bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Apc Rapidly Impairs DNA Methylation Programs and Cell Fate Decisions in Lgr5+ Intestinal Stem Cells
Authors: Bruschi Marco , Garnier Laure , Cleroux Elouan , Giordano Alicia , Dumas Michael , Bardet Anaïs F. , Kergrohen Thomas , Quesada Stanislas , Cesses Pierre , Weber Michael , Gerbe François , Jay Philippe 
Published: March 2020

Abstract

Colorectal cancer initiation and progression result from the accumulation of genetic and epigenetic alterations. Although aberrant gene expression and DNA methylation profiles are considered hallmarks of colorectal cancer development, the precise timing at which these are produced during tumor establishment remains elusive. Here we investigated the early transcriptional and epigenetic changes induced by adenomatous polyposis coli (Apc) inactivation in intestinal crypts. Hyperactivation of the Wnt pathway via Apc inactivation in crypt base columnar intestinal stem cells (ISC) led to their rapid accumulation driven by an impaired molecular commitment to differentiation, which was associated with discrete alterations in DNA methylation. Importantly, inhibiting the enzymes responsible for de novo DNA methylation restored the responsiveness of Apc-deficient intestinal organoids to stimuli regulating the proliferation-to-differentiation transition in ISC. This work reveals that early DNA methylation changes play critical roles in the establishment of the impaired fate decision program consecutive to Apc loss of function.

Significance:
This study demonstrates the functional impact of changes in DNA methylation to determine the colorectal cancer cell phenotype following loss of Apc function.
PSF Promotes ER-Positive Breast Cancer Progression via Posttranscriptional Regulation of ESR1 and SCFD2
Authors: Mitobe Yuichi , Iino Kaori , Takayama Ken-ichi , Ikeda Kazuhiro , Suzuki Takashi , Aogi Kenjiro , Kawabata Hidetaka , Suzuki Yutaka , Horie-Inoue Kuniko , Inoue Satoshi 
Published: March 2020

Abstract

Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here, we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of patients with ER-positive breast cancer by posttranscriptionally regulating ERα (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in patients with ER-positive breast cancer. PSF was predominantly expressed in a model of tamoxifen-resistant breast cancer cells, and depletion of PSF attenuated proliferation of cultured cells and xenografted tumors. PSF expression was significantly associated with estrogen signaling. PSF siRNA downregulated ESR1 mRNA by inhibiting nuclear export of the RNA. Integrative analyses of microarray and RNA immunoprecipitation sequencing also identified SCFD2, TRA2B, and ASPM as targets of PSF. Among the PSF targets, SCFD2 was a poor prognostic indicator of breast cancer and SCFD2 knockdown significantly suppressed breast cancer cell proliferation. Collectively, this study shows that PSF plays a pathophysiologic role in ER-positive breast cancer by posttranscriptionally regulating expression of its target genes such as ESR1 and SCFD2. Overall, PSF and SCFD2 could be potential diagnostic and therapeutic targets for primary and hormone-refractory breast cancers.

Significance:
This study defines oncogenic roles of RNA-binding protein PSF, which exhibits posttranscriptional regulation in ER-positive breast cancer.
Consumption of the Fish Oil High-Fat Diet Uncouples Obesity and Mammary Tumor Growth through Induction of Reactive Oxygen Species in Protumor Macrophages
Authors: Liu Lianliang , Jin Rong , Hao Jiaqing , Zeng Jun , Yin Di , Yi Yanmei , Zhu Mingming , Mandal Anita , Hua Yuan , Ng Chin K. , Egilmez Nejat K. , Sauter Edward R. , Li Bing 
Published: March 2020

Abstract

Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in protumor macrophages. Compared with fatty acid (FA) components in both HFDs, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the protumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA–mediated ROS production and macrophage death in vitro and in vivo. Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated protumor macrophage death in an A-FABP–dependent manner.

Significance:
This study provides mechanistic insight into dietary supplementation with fish oil for breast cancer prevention and advances a new concept that not all HFDs leading to obesity are tumorigenic.
Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors
Authors: Tsurutani Junji , Iwata Hiroji , Krop Ian , Jänne Pasi A. , Doi Toshihiko , Takahashi Shunji , Park Haeseong , Redfern Charles , Tamura Kenji , Wise-Draper Trisha M. , Saito Kaku , Sugihara Masahiro , Singh Jasmeet , Jikoh Takahiro , Gallant Gilles , Li Bob T. 
Published: March 2020

Abstract

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (&gt;50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8–11.1] months. In HER2-mutant non–small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1–14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors.

