.828–19.680) (
p
<0.001) and 8.397 (3.146–22.414) (
p
<0.001) for DAV ≥2 cal, respectively. In former smokers with >800 cigarette-years, odds ratios (95%CI) were 3.780 (1.970–7.254) (
p
<0.001) for DAV, 10.035 (3.801–26.496) (
p
<0.001) for DAV ≥2 cal. Compared with current smokers, former smokers with quitting smoking >10 years had significantly lower risk of DAV and DAV ≥2 cal.

Conclusions:
In apparently healthy male workers, DAV disease was strongly associated with smoking. Cumulative smoking exposure was associated with dose-dependent relationship on subclinical DAV disease both in current smokers and former smokers.
apoB/apoA‐I Ratio and Lp(a) Associations With Aortic Valve Stenosis Incidence: Insights From the EPIC‐Norfolk Prospective Population Study
Authors: Zheng Kang H. , Arsenault Benoit J. , Kaiser Yannick , Khaw Kay‐Tee , Wareham Nicholas J. , Stroes Erik S. G. , Boekholdt S. Matthijs 
Published: August 2019

Background

Apolipoprotein B/apolipoprotein A‐I (apoB/apoA‐I) ratio and lipoprotein(a) (Lp[a]) are associated with aortic valve stenosis (
AVS
) disease progression. Clinical characteristics such as age, sex, and presence of concomitant coronary artery disease may strongly modify these associations; however, these effects have not been well defined in longitudinal studies. We set out to assess these associations between apoB/apoA‐I ratio, Lp(a), and
AVS
incidence in a large population study.

Methods and Results

We analyzed data from 17 745 participants (mean age, 59.2±9.1 years; men, 44.9%) in the
EPIC
‐Norfolk (European Prospective Investigation Into Cancer in Norfolk Prospective Population Study) population study in whom apoB/apoA‐I and Lp(a) levels were measured. Participants were identified as having incident
AVS
if they were hospitalized or died with
AVS
as an underlying cause. After a median follow‐up of 19.8 years (17.9–21.0 years) there were 403 (2.2%) incident cases of
AVS
. The hazard ratio for
AVS
risk was 1.30 (95%
CI
, 1.19–1.41;
P
<0.001) per SD increase in apoB/apoA‐I. Adjusting for age, sex, and coronary artery disease, there was no significant association between apoB/apoA‐I and
AVS
incidence (hazard ratio, 1.06; 95%
CI
, 0.97–1.17 [
P
=0.215]). Elevated Lp(a) (>50 mg/
dL
) remained an independent risk factor for
AVS
after adjustment for age, sex, low‐density lipoprotein cholesterol, and concomitant coronary artery disease (hazard ratio, 1.70; 95%
CI
, 1.33–2.19 [
P
<0.001]).

Conclusions

In this population study, apoB/apoA‐I ratio was associated with risk of
AVS
incidence, especially in younger and female participants and those without concomitant coronary artery disease. Lp(a) was an independent risk factor for
AVS
incidence. Interventional trials are needed to investigate whether modulating apoB/apoA‐I or lowering Lp(a) can prevent or slow down
AVS
.
Prognostication Accuracy, Confidence, and Decisional Conflict Across Training Levels of Internal Medicine Providers
Authors: Namavar Aram A. , Vangala Sitaram , Pietras Christopher , Dowling Erin P. 
Published: August 2019

Context: Providing patient care at the end of a patient’s life is a humbling and sacred experience for both patient and provider. Without a truthful and meaningful conversation about end-of-life care preferences, the care that is delivered may not be the care that the patient prefers. Objectives: Determine if there is a relationship between level of training, confidence, and presence of decisional conflict in making an accurate prognosis for 2 standardized cases. Additionally, we evaluated the correctness of the prognosis as measured against survival outcomes for patients with similar diagnoses. Methods: Decisional conflict was measured with the SURE tool, a validated 4-item tool that has been used in assessing for the presence of decisional conflict. Results: Following analysis of data, it was found that providers with no decisional conflict were much more likely to be attendings with more than 5 years’ experience. Providers were more conflicted overall when confronted with a case with a more grave prognosis. It was determined that providers with a lower level of training were more likely to have decisional conflict. Conclusions: Provider confidence increases and decisional conflict decreases as one increases their level of training. However, the degree in which the provider is correct in their prognosis does not change as one increases their level of training. These findings have broad implications on patients, providers, and the health-care system.
Two interpretations of the rational choice theory and the relevance of behavioral critique
Authors: Hudik Marek 
Published: August 2019

