bluuebunny/crossref_metadata_2025_split huggingface dataset:
MemSZ
Authors: Eldstål-Ahrens Albin , Sourdis Ioannis 
Published: November 2020

This article describes Memory Squeeze (MemSZ), a new approach for lossy general-purpose memory compression. MemSZ introduces a low latency, parallel design of the Squeeze (SZ) algorithm offering aggressive compression ratios, up to 16:1 in our implementation. Our compressor is placed between the memory controller and the cache hierarchy of a processor to reduce the memory traffic of applications that tolerate approximations in parts of their data. Thereby, the available off-chip bandwidth is utilized more efficiently improving system performance and energy efficiency. Two alternative multi-core variants of the MemSZ system are described. The first variant has a shared last-level cache (LLC) on the processor-die, which is modified to store both compressed and uncompressed data. The second has a 3D-stacked DRAM cache with larger cache lines that match the granularity of the compressed memory blocks and stores only uncompressed data. For applications that tolerate aggressive approximation in large fractions of their data, MemSZ reduces baseline memory traffic by up to 81%, execution time by up to 62%, and energy costs by up to 25% introducing up to 1.8% error to the application output. Compared to the current state-of-the-art lossy memory compression design, MemSZ improves the execution time, energy, and memory traffic by up to 15%, 9%, and 64%, respectively.
Turnover Modulates the Need for a Cost of Resistance in Adaptive Therapy
Authors: Strobl Maximilian A.R. , West Jeffrey , Viossat Yannick , Damaghi Mehdi , Robertson-Tessi Mark , Brown Joel S. , Gatenby Robert A. , Maini Philip K. , Anderson Alexander R.A. 
Published: November 2020

Abstract

Adaptive therapy seeks to exploit intratumoral competition to avoid, or at least delay, the emergence of therapy resistance in cancer. Motivated by promising results in prostate cancer, there is growing interest in extending this approach to other neoplasms. As such, it is urgent to understand the characteristics of a cancer that determine whether or not it will respond well to adaptive therapy. A plausible candidate for such a selection criterion is the fitness cost of resistance. In this article, we study a general, but simple, mathematical model to investigate whether the presence of a cost is necessary for adaptive therapy to extend the time to progression beyond that of a standard-of-care continuous therapy. Tumor cells were divided into sensitive and resistant populations and we model their competition using a system of two ordinary differential equations based on the Lotka–Volterra model. For tumors close to their environmental carrying capacity, a cost was not required. However, for tumors growing far from carrying capacity, a cost may be required to see meaningful gains. Notably, it is important to consider cell turnover in the tumor, and we discuss its role in modulating the impact of a resistance cost. To conclude, we present evidence for the predicted cost–turnover interplay in data from 67 patients with prostate cancer undergoing intermittent androgen deprivation therapy. Our work helps to clarify under which circumstances adaptive therapy may be beneficial and suggests that turnover may play an unexpectedly important role in the decision-making process.

Significance:
Tumor cell turnover modulates the speed of selection against drug resistance by amplifying the effects of competition and resistance costs; as such, turnover is an important factor in resistance management via adaptive therapy.
See related commentary by Strobl et al., p. 811
Frizzled-7 Identifies Platinum-Tolerant Ovarian Cancer Cells Susceptible to Ferroptosis
Authors: Wang Yinu , Zhao Guangyuan , Condello Salvatore , Huang Hao , Cardenas Horacio , Tanner Edward J. , Wei JianJun , Ji Yanrong , Li Junjie , Tan Yuying , Davuluri Ramana V. , Peter Marcus E. , Cheng Ji-Xin , Matei Daniela 
Published: November 2020

