bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Switch for TGFβ in Cancer
Authors: Yeh Hsi-Wen , Lee Szu-Shuo , Chang Chieh-Yu , Lang Yaw-Dong , Jou Yuh-Shan 
Published: July 2019

Abstract
The TGFβ cytokine plays dichotomous roles during tumor progression. In normal and premalignant cancer cells, the TGFβ signaling pathway inhibits proliferation and promotes cell-cycle arrest and apoptosis. However, the activation of this pathway in late-stage cancer cells could facilitate the epithelial-to-mesenchymal transition, stemness, and mobile features to enhance tumorigenesis and metastasis. The opposite functions of TGFβ signaling during tumor progression make it a challenging target to develop anticancer interventions. Nevertheless, the recent discovery of cellular contextual determinants, especially the binding partners of the transcription modulators Smads, is critical to switch TGFβ responses from proapoptosis to prometastasis. In this review, we summarize the recently identified contextual determinants (such as PSPC1, KLF5, 14-3-3ζ, C/EBPβ, and others) and the mechanisms of how tumor cells manage the context-dependent autonomous TGFβ responses to potentiate tumor progression. With the altered expression of some contextual determinants and their effectors during tumor progression, the aberrant molecular prometastatic switch might serve as a new class of theranostic targets for developing anticancer strategies.
Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
Authors: Laddha Saurabh V. , da Silva Edaise M. , Robzyk Kenneth , Untch Brian R. , Ke Hua , Rekhtman Natasha , Poirier John T. , Travis William D. , Tang Laura H. , Chan Chang S. 
Published: July 2019

Abstract

Lung carcinoids (LC) are rare and slow growing primary lung neuroendocrine tumors. We performed targeted exome sequencing, mRNA sequencing, and DNA methylation array analysis on macro-dissected LCs. Recurrent mutations were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C, and KMT2A) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed three robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be exclusively enriched in the LC2 subtype. LC1 and LC3 subtypes were predominately found at peripheral and endobronchial lung, respectively. The LC3 subtype was diagnosed at a younger age than LC1 and LC2 subtypes. IHC staining of two biomarkers, ASCL1 and S100, sufficiently stratified the three subtypes. This molecular classification of LCs into three subtypes may facilitate understanding of their molecular mechanisms and improve diagnosis and clinical management.

Significance:
Integrative genomic analysis of lung carcinoids identifies three novel molecular subtypes with distinct clinical features and provides insight into their distinctive molecular signatures of tumorigenesis, diagnosis, and prognosis.
Are Platelets the Primary Target of Aspirin's Remarkable Anticancer Activity?
Authors: Lichtenberger Lenard M. , Vijayan K. Vinod 
Published: July 2019

Abstract
Aspirin, when administered at low doses, has emerged as a powerful anticancer drug due to both chemopreventive activity against many forms of cancer and its ability to block metastases when administered postdiagnosis. Platelets, which are often elevated in circulation during the latter stages of cancer, are known to promote epithelial–mesenchymal transition, cancer cell growth, survival in circulation, and angiogenesis at sites of metastases. Low-dose aspirin has been demonstrated to block this procarcinogenic action of platelets. In this article, we present evidence that aspirin's unique ability to irreversibly inhibit platelet cyclooxygenase-1 is a key mechanism by which aspirin exerts anticancer activity.
Circulating Tumor DNA Profiling in Small-Cell Lung Cancer Identifies Potentially Targetable Alterations
Authors: Devarakonda Siddhartha , Sankararaman Sumithra , Herzog Brett H. , Gold Kathryn A. , Waqar Saiama N. , Ward Jeffrey P. , Raymond Victoria M. , Lanman Richard B. , Chaudhuri Aadel A. , Owonikoko Taofeek K. , Li Bob T. , Poirier John T. , Rudin Charles M. , Govindan Ramaswamy , Morgensztern Daniel 
Published: July 2019

Abstract

Purpose:
Patients with SCLC rarely undergo biopsies at relapse. When pursued, tissue obtained can be inadequate for molecular testing, posing a challenge in identifying potentially targetable alterations in a clinically meaningful time frame. We examined the feasibility of circulating tumor DNA (ctDNA) testing in identifying potentially targetable alterations in SCLC.

Experimental Design:
ctDNA test results were prospectively collected from patients with SCLC between 2014 and 2017 and analyzed. ctDNA profiles of SCLC at diagnosis and relapse were also compared.