I compare two interpretations of the rational choice theory: decision-theoretic and price-theoretic. The former takes the assumption of utility maximization as a literal description of a decision procedure. The latter considers it as a modeling device used to explain changes/variability of behavior on an aggregate level. According to the price-theoretic interpretation, these changes/variability are explained by constraints (“prices”) rather than differences in intrinsic characteristics between human populations (“tastes”). While the decision-theoretic interpretation of rationality represents a possible foundation of the price-theoretic interpretation of rationality, I argue that it is not its only possible foundation. I then show that critiques raised by behavioral economics apply to the decision-theoretic interpretation and much less so to the price-theoretic one. From the perspective of the price theory, behavioral and rational choice models are predominantly complementary. Price-theoretic interpretation helps to explain why the rational choice theory continues to play an important role in economics, even after the behavioral revolution. JEL codes: D01, D03, B41, A10
Improving quality and performance in substance use treatment programs: What is being done and why is it so hard?
Authors: Davis Margot T , Torres Maria , Nguyen AnMarie , Stewart Maureen , Reif Sharon 
Published: August 2019

Summary As states plan to implement system-wide change of any kind, it is important to understand program directors’ perspectives on challenges they face. This is especially true with quality improvement reforms. Much research has focused on quality improvement in medicine, but there is a gap in our knowledge about programs that treat individuals with drug or alcohol use. From 2007 to 2016, Maine contracted with selected substance use treatment programs using financial incentives to improve quality, with focus on treatment access, engagement, retention, and completion as measures of quality. Using surveys and in-depth interviews, this research documents strategies that programs used to improve performance and challenges faced in implementing reforms. Only programs that received federal block grant funding through the state to provide substance use treatment were eligible for an incentive contract, creating a natural experiment with non-block grant programs (non-incentive). Directors were interviewed in incentive ( n = 13) and non-incentive programs ( n = 12). Findings Thematic analysis revealed that: (1) programs focused on quality improvement, incentive and non-incentive programs focused on different quality measures, (2) most of the reforms in both groups targeted improving treatment access and retention, and (3) programs faced substantial challenges in undertaking reforms. Despite efforts, many programs could not meet quality measures consistently over time and faced environmental and system barriers. Applications Policy makers and program administrators will benefit from knowing the challenges of undertaking quality improvement initiatives and provide support for the programs.
Targeting of the dentato-rubro-thalamic tract for MR-guided focused ultrasound treatment of essential tremor
Authors: Miller Timothy R , Zhuo Jiachen , Eisenberg Howard M , Fishman Paul S , Melhem Elias R , Gullapalli Rao , Gandhi Dheeraj 
Published: August 2019

Background Magnetic resonance-guided focused ultrasound ablation of the thalamic ventral intermediate nucleus is a safe and effective treatment for medically refractory essential tremor. However, indirect targeting of the ventral intermediate nucleus using stereotactic coordinates from normal neuroanatomy can be inefficient. We therefore evaluated the feasibility of supplementing this method with direct targeting of the dentato-rubro-thalamic tract. Methods We retrospectively identified four patients undergoing magnetic resonance-guided focused ultrasound ablation for essential tremor in which preoperative diffusion tractography imaging of the dentato-rubro-thalamic tract was fused with T2 weighted-imaging and utilized for intra-procedural targeting. The size and location of the dentato-rubro-thalamic tract and 24-hour lesion, as well as the center of the stereotactic coordinates, was evaluated. Finally, the amount of overlap between the dentato-rubro-thalamic tract and the lesion was calculated. Results The 24-hour lesion size was homogeneous in the cohort (mean 31.3 mm2, range 30–32 mm2), while there was substantial variation in the dentato-rubro-thalamic tract area (mean 14.3 mm2, range 3–24 mm2). The center of the stereotactic coordinates and dentato-rubro-thalamic tract diverged by more than 1 mm in mediolateral and anterposterior directions in all patients, while the dentato-rubro-thalamic tract and lesion centers were in close proximity (mean mediolateral separation 1 mm, range 0.1–2.2 mm; mean anteroposterior separation 0.75 mm, range 0.4–1.2 mm). There was greater than 50% coverage of the dentato-rubro-thalamic tract by the lesion in all patients (mean 82.9%, range 66.7–100%). All patients experienced durable tremor relief. Conclusion Direct targeting of the dentato-rubro-thalamic tract using diffusion tractography imaging fused to T2 weighted-imaging may be a useful strategy for focused ultrasound treatment of essential tremor. Further investigation of the technique is warranted.