Significance:
T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs.
See related commentary by Rolfo and Russo, p. 643.
This article is highlighted in the In This Issue feature, p. 627
Typical and Atypical Symptoms of Acute Coronary Syndrome: Time to Retire the Terms?
Authors: DeVon Holli A. , Mirzaei Sahereh , Zègre‐Hemsey Jessica 
Published: March 2020

Abstract

Studies indicate that symptoms labeled as “atypical” are more common in women evaluated for myocardial infarction (MI) and may contribute to the lower likelihood of a diagnosis and delayed treatment and result in poorer outcomes compared with men with MI. Atypical pain is frequently defined as epigastric or back pain or pain that is described as burning, stabbing, or characteristic of indigestion. Typical symptoms usually include chest, arm, or jaw pain described as dull, heavy, tight, or crushing. In a recent article published in the
Journal of the American Heart Association
(
JAHA
), Ferry and colleagues addressed presenting symptoms in men and women diagnosed with MI and reported that typical symptoms in women were more predictive of a diagnosis of MI than for men. A critical question is, are there really typical or atypical symptoms, and if so, who is the reference group? We propose that researchers and clinicians either discontinue using the terms
typical
and
atypical
or provide the reference group to which the terms apply (eg, men versus women). We believe it is past time to standardize the symptom assessment for MI so that proper and rapid diagnostic testing can be undertaken; however, we cannot standardize the symptom experience. When we do this, we are at risk of having study results, such as those of Ferry and colleagues, that vary from prior evidence and could lead to what the authors hope to avoid: disadvantaging women in receiving expeditious diagnostic testing and treatment for acute coronary syndrome.
Dabigatran Reversal Before Intravenous Tenecteplase in Acute Ischemic Stroke
Authors: Beharry James , Waters Michael J. , Drew Roy , Fink John N. , Wilson Duncan , Campbell Bruce C.V. , Parsons Mark W. , Kleinig Timothy J. , Wu Teddy Y. 
Published: March 2020

Background and Purpose—
Reversal of dabigatran before intravenous thrombolysis in patients with acute ischemic stroke has been well described using alteplase but experience with intravenous tenecteplase is limited. Tenecteplase seems at least noninferior to alteplase in patients with intracranial large vessel occlusion. We report on the experience of dabigatran reversal before tenecteplase thrombolysis for acute ischemic stroke.

Methods—
We included consecutive patients with ischemic stroke receiving dabigatran prestroke treated with intravenous tenecteplase after receiving idarucizumab. Patients were from 2 centers in New Zealand and Australia. We reported the clinical, laboratory, and radiological characteristics and their functional outcome.

Results—
We identified 13 patients receiving intravenous tenecteplase after dabigatran reversal. Nine (69%) were male, median age was 79 (interquartile range, 69–85) and median baseline National Institutes of Health Stroke Scale score was 6 (interquartile range, 4–21). Atrial fibrillation was the indication for dabigatran therapy in all patients. All patients had a prolonged thrombin clotting time (median, 80 seconds [interquartile range, 57–113]). Seven patients with large vessel occlusion were referred for endovascular thrombectomy, 2 of these patients (29%) had early recanalization with tenecteplase abrogating thrombectomy. No patients had parenchymal hemorrhage or symptomatic hemorrhagic transformation. Favorable functional outcome (modified Rankin Scale score, 0–2) occurred in 8 (62%) patients. Two deaths occurred from large territory infarction.

Conclusions—
Our experience suggests intravenous thrombolysis with tenecteplase following dabigatran reversal using idarucizumab may be safe in selected patients with acute ischemic stroke. Further studies are required to more precisely estimate the efficacy and risk of clinically significant hemorrhage.
Impact of Treatment Delay on Outcome in the International Subarachnoid Aneurysm Trial
Authors: van Donkelaar Carlina E. , Bakker Nicolaas A. , Birks Jacqueline , Clarke Alison , Sneade Mary , Kerr Richard S.C. , Veeger Nic J.G.M. , van Dijk J. Marc C. , Molyneux Andrew J. 
Published: March 2020

Background and Purpose—
ISAT (International Subarachnoid Aneurysm Trial) demonstrated that 1 year after aneurysmal subarachnoid hemorrhage, coiling resulted in a significantly better clinical outcome than clipping. After 5 years, this difference did not reach statistical significance, but mortality was still higher in the clipping group. Here, we present additional analyses, reporting outcome after excluding pretreatment deaths.

