bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contextual equipoise: a novel concept to inform ethical implications for implementation research in low-income and middle-income countries
Authors: Seward Nadine , Hanlon Charlotte , Murdoch Jamie , Colbourn Tim , Prince Martin James , Venkatapuram Sridhar , Sevdalis Nick 
Published: December 2020

The call for universal health coverage requires the urgent implementation and scale-up of interventions that are known to be effective, in resource-poor settings. Achieving this objective requires high-quality implementation research (IR) that evaluates the complex phenomenon of the influence of context on the ability to effectively deliver evidence-based practice. Nevertheless, IR for global health is failing to apply a robust, theoretically driven approach, leading to ethical concerns associated with research that is not methodologically sound.Inappropriate methods are often used in IR to address and report on context. This may result in a lack in understanding of how to effectively adapt the intervention to the new setting and a lack of clarity in conceptualising whether there is sufficient evidence to generalise findings from previous IR to a new setting, or if a randomised controlled trial (RCT) is needed. Some of the ethical issues arising from this shortcoming include poor-quality research that may needlessly expose vulnerable participants to research that has not been adapted to suit local needs and priorities, and the inappropriate use of RCTs that denies participants in the control arm access to treatment that is effective within the local context.To address these concerns, we propose a complementary approach to clinical equipoise for IR, known ascontextual equipoise. We discuss challenges in the evaluation of context and also with assessing the certainty of evidence to justify an RCT. Finally, we describe methods that can be applied to improve the evaluation and reporting of context and to help understand if contextual equipoise can be justified or if significant adaptations are required. We hope our analysis offers helpful insight to better understand and ensure that the ethical principle of beneficence is upheld in the real-world contexts of IR in low-resource settings.
Creating a prepared mental health workforce: comparative illustrations of implementation strategies
Authors: Chorpita Bruce F , Daleiden Eric L , Vera Juan Diego , Guan Karen 
Published: December 2020

BackgroundPsychotherapy implementation must contend with the task of preparing a mental health workforce to provide the highest quality services to as much of a service population as possible, in high-income as well as low-to-middle income countries.ObjectiveWe outline general challenges and solutions and investigate how well various implementation strategies would fit a clinical population.MethodsUsing a data set from a prior cluster randomised trial with a clinically diverse population and 33 intervention practices, we presented multiple illustrations comparing the ability of different implementation strategies to serve youth and families with procedures in which service providers were trained.FindingsA series of survival functions demonstrated that many common implementation strategies are unlikely to create a prepared workforce, given the large and diverse number of practices needed to be mastered by providers.Clinical implications‘Benchmark’ solutions that afforded superior coverage of the service population could be supported through paced learning approaches (ie, training interventions a little at a time) using extensible, modular intervention designs.
Generalized Hesitant Fuzzy Ideals in Semigroups
Authors: Muhiuddin G. , Alanazi A. M. , Mahboob A. , Al-Kadi D. 
Published: December 2020

In this paper, as a generalization of the concepts of hesitant fuzzy bi-ideals and hesitant fuzzy right (resp. left) ideals of semigroups, the concepts of hesitant fuzzy

m
,
n

-ideals and hesitant fuzzy

m
,
0

-ideals (resp.

0
,
n

-ideals) are introduced. Furthermore, conditions for a hesitant fuzzy

m
,
n

-ideal (

m
,
0

-ideal,

0
,
n

-ideal) to be a hesitant fuzzy bi-ideal (right ideal, left ideal) are provided. Moreover, several correspondences between bi-ideals (right ideals, left ideals) and hesitant fuzzy

m
,
n

-ideals (

m
,
0

-ideals,

0
,
n

-ideals) are obtained. Also, the characterizations of different classes of semigroups in terms of their hesitant fuzzy

m
,
n

-ideals and hesitant fuzzy

m
,
0

-ideals (

0
,
n

-ideals) are investigated.
Cancer-Induced Muscle Wasting Requires p38β MAPK Activation of p300
Authors: Sin Thomas K. , Zhang Guohua , Zhang Zicheng , Zhu James Z. , Zuo Yan , Frost Jeffrey A. , Li Min , Li Yi-Ping 
Published: December 2020

AbstractCancer-associated cachexia, characterized by muscle wasting, is a lethal metabolic syndrome without defined etiology or established treatment. We previously found that p300 mediates cancer-induced muscle wasting by activating C/EBPβ, which then upregulates key catabolic genes. However, the signaling mechanism that activates p300 in response to cancer is unknown. Here, we show that upon cancer-induced activation of Toll-like receptor 4 in skeletal muscle, p38β MAPK phosphorylates Ser-12 on p300 to stimulate C/EBPβ acetylation, which is necessary and sufficient to cause muscle wasting. Thus, p38β MAPK is a central mediator and therapeutic target of cancer-induced muscle wasting. In addition, nilotinib, an FDA-approved kinase inhibitor that preferentially binds p38β MAPK, inhibited p300 activation 20-fold more potently than the p38α/β MAPK inhibitor, SB202190, and abrogated cancer cell–induced muscle protein loss in C2C12 myotubes without suppressing p38α MAPK–dependent myogenesis. Systemic administration of nilotinib at a low dose (0.5 mg/kg/day, i.p.) in tumor-bearing mice not only alleviated muscle wasting, but also prolonged survival. Therefore, nilotinib appears to be a promising treatment for human cancer cachexia due to its selective inhibition of p38β MAPK.Significance:These findings demonstrate that prevention of p38β MAPK–mediated activation of p300 by the FDA-approved kinase inhibitor, nilotinib, ameliorates cancer cachexia, representing a potential therapeutic strategy against this syndrome.
Assessing Drug Development Risk Using Big Data and Machine Learning
Authors: Vergetis Vangelis , Skaltsas Dimitrios , Gorgoulis Vassilis G. , Tsirigos Aristotelis 
Published: December 2020