AbstractDefining traits of platinum-tolerant cancer cells could expose new treatment vulnerabilities. Here, new markers associated with platinum-tolerant cells and tumors were identified using in vitro and in vivo ovarian cancer models treated repetitively with carboplatin and validated in human specimens. Platinum-tolerant cells and tumors were enriched in ALDH+ cells, formed more spheroids, and expressed increased levels of stemness-related transcription factors compared with parental cells. Additionally, platinum-tolerant cells and tumors exhibited expression of the Wnt receptor Frizzled-7 (FZD7). Knockdown of FZD7 improved sensitivity to platinum, decreased spheroid formation, and delayed tumor initiation. The molecular signature distinguishing FZD7+ from FZD7− cells included epithelial-to-mesenchymal (EMT), stemness, and oxidative phosphorylation-enriched gene sets. Overexpression of FZD7 activated the oncogenic factor Tp63, driving upregulation of glutathione metabolism pathways, including glutathione peroxidase 4 (GPX4), which protected cells from chemotherapy-induced oxidative stress. FZD7+ platinum-tolerant ovarian cancer cells were more sensitive and underwent ferroptosis after treatment with GPX4 inhibitors. FZD7, Tp63, and glutathione metabolism gene sets were strongly correlated in the ovarian cancer Tumor Cancer Genome Atlas (TCGA) database and in residual human ovarian cancer specimens after chemotherapy. These results support the existence of a platinum-tolerant cell population with partial cancer stem cell features, characterized by FZD7 expression and dependent on the FZD7–β-catenin–Tp63–GPX4 pathway for survival. The findings reveal a novel therapeutic vulnerability of platinum-tolerant cancer cells and provide new insight into a potential “persister cancer cell” phenotype.Significance:Frizzled-7 marks platinum-tolerant cancer cells harboring stemness features and altered glutathione metabolism that depend on GPX4 for survival and are highly susceptible to ferroptosis.
AXL Inhibition Induces DNA Damage and Replication Stress in Non–Small Cell Lung Cancer Cells and Promotes Sensitivity to ATR Inhibitors
Authors: Ramkumar Kavya , Stewart C. Allison , Cargill Kasey R. , Della Corte Carminia M. , Wang Qi , Shen Li , Diao Lixia , Cardnell Robert J. , Peng David H. , Rodriguez B. Leticia , Fan You-Hong , Heymach John V. , Wang Jing , Gay Carl M. , Gibbons Don L. , Byers Lauren A. 
Published: November 2020

AbstractAXL, a TAM (TYRO3, AXL, and MERTK) family receptor tyrosine kinase, is increasingly being recognized as a key determinant of resistance to targeted therapies, as well as chemotherapy and radiation in non–small cell lung cancer (NSCLC) and other cancers. We further show here that high levels of AXL and epithelial-to-mesenchymal transition were frequently expressed in subsets of both treatment-naïve and treatment-relapsed NSCLC. Previously, we and others have demonstrated a role for AXL in mediating DNA damage response (DDR), as well as resistance to inhibition of WEE1, a replication stress response kinase. Here, we show that BGB324 (bemcentinib), a selective small-molecule AXL inhibitor, caused DNA damage and induced replication stress, indicated by ATR/CHK1 phosphorylation, more significantly in TP53-deficient NSCLC cell lines. Similar effects were also observed in large-cell neuroendocrine carcinoma (LCNEC) cell lines. High AXL protein levels were also associated with resistance to ATR inhibition. Combined inhibition of AXL and ATR significantly decreased cell proliferation of NSCLC and LCNEC cell lines. Mechanistically, combined inhibition of AXL and ATR significantly increased RPA32 hyperphosphorylation and DNA double-strand breaks and induced markers of mitotic catastrophe. Notably, NSCLC cell lines with low levels of SLFN11, a known predictive biomarker for platinum and PARP inhibitor sensitivity, were more sensitive to AXL/ATR cotargeting. These findings demonstrate a novel and unexpected role for AXL in replication stress tolerance, with potential therapeutic implications.Implications:These findings demonstrate that the combination of AXL and ATR inhibitors could be a promising therapeutic combination for NSCLC, LCNEC, and other cancers.
5-Azacytidine Transiently Restores Dysregulated Erythroid Differentiation Gene Expression in TET2-Deficient Erythroleukemia Cells
Authors: Reilly Brian M. , Luger Timothy , Park Soo , Lio Chan-Wang Jerry , González-Avalos Edahí , Wheeler Emily C. , Lee Minjung , Williamson Laura , Tanaka Tiffany , Diep Dinh , Zhang Kun , Huang Yun , Rao Anjana , Bejar Rafael 
Published: November 2020

Abstract

DNA methyltransferase inhibitors (DNMTI) like 5-Azacytidine (5-Aza) are the only disease-modifying drugs approved for the treatment of higher-risk myelodysplastic syndromes (MDS), however less than 50% of patients respond, and there are no predictors of response with clinical utility. Somatic mutations in the DNA methylation regulating gene tet-methylcytosine dioxygenase 2 (TET2) are associated with response to DNMTIs, however the mechanisms responsible for this association remain unknown. Using bisulfite padlock probes, mRNA sequencing, and hydroxymethylcytosine pull-down sequencing at several time points throughout 5-Aza treatment, we show that TET2 loss particularly influences DNA methylation (5mC) and hydroxymethylation (5hmC) patterns at erythroid gene enhancers and is associated with downregulation of erythroid gene expression in the human erythroleukemia cell line TF-1. 5-Aza disproportionately induces expression of these down-regulated genes in TET2KO cells and this effect is related to dynamic 5mC changes at erythroid gene enhancers after 5-Aza exposure. We identified differences in remethylation kinetics after 5-Aza exposure for several types of genomic regulatory elements, with distal enhancers exhibiting longer-lasting 5mC changes than other regions. This work highlights the role of 5mC and 5hmC dynamics at distal enhancers in regulating the expression of differentiation-associated gene signatures, and sheds light on how 5-Aza may be more effective in patients harboring TET2 mutations.