Results:
A total of 609 samples collected from 564 patients between 2014 and 2017 were analyzed. The median turnaround time for test results was 14 days. Among patients with data on treatment status, there were 61 samples from 59 patients and 219 samples from 206 patients collected at diagnosis and relapse, respectively. The number of mutations or amplifications detected per sample did not differ by treatment status. Potentially targetable alterations in DNA repair, MAPK and PI3K pathways, and genes such as MYC and ARID1A were identifiable through ctDNA testing. Furthermore, our results support that it may be possible to reconstruct the clonal relationship between detected variants through ctDNA testing.

Conclusions:
Patients with relapsed SCLC rarely undergo biopsies for molecular testing and often require prompt treatment initiation. ctDNA testing is less invasive and capable of identifying alterations in relapsed disease in a clinically meaningful timeframe. ctDNA testing on an expanded gene panel has the potential to advance our knowledge of the mechanisms underlying treatment resistance in SCLC and aid in the development of novel treatment strategies.
Treatment with Humanized Selective CD19CAR-T Cells Shows Efficacy in Highly Treated B-ALL Patients Who Have Relapsed after Receiving Murine-Based CD19CAR-T Therapies
Authors: Zhao Yu , Liu Zhongfeng , Wang Xuan , Wu Huantong , Zhang Jianping , Yang Junfang , Zhang Fayou , Liu Lining , Long Jiafu , Lu Peihua , Chen Zhiguo 
Published: July 2019

Abstract

Purpose:
CD19 chimeric antigen receptor (CAR)-T therapy has shown impactful results in treatment of B-cell malignancies. However, immune recognition of the murine scFv may render subsequent infusion(s) ineffective. Also, nonselective expansion of both CAR-transduced and nontransduced T cells during the production stage affects the yield and purity of final products. Here, we aim to develop a humanized selective (hs) CD19 CAR to solve the above problems.
Experimental Design: A CD19 hsCAR was designed, which incorporated a short selective domain between the humanized heavy chain and light chain. The CAR was examined for its property, and then trialed in 5 highly treated B-ALL patients.

Results:
hsCAR possessed around 6-fold higher affinity to CD19 versus murine CAR (mCAR). Incubation with selective domain-specific mAbs (SmAb) selectively expanded CAR-transduced T cells, and led to a higher proportion of central memory T cells in the final products. SmAb-stimulated CD19 hsCAR-T cells exhibited superior antitumor cytotoxic functions in vitro and in vivo. Autologous (n = 2) and allogeneic donor (n = 3, with hematopoietic stem cell transplantation) hsCAR-T cells were infused into 5 patients who had relapsed after receiving mCAR-T treatments. Two patients received mCAR-T treatments twice previously but the second treatments were ineffective. In contrast, subsequent hsCAR-T treatments proved effective in all 5 patients and achieved complete molecular remission in four, including one with extramedullary disease with central nervous system involvement.

Conclusions:
hsCD19 CAR-T treatment shows efficacy in highly treated B-ALL patients who have relapsed after receiving CD19 mCAR-T therapies.
Loss of MAP3K7 Sensitizes Prostate Cancer Cells to CDK1/2 Inhibition and DNA Damage by Disrupting Homologous Recombination
Authors: Washino Satoshi , Rider Leah C. , Romero Lina , Jillson Lauren K. , Affandi Trisiani , Ohm Angela M. , Lam Elaine T. , Reyland Mary E. , Costello James C. , Cramer Scott D. 
Published: July 2019

Abstract

The combined loss of CHD1 and MAP3K7 promotes aggressive prostate cancer by unknown mechanisms. Because both of these genes are lost genetically in prostate cancer, they cannot be directly targeted. We applied an established computational systems pharmacology approach (TRAP) to identify altered signaling pathways and associated druggable targets. We compared gene expression profiles of prostate cancer with coloss of CHD1 and MAP3K7 with prostate cancer diploid for these genes using The Cancer Genome Atlas patient samples. This analysis prioritized druggable target genes that included CDK1 and CDK2. We validated that inhibitors of these druggable target genes, including the CDK1/CDK2 inhibitor dinaciclib, had antiproliferative and cytotoxic effects selectively on mouse prostate cells with knockdown of Chd1 and Map3k7. Dinaciclib had stronger effects on prostate cells with suppression of Map3k7 independent of Chd1 and also compared with cells without loss of Map3k7. Dinaciclib treatment reduced expression of homologous recombination (HR) repair genes such as ATM, ATR, BRCA2, and RAD51, blocked BRCA1 phosphorylation, reduced RAD51 foci formation, and increased γH2AX foci selectively in prostate cells with suppression of Map3k7, thus inhibiting HR repair of chromosomal double-strand breaks. Dinaciclib-induced HR disruption was also observed in human prostate cells with knockdown of MAP3K7. Cotreatment of dinaciclib with DNA-damaging agents or PARP inhibitor resulted in a stronger cytotoxic effect on prostate cells with suppression of MAP3K7 compared with those without loss of MAP3K7, or to each single agent.