Methods—
Outcome measures were death with or without dependency at 1 and 5 years after treatment, after exclusion of all pretreatment deaths. Treatment differences were assessed using relative risks (RRs). With sensitivity and exploratory analyses, the relation between treatment delay and outcome was analyzed.

Results—

After exclusion of pretreatment deaths, at 1-year follow-up coiling was favorable over clipping for death or dependency (RR, 0.77 [95% CI, 0.67–0.89]) but not for death alone (RR, 0.88 [95% CI, 0.66–1.19]). After 5 years, no significant differences were observed, neither for death or dependency (RR, 0.88 [95% CI, 0.77–1.02]) nor for death alone (RR, 0.82 [95% CI, 0.64–1.05]). Sensitivity analyses showed a similar picture. In good-grade patients, coiling remained favorable over clipping in the long-term. Time between randomization and treatment was significantly longer in the clipping arm (mean 1.7 versus 1.1 days;
P
<0.0001), during which 17 patients died because of rebleeding versus 6 pretreatment deaths in the endovascular arm (RR, 2.81 [95% CI, 1.11–7.11]).

Conclusions—
These additional analyses support the conclusion of ISAT that at 1-year follow-up after aneurysmal subarachnoid hemorrhage coiling has a better outcome than clipping. After 5 years, with pretreatment mortality excluded, the difference between coiling and clipping is not significant. The high number of pretreatment deaths in the clipping group highlights the importance of urgent aneurysm treatment to prevent early rebleeding.
The Material Conditions of Representation
Authors: Genadry Daniele 
Published: March 2020

Abstract
Seethrough Mountain interrupts this journal through a physical shift in paper, texture and scale, and thereby proposes a pause or possible site of hesitation where the reader can consider the qualitative and material aspect of what they hold in their hands. The two works, a drawing and a constructed photograph, each creating the illusion of transparency, orient the reader’s attention to the material support of the images, and institute a shock, so that the reader might see through the representations to their material conditions. Seethrough Mountain draws attention to the nature of varying forms of information, and proposes that both sensual and intellectual awareness are necessary to perceive the real.
Serto before Serto: Reexamining the Earliest Development of Syriac Script
Authors: Penn Michael , Crouser R. Jordan , Abbott Philip 
Published: March 2020

Abstract
Scholars have traditionally categorised early Syriac manuscripts as either Estrangela or Serto. The same categories dominate the prevailing narrative of how Syriac script is thought to have developed. Most see Estrangela as the earliest strata of Syriac and Serto as a later development. More recent scholarship explores how early manuscripts support neither this stark division between script styles nor a sequential development. Of particular challenge to this paradigm are a series of securely dated colophons and notes which use a script style different than the main part of the text. But previous work has looked at only five examples of this phenomenon. By expanding this investigation to 30 examples and drawing upon a recent compiled digital corpus of over 100,000 early Syriac letter forms, the present article explores how large data sets, digital analysis, and visual analytics can help one better understand the development of Aramaic scripts.
How Far Can a “Radical” Philosopher Go? Thomas Hobbes’s Paradox of Gender Relations, and One Possible Solution
Authors: Paganini Gianni 
Published: March 2020

This article challenges the idea that Hobbes presents a negative anthropology and shows, to the contrary, that there is a thick web of social relations in his state of nature and laws of nature. It considers the contradiction between human natural equality claimed by Hobbes, and female subjection that de facto characterizes most of his passages on gender relations. The key to this puzzle is found in comparison of the notions of conquest and consent, and of acquisition and institution, comparisons that establish a similarity between paternal authority and despotic dominion. A step towards the solution is provided by the hypothesis that the divide between “vainglorious” and “moderate” is gendered, with women more disposed to moderation than men. This can be explained by the idea that, “for society’s sake,” women in the state of nature appreciate more the advantages of long-term cooperation, even at the price of some subordination.
Assessing the Operationalization of Cultural Theory through Surveys Investigating the Social Aspects of Climate Change Policy Making
Authors: Cambardella Claire , Fath Brian D. , Werdenigg Andrea , Gulas Christian , Katzmair Harald 
Published: March 2020