Implications:
TET2 loss in erythroleukemia cells induces hypermethylation and impaired expression of erythroid differentiation genes which can be specifically counteracted by 5-Azacytidine, providing a potential mechanism for the increased efficacy of 5-Aza in TET2-mutant patients with MDS.

Visual Overview:
http://mcr.aacrjournals.org/content/molcanres/19/3/451/F1.large.jpg.
Balloon Angioplasty for Native Aortic Coarctation in 3- to 12-Month-Old Infants
Authors: Sandoval Juan Pablo , Kang Sok-Leng , Lee Kyong-Jin , Benson Lee , Asoh Kentaro , Chaturvedi Rajiv R. 
Published: November 2020

Background:
Balloon angioplasty for native coarctation of the aorta (CoA) is successful in children and adults but in neonates results in frequent restenosis. The efficacy of balloon angioplasty for native CoA during infancy beyond the neonatal period was examined in infants aged 3 to 12 months of age.

Methods:
A retrospective review of 68 infants who underwent balloon angioplasty for native CoA. 95% CI are in parentheses.

Results:
Procedural age was (mean±SD) 6±3.4 months and weight was 7±1.8 kg. Balloon angioplasty produced a large decrease in both the noninvasive arm-to-leg blood pressure gradient (41.2±18.7 to 5.6±9.6 mm Hg) and the invasive peak systolic pressure gradient (34±12 to 11±9 mm Hg). Balloon angioplasty increased the CoA diameter from 2.7±1 mm to 4.6±1.2 mm. One patient was lost to follow-up. A catheter reintervention was required in 11.8% and surgery in 10.3%. The hazard of reintervention was highest early. Median freedom from reintervention was 89% (95% CI, 80%–96%) at 1 year, 83% (95% CI, 73%–92%) at 5 years, and 81% (95% CI, 69%–90%) at 10 years. Femoral artery thrombosis was documented in 6 (9%) infants without any long-term consequence. One patient developed a small aortic aneurysm late and has not required treatment. A robust estimate of the frequency of aortic aneurysms remains to be determined as the majority of subjects have not had cross-sectional imaging.

Conclusions:
Balloon angioplasty of native CoA is effective and safe in infants aged 3 to 12 months with outcomes comparable to those in older children and adults. Catheter reinterventions can avoid the need for surgery in most patients.
Circuit Determinants of Ventricular Tachycardia Cycle Length
Authors: Nishimura Takuro , Upadhyay Gaurav A. , Aziz Zaid A. , Beaser Andrew D. , Shatz Dalise Y. , Nayak Hemal M. , Tung Roderick 
Published: November 2020

Background:
Fast ventricular tachycardias (VTs) have historically been attributed to shorter path lengths with smaller reentrant circuit dimensions in animal models. The relationship between the dimensions of the reentrant VT circuit and tachycardia cycle length (TCL) has not been examined in humans. This study aimed to analyze the determinants of the rate of human VT with comparison of circuit dimensions and conduction velocity (CV) across a wide range of both stable and unstable VTs delineated by high-resolution mapping.

Methods:
Fifty-four VTs with complete circuit delineation (>90% TCL) by high-resolution multielectrode mapping were analyzed in 49 patients (men, 88%; age, 65 years [58–71 years]; nonischemic, 47%). Fast VT was defined as TCL <333 milliseconds (rate >180 bpm). Unstable VT was defined by hemodynamic deterioration with an intrinsic mean arterial pressure <60 mm Hg during a sustained episode.