Abstract
Identifying new drug targets and developing safe and effective drugs is both challenging and risky. Furthermore, characterizing drug development risk, the probability that a drug will eventually receive regulatory approval, has been notoriously hard given the complexities of drug biology and clinical trials. This inherent risk is often misunderstood and mischaracterized, leading to inefficient allocation of resources and, as a result, an overall reduction in R&D productivity. Here we argue that the recent resurgence of Machine Learning in combination with the availability of data can provide a more accurate and unbiased estimate of drug development risk.
MEK Inhibition Reverses Aberrant Signaling in Melanoma Cells through Reorganization of NRas and BRAF in Self Nanoclusters
Authors: Yakovian Oren , Sajman Julia , Arafeh Rand , Neve-Oz Yair , Alon Michal , Samuels Yardena , Sherman Eilon 
Published: December 2020

Abstract

Hotspot mutations of the oncogenes BRAF and NRas are the most common genetic alterations in cutaneous melanoma. Still, the nanoscale organization and signal coupling of these proteins remain incompletely understood, particularly upon expression of oncogenic NRas mutants. Here we employed single-molecule localization microscopy to study the nanoscale organization of NRas and BRAF at the plasma membrane (PM) of melanoma cells. NRas and BRAF resided in self-clusters that did not associate well in resting cells. In EGF-activated cells, NRas clusters became more diffused while overall protein levels at the PM increased; thus allowing enhanced association of NRas and BRAF and downstream signaling. In multiple melanoma cell lines, mutant NRas resided in more pronounced self-clusters relative to wild-type (WT) NRas yet associated more with the clustered and more abundant BRAF. In cells resistant to trametinib, a clinical MEK inhibitor (MEKi), a similar coclustering of NRas and BRAF was observed upon EGF activation. Strikingly, treatment of cells expressing mutant NRas with trametinib reversed the effect of mutant NRas expression by restoring the nonoverlapping self-clusters of NRas and BRAF and by reducing their PM levels and elevated pERK levels caused by mutant NRas. Our results indicate a new mechanism for signal regulation of NRas in melanoma through its nanoscale dynamic organization and a new mechanism for MEKi function in melanoma cells carrying NRas mutations but lacking MEK mutations.

Significance:
Nanoscale dynamic organization of WT and mutant NRas relative to BRAF serves as a regulatory mechanism for NRas signaling and may be a viable therapeutic target for its sensitivity to MEKi.
USP24 Is a Cancer-Associated Ubiquitin Hydrolase, Novel Tumor Suppressor, and Chromosome Instability Gene Deleted in Neuroblastoma
Authors: Bedekovics Tibor , Hussain Sajjad , Zhang Ying , Ali Asma , Jeon Young J. , Galardy Paul J. 
Published: December 2020

Abstract

Deubiquitinating enzymes are increasingly recognized to play important roles in cancer, with many acting as oncogenes or tumor suppressors. In this study, we employed a bioinformatics approach to screen for enzymes from this family involved in cancer and found USP24 as a potent predictor of poor outcomes in neuroblastoma, an aggressive childhood cancer. USP24 resides in a region commonly deleted in neuroblastoma, yet was independently associated with poor outcomes in this disease. Deletion of Usp24 in a murine model resulted in degradation of collapsin response mediator protein 2 (CRMP2), a regulator of axon growth, guidance, and neuronal polarity. Cells lacking USP24 had significant increases in spindle defects, chromosome missegregation, and aneuploidy, phenotypes that were rescued by the restoration of CRMP2. USP24 prevented aneuploidy by maintaining spindle-associated CRMP2, which is required for mitotic accuracy. Our findings further indicate that USP24 is a tumor suppressor that may play an important role in the pathogenesis of neuroblastoma.

Significance:
This study identifies the chromosome instability gene USP24 as frequently deleted in neuroblastoma and provides important insight into the pathogenesis of this aggressive childhood cancer.
Posttraumatic Stress Disorder and Likelihood of Hormone Therapy Use among Women in the Nurses' Health Study II: A 26-Year Prospective Analysis
Authors: Lawn Rebecca B. , Nishimi Kristen M. , Kim Yongjoo , Jung Sun Jae , Roberts Andrea L. , Sumner Jennifer A. , Thurston Rebecca C. , Chibnik