Implications:
These findings demonstrate that loss of MAP3K7 is a main contributing factor to drug response through disruption of HR in prostate cancer.
Comparison of the Ventricular Tachycardia Circuit Between Patients With Ischemic and Nonischemic Cardiomyopathies
Authors: Shirai Yasuhiro , Liang Jackson J. , Santangeli Pasquale , Arkles Jeffrey S. , Schaller Robert D. , Supple Gregory E. , Nazarian Saman , Garcia Fermin C. , Lin David , Dixit Sanjay , Callans David J. , Marchlinski Francis E. , Frankel David S. 
Published: July 2019

Background:
There has been increasing awareness of the 3-dimensional nature of ventricular tachycardia (VT) circuits. VT circuits in patients with ischemic cardiomyopathies (ICM) and non-ICM (NICM) may differ in this regard.

Methods:
Among patients with structural heart disease and at least 1 hemodynamically tolerated VT undergoing ablation, we retrospectively analyzed responses to all entrainment maneuvers.

Results:

Of 445 patients (ICM 228, NICM 217) undergoing VT ablation, detailed entrainment mapping of at least 1 tolerated VT was performed in 111 patients (ICM 71, NICM 40). Of 89 ICM VTs, the isthmus could be identified by endocardial entrainment in 55 (62%), compared with only 8 of 47 (17%) NICM VTs (
P
<0.01). With combined endocardial and epicardial mapping, the isthmus could be identified in 56 (63%) ICM VTs and 12 (26%) NICM VTs (
P
<0.01), whereas any critical component (defined as entrance, isthmus or exit) could be identified in 76 (85%) ICM VTs and 37 (79%) NICM VTs (
P
=0.3). Complete success (no inducible VT at the end of ablation, 82% versus 65%,
P
=0.04) and 1-year, single-procedure VT-free survival (82% versus 55%,
P
<0.01) were both higher among patients with ICM.

Conclusions:
Among mappable ICM VTs, critical circuit components can usually be identified on the endocardium. In contrast, among mappable NICM VTs, although some critical component can typically be identified with the addition of epicardial mapping, the isthmus is less commonly identified, possibly due to midmyocardial location.
Central Adjudication Identified Additional and Prognostically Important Myocardial Infarctions in Patients Undergoing Percutaneous Coronary Intervention
Authors: Olivier Christoph B. , Bhatt Deepak L. , Leonardi Sergio , Stone Gregg W. , Gibson C. Michael , Steg Ph. Gabriel , Hamm Christian W. , Wilson Matthew D. , Mangum Stacey , Price Matthew J. , Prats Jayne , White Harvey D. , Lopes Renato D. , Harrington Robert A. , Mahaffey Kenneth W. ,   on Behalf of the CHAMPION PHOENIX Investigators*
Published: July 2019

Background:
In the CHAMPION PHOENIX trial, cangrelor reduced the primary composite end point of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis at 48 hours. This study aimed to explore the impact of event adjudication and the prognostic importance of MI reported by a clinical events committee (CEC) or site investigators (SIs).

Methods and Results:

Data from the CHAMPION PHOENIX trial of patients undergoing elective or nonelective percutaneous coronary intervention were analyzed. A CEC systematically identified and adjudicated MI using predefined criteria, a computer algorithm to identify suspected events, and semilogarithmic plots to review biomarker changes. Thirty-day death was modeled using baseline characteristics. Of 10 942 patients, 462 (4.2%) patients had at least 1 MI by 48 hours identified by the CEC (207 [3.8%] cangrelor; 255 [4.7%] clopidogrel; odds ratio [OR] 0.80; 95% CI, 0.67–0.97;
P
=0.022), and 143 patients had at least 1 MI by 48 hours reported by the SI (60 [1.1%] cangrelor; 83 [1.5%] clopidogrel; OR, 0.72; 95% CI, 0.52–1.01;
P
=0.053). Of the 462 MIs identified by the CEC, 92 (20%) were reported by SI, and 370 (80%) were not. Of the 143 MI reported by the SI, 51 (36%) were not confirmed by CEC. All categories were associated with an increased adjusted risk for 30-day death (CEC: OR, 5.35; 95% CI, 2.56–11.2;
P
<0.001; SI: 9.08 [4.01–20.5];
P
<0.001; CEC and SI: 10.9 [3.23–36.6];
P
<0.001; CEC but not SI: 4.69 [1.94–11.3];
P
<0.001; SI but not CEC: 15.4 [5.26–44.9];
P
<0.001).