AbstractCultural theory (CT) provides a framework for understanding how social dimensions shape cultural bias and social relations of individuals, including values, view of the natural world, policy preferences, and risk perceptions. The five resulting cultural solidarities are each associated with a “myth of nature”—a concept of nature that aligns with the worldview of each solidarity. When applied to the problem of climate protection policy making, the relationships and beliefs outlined by CT can shed light on how members of the different cultural solidarities perceive their relationship to climate change and associated risk. This can be used to deduce what climate change management policies may be preferred or opposed by each group. The aim of this paper is to provide a review of how CT has been used in surveys of the social aspects of climate change policy making, to assess the construct validity of these studies, and to identify ways for climate change protection policies to leverage the views of each of the cultural solidarities to develop clumsy solutions: policies that incorporate strengths from each of the cultural solidarities’ perspectives. Surveys that include measures of at least fatalism, hierarchism, individualism, and egalitarianism and their associated myths of nature as well as measures of climate change risk perceptions and policy preferences have the highest translation and predictive validity. These studies will be useful in helping environmental managers find clumsy solutions and develop resilient policy according to C.S. Holling’s adaptive cycle.
Relation of serum melatonin levels to postoperative delirium in older patients undergoing major abdominal surgery
Authors: Shen Qi-hong , Li Hui-fang , Zhou Xu-yan , Lu Ya-ping , Yuan Xiao-zong 
Published: March 2020

Objective Postoperative delirium (POD) is a perennial and distressing complication in older patients, and it may be caused by various factors. This study aimed to determine whether serum melatonin levels are associated with POD in older patients who undergo major abdominal surgery. Methods We collected serum samples from patients undergoing major abdominal surgery. Melatonin was measured by enzyme-linked immunosorbent assay and delirium was assessed by the Confusion Assessment Method after surgery. We classified the patients into the POD group and non-POD group. Results A total of 120 patients met the inclusion criteria and 104 patients were included in the analysis. Postoperative serum melatonin levels were significantly lower than preoperative levels. Multivariate analyses showed that a longer duration of anesthesia (odds ratio [OR] = 1.29, 95% confidence interval [CI] = 1.02–1.64), advanced age (OR = 3.36, 95% CI = 1.37–8.22), and lower postoperative levels of melatonin (OR = 0.50, 95% CI = 0.25–1.00) were associated with POD. Conclusions Serum melatonin levels significantly decline after surgery and anesthesia. Significantly decreased serum melatonin concentrations postoperatively may be a biomarker for predicting POD in older patients undergoing major abdominal surgery with general anesthesia.
Enhanced participation or just another activity? The social shaping of iPad use for youths with intellectual disabilities
Authors: Isaksson Charlotta , Björquist Elisabet 
Published: March 2020

The use of smartphones and tablet devices in activities is believed to have great potential for enhancing the participation of people with intellectual disabilities. However, these technologies, in themselves, do not contribute to participation. What matters is how they are used. Employing the concept of domestication and insights gained from interviews with staff, this article examines conditions for the enhanced participation of youths with intellectual disability and how tablet devices are being integrated into social care settings, in particular. The findings reveal two approaches to tablet integration. In one approach, tablet use is an organized practice focused on technology acquisition, skills improvement and entertainment. In the other, it is integrated into existing practices as an aid to interpersonal communication. The organized digital activities create conditions for the youths to participate like non-disabled peers. The greatest potential for enabling participation with each other is when the youths themselves initiate the use of tablets.
What is the incidence of complex regional pain syndrome (CRPS) Type I within four months of a wrist fracture in the adult population? A systematic review
Authors: Rolls Catherine , McCabe Candy , Llewellyn Alison , Jones Gareth T 
Published: March 2020

Introduction Complex regional pain syndrome (CRPS) is a severe chronic pain condition, the symptoms of which may develop following trauma to a limb. Despite wrist fracture being a common antecedent, estimates of the incidence of CRPS following this injury vary widely. Our objective was to establish the incidence of CRPS in adults within four months of a wrist fracture, using a systematic review of the literature published since 2010. Methods The databases MEDLINE, PubMed, EMBASE, PsychINFO, CINAHL, BNI and AMED were searched for observational studies reporting the incidence of CRPS following a wrist fracture. Inclusion criteria were the use of a validated diagnostic tool to assess for CRPS within four months of the fracture. Randomised controlled trials and clinical trials were excluded, as were data from patients with evidence of prior neurology. Incidence risk was then extracted or calculated. Included studies were assessed for methodological rigour using the Newcastle–Ottowa Scale for assessment of bias. Results Nine studies met the inclusion criteria. There was a high degree of heterogeneity in study populations including study setting, fracture management and diagnostic criteria. From the three studies with the highest methodological rigour we determined that the incidence risk of CRPS in adults is between 3.7% and 14% using the Budapest criteria, with an observation of lower rates in conservatively managed fractures. Discussion We found evidence that the reported incidence of CRPS is influenced by choice of diagnostic criteria, along with the study location and/or how the fracture is managed.