Results:

The median TCL of VT was 365 milliseconds (306–443 milliseconds), and 24 fast VTs were characterized. A wide range of CVs was observed within the entrance (0.03–0.55 m/s), common pathway (0.03–0.77 m/s), exit (0.03–0.53 m/s), and outer loop (0.17–1.13 m/s). There were no significant differences in the median dimensions of the isthmus and path length between fast and slow VTs and between unstable and stable VTs. The outer loop CV was the only circuit component that correlated with TCL in both ischemic cardiomyopathy (
r
=−0.5,
P
=0.006) and nonischemic cardiomyopathy (
r
=−0.45,
P
=0.028). The duration of the longest diastolic electrogram was inversely correlated with the dimensions of common pathway (length:
r
=−0.46,
P
=0.001, width:
r
=−0.3,
P
=0.047) and predictive of rapid VT termination by a single radiofrequency application (
r
=−0.41,
P
=0.023).

Conclusions:
Because of a wide spectrum of CV observed within the reentrant path during human VT, the dimensions of the circuit were not predictive of VT cycle length. For the first time, we demonstrate that the CV of the outer loop, rather than isthmus, is the principal determinant of the rate of VT. The size of the circuit was similar between fast and slow VTs and between unstable and stable VTs. Long, continuous electrograms were indicative of spatially confined isthmus dimensions, confirmed by rapid termination of VT during radiofrequency delivery.
Early Determinants of Childhood Blood Pressure at the Age of 6 Years: The GECKO Drenthe and ABCD Study Birth Cohorts
Authors: Xie Tian , Falahi Fahimeh , Schmidt‐Ott Tabea , Vrijkotte Tanja G. M. , Corpeleijn Eva , Snieder Harold 
Published: November 2020

Background
There is still uncertainty about the nature and relative impact of early determinants on childhood blood pressure. This study explored determinants of blood pressure at the age of 6 years in 2 Dutch birth cohorts.

Methods and Results
Results of hierarchical multiple linear regression analyses in GECKO (Groningen Expert Center for Kids With Obesity) Drenthe study (n=1613) were replicated in ABCD (Amsterdam Born Children and Their Development) study (n=2052). All analyses were adjusted for child's age, sex, height, and body mass index (BMI), and maternal education and subsequently performed in the combined sample. No associations were found between maternal smoking during pregnancy and childhood blood pressure. In the total sample, maternal prepregnancy BMI was positively associated with systolic blood pressure (SBP) (β [95% CI], 0.09 [0.02–0.16] mm Hg) and diastolic blood pressure (β [95% CI], 0.11 [0.04–0.17] mm Hg). Children of women with hypertension had higher SBP (β [95% CI], 0.98 [0.17–1.79] mm Hg). Birth weight standardized for gestational age was inversely associated with SBP (β [95% CI], −6.93 [−9.25 to −4.61] mm Hg) and diastolic blood pressure (β [95% CI], −3.65 [−5.70 to −1.61] mm Hg). Longer gestational age was associated with lower SBP (β [95% CI] per week, −0.25 [−0.42 to −0.08] mm Hg). Breastfeeding for 1 to 3 months was associated with lower SBP (β [95% CI], −0.96 [−1.82 to −0.09] mm Hg) compared with no or <1 month of breastfeeding. Early BMI gain from the age of 2 to 6 years was positively associated with SBP (β [95% CI], 0.41 [0.08–0.74] mm Hg) and diastolic blood pressure (β [95% CI], 0.37 [0.07–0.66] mm Hg), but no effect modification by birth weight was found.

Conclusions
Higher maternal prepregnancy BMI, maternal hypertension, a relatively lower birth weight for gestational age, shorter gestational age, limited duration of breastfeeding, and more rapid early BMI gain contribute to higher childhood blood pressure at the age of 6 years.
Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension
Authors: Brittain Evan L. , Niswender Kevin , Agrawal Vineet , Chen Xinping , Fan Run , Pugh Meredith E. , Rice Todd W. , Robbins Ivan M. , Song Haocan , Thompson Christopher , Ye Fei , Yu Chang , Zhu He , West James , Newman John H. , Hemnes Anna R. 
Published: November 2020

Background
Metabolic dysfunction is highly prevalent in pulmonary arterial hypertension (PAH) and likely contributes to both pulmonary vascular disease and right ventricular (RV) failure in part because of increased oxidant stress. Currently, there is no cure for PAH and human studies of metabolic interventions, generally well tolerated in other diseases, are limited in PAH. Metformin is a commonly used oral antidiabetic that decreases gluconeogenesis, increases fatty acid oxidation, and reduces oxidant stress and thus may be relevant to PAH.