Conclusions:
In patients undergoing percutaneous coronary intervention, CEC procedures identified 3 times as many MIs as the SI reported. Compared with clopidogrel, cangrelor significantly reduced MIs identified by the CEC with a qualitatively similar relative risk reduction in MIs reported by the SI. MIs identified by CEC or reported by SI were independently associated with worse 30-day death. Central adjudication identified additional, prognostically important events.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01156571.
Enjoying the Tension: Reading Qoh 2:25 in the Context of Qoh 2:24-26
Authors: Dell Katharine , Forti Tova 
Published: July 2019

Abstract
Qoheleth’s experiential method and inner-dialogue creates tensions on the levels of language, style, content and theological ideas. In this paper we seek to explore this tension in relation to a short section (Qoh 2:24-26) that is placed at the end of chapter 2. In the process we question the section division itself and the usual emendation of the translation of v. 25 to fit into the thought of these three verses and that of their neighbouring verses. We engage in a detailed analysis of the versions and of scholarly opinion on the translation, key terms and structure of these verses. We argue that this is just one example of where literary structure has dictated translational options and we prefer instead to ‘enjoy the tension’ of the more convincing and less accepted translation of verse 25 as “For who can eat or even sense, apart from me.”
Towards a Feminist Public Theology: on Wounds, Scars and Healing in the Book of Jeremiah and Beyond
Authors: Claassens L. Juliana 
Published: July 2019

Abstract
In this article, I am contributing to the ongoing conversation on a feminist public theology. Drawing on examples of feminist public theologians in my own context in (South) Africa, I propose that a feminist public theology ought to deal honestly and constructively with the reality of the deep wounds and the scars caused by racism, sexism, xenophobia, and homophobia, which, if left unattended, may fester and return with a vengeance. It is also imperative that a feminist public theology continues to imagine the world to be otherwise, thus helping not only to name the injustice of the past, but also to be able to see beyond the violence to help foster values such as compassion, justice, resistance and resilience. Drawing on examples from the book of Jeremiah, I will illustrate something of my own vocation as a feminist public theologian in the context of South Africa today.
‘Making Public Theology Operational’: Public Theology and the Church
Authors: van Oorschot Frederike 
Published: July 2019

Abstract
This article examines how public theologians aim to bring their theology into the practice of the church. In the first part it analyses the references to the church in the work of contemporary public theologians from the United States and Germany and suggests four different categories for the relations explored (explicit function, implicit function, public church, church as public). In the second part, it discusses three systematic aspects of these relations. First, following Kuyper, it defines the term ‘church’ more accurately. Second, it offers insights into liturgical research in order to help to sharpen the places where and means by which the implicit shaping of individual ethical behaviour in the church takes place, as exemplified in the work of Dirk Smit. Third, it discusses the task of pastors as mediators between church and theology.
Distinct Patterns of Cloud Changes Associated with Decadal Variability and Their Contribution to Observed Cloud Cover Trends
Authors: Chen Yong-Jhih , Hwang Yen-Ting , Zelinka Mark D. , Zhou Chen 
Published: July 2019

Abstract
With the goal of understanding the relative roles of anthropogenic and natural factors in driving observed cloud trends, this study investigates cloud changes associated with decadal variability including the Pacific decadal oscillation (PDO) and the Atlantic multidecadal oscillation (AMO). In the preindustrial simulations of CMIP5 global climate models (GCMs), the spatial patterns and the vertical structures of the PDO-related cloud cover changes in the Pacific are consistent among models. Meanwhile, the models show consistent AMO impacts on high cloud cover in the tropical Atlantic, subtropical eastern Pacific, and equatorial central Pacific, and on low cloud cover in the North Atlantic and subtropical northeast Pacific. The cloud cover changes associated with the PDO and the AMO can be understood via the relationships between large-scale meteorological parameters and clouds on interannual time scales. When compared to the satellite records during the period of 1983–2009, the patterns of total and low cloud cover trends associated with decadal variability are significantly correlated with patterns of cloud cover trends in ISCCP observations. On the other hand, the pattern of the estimated greenhouse gas (GHG)-forced trends of total cloud cover differs from that related to decadal variability, and may explain the positive trends in the subtropical southeast Pacific, negative trends in the midlatitudes, and positive trends poleward of 50°N/S. In most models, the magnitude of the estimated decadal variability contribution to the observed cloud cover trends is larger than that contributed by GHG, suggesting the observed cloud cover trends are more closely related to decadal variability than to GHG-induced warming.
Neuroanatomical alterations in people with high and low cannabis dependence
Authors: Lorenzetti Valentina , Chye Yann , Suo Chao , Walterfang Mark , Lubman Dan I , Takagi Michael , Whittle Sarah , Verdejo-Garcia Antonio , Cousijn Janna , Pantelis Christos , Seal Marc , Fornito Alex , Yücel Murat , Solowij Nadia 
Published: July 2019

Objectives: We aimed to investigate whether severity of cannabis dependence is associated with the neuroanatomy of key brain regions of the stress and reward brain circuits. Methods: To examine dependence-specific regional brain alterations, we compared the volumes of regions relevant to reward and stress, between high-dependence cannabis users (CD+, n = 25), low-dependence cannabis users (CD−, n = 20) and controls ( n = 37). Results: Compared to CD− and/or controls, the CD+ group had lower cerebellar white matter and hippocampal volumes, and deflation of the right hippocampus head and tail. Conclusion: These findings provide initial support for neuroadaptations involving stress and reward circuits that are specific to high-dependence cannabis users.
Are temporal trends in colonoscopy among young adults concordant with colorectal cancer incidence?
Authors: Fedewa Stacey A , Siegel Rebecca L , Jemal Ahmedin 
Published: July 2019

Objective In the United States, colorectal cancer incidence has increased in adults under age 55. Although debate remains about whether this rise is a result of increased detection because of more colonoscopy utilization, population-based trends in colonoscopy among this age group are unknown. We examined changes in colonoscopy rates, as well as colorectal cancer incidence, among adults aged 40–54, using nationally representative data. Methods Recent (past year) colonoscopy rates were computed among 53,175 respondents aged 40–54 in National Health Interview Survey data from 2000 through 2015 by five-year age group. Colorectal cancer incidence rates and incidence rate ratios were estimated from 18 population-based Surveillance Epidemiology and End Result registries during the same period. Results Among respondents aged 40–44, past-year colonoscopy rates were stable during 2000–2015, and ranged from 2.3% to 3.5% ( p-value for trend = 0.771). In contrast, colonoscopy rates increased from 2.5% in 2000 to 5.2% in 2015 among ages 45–49, and from 5.0% to 14.1% in ages 50–54 (test for trend p-values < 0.001). During 2000–2015, colorectal cancer incidence rates increased by 28% in people aged 40–44 (incidence rate ratio = 1.28, 95% CI 1.20, 2.37), 15% in those aged 45–49 (incidence rate ratio = 1.15, 95%CI 1.10, 1.21), and 17% in those aged 50–54 (incidence rate ratio = 1.17, 95%CI 1.13, 1.21), respectively. Conclusion Increases in colonoscopy rates were confined to ages 45–54, whereas colorectal cancer incidence rates rose in those aged 40–44, 45–49, and 50–54. Colonoscopy trends do not fully align with colorectal cancer incidence patterns.
Health Equity, School Discipline Reform, and Restorative Justice
Authors: González Thalia , Etow Alexis , De La Vega Cesar 
Published: July 2019

Every day, students from marginalized communities disproportionately face adversity and trauma. It is well documented that exposure to adverse childhood experiences (ACEs) can impact children's ability to focus, learn, and even regulate their emotions. Many schools, rather than providing multi-tiered systems of support to address the root causes of behavior, place these students at greater risk of experiencing health disparities through the use of exclusionary school discipline (ESD) practices. ESDs not only deny students important educational opportunities, but also can compound existing social, economic, and health inequities. Thus, ESD practices must be understood as more than simply impacting what happens in the classroom. Instead, they should be conceptualized as public health policies with far-reaching impacts on a child's lifelong health and well-being. Even though school discipline has largely been overlooked by the public health community, current reform efforts are one aspect of a holistic health justice framework.This article seeks to begin to bridge current gaps in the literature and public discourse by identifying key linkages between ESD practices and health. It then presents evidence-based design principles to ensure education policy is aligned with a health justice framework. And finally, it explores a specific school-based intervention, restorative justice.