Methods and Results

We performed a single‐center, open‐label 8‐week phase II trial of up to 2 g/day of metformin in patients with idiopathic or heritable PAH with the co‐primary end points of safety, including development of lactic acidosis and study withdrawal, and plasma oxidant stress markers. Exploratory end points included RV function via echocardiography, plasma metabolomic analysis performed before and after metformin therapy, and RV triglyceride content by magnetic resonance spectroscopy in a subset of 9 patients. We enrolled 20 patients; 19/20 reached the target dose and all completed the study protocol. There was no clinically significant lactic acidosis or change in oxidant stress markers. Metformin did not change 6‐minute walk distance but did significantly improve RV fractional area change (23±8% to 26±6%,
P
=0.02), though other echocardiographic parameters were unchanged. RV triglyceride content decreased in 8/9 patients (3.2±1.8% to 1.6±1.4%,
P
=0.015). In an exploratory metabolomic analysis, plasma metabolomic correlates of ≥50% reduction in RV lipid included dihydroxybutyrate, acetylputrescine, hydroxystearate, and glucuronate (
P
<0.05 for all). In the entire cohort, lipid metabolites were among the most changed by metformin.

Conclusions
Metformin therapy was safe and well tolerated in patients with PAH in this single‐arm, open‐label phase II study. Exploratory analyses suggest that metformin may be associated with improved RV fractional area change and, in a subset of patients, reduced RV triglyceride content that correlated with altered lipid and glucose metabolism markers.

Registration

URL:
http://www.clinicaltrials.gov
; Unique identifier: NCT01884051.
Recognizing Cardiovascular Risk After Preeclampsia: The P4 Study
Authors: Brown Mark A. , Roberts Lynne , Hoffman Anna , Henry Amanda , Mangos George , O’Sullivan Anthony , Pettit Franziska , Youssef George , Xu Lily , Davis Gregory K. 
Published: November 2020

Background
There is increased risk of hypertension, early cardiovascular disease, and premature mortality in women who have had preeclampsia. This study was undertaken to determine the upper limit of normal blood pressure (BP) 6 months postpartum and the frequency of women with prior preeclampsia who had BP above these limits, as part of the P4 (Post‐Partum Physiology, Psychology and Pediatric) follow‐up study.

Methods and Results

BP was measured by sphygmomanometer, 24‐hour ambulatory BP monitoring, and non‐invasive central BP at 6 months postpartum in 302 women who had normotensive pregnancy and 90 who had preeclampsia. The upper limit of normal BP (mean+2 SD) for women with normotensive pregnancy was 122/79 mm Hg for routine BP, 115/81 mm Hg for central BP, and 121/78 mm Hg for 24‐hour ambulatory BP monitoring. Traditional normal values detected only 3% of women who had preeclampsia as having high BP 6 months postpartum whereas these new values detected between 13% and 19%. Women with preeclampsia had greater body mass index (27.8 versus 25.0,
P
<0.001) and left ventricular wall thickness but similar augmentation index. They also had lower high‐density lipoprotein (59±15 versus 65±16 mg/dL,
P
=0.002), higher triglycerides (77±51 versus 61±35 mg/dL,
P
=0.005), and higher homeostatic model assessment score (2.1±1.8 versus 1.3±1.9,
P
<0.001).

Conclusions
Clinicians wishing to detect high BP in these women should be aware of the lower than usual upper limit of normal for this young cohort and where possible should use 24‐hour ambulatory BP monitoring to detect these changes. This may define a subgroup of women who had preeclampsia for whom targeted BP lowering therapy would be successful.

Registration

URL:
https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365295&isReview=true
; Unique identifier: ACTRN12613001260718.
Why Socrates’ Legs Didn’t Run Off to Megara
Authors: Wasmuth Ellisif 
Published: November 2020

Abstract
I argue that the arguments presented in Socrates’ dialogue with the personified Laws of the Crito are arguments Socrates endorses and relies upon when deciding to remain in prison. They do not, however, entail blind obedience to every court verdict, nor do they provide necessary and sufficient conditions for resolving every dilemma of civil disobedience. Indeed, lacking definitional knowledge of justice, we should not expect Socrates to be able to offer such conditions. Instead, the Laws present an argument that is sufficient for resolving Socrates’ specific dilemma, showing us how Socrates can deliberate and act despite his lack of knowledge.
Duces caecorum: On Two Recent Translations of Wyclif
Authors: Thakkar Mark 
Published: November 2020

Abstract
Two recent publications have greatly increased the amount of Wyclif available in translation: the Trialogus, translated by Stephen Lahey, and a thematic anthology translated by Stephen Penn. This review article documents the failings that make these translations worse than useless. A post mortem leads the author to claim that the publication of these volumes, the first of which has already been warmly received, is a sign of a gathering crisis in medieval studies, and one that we should take steps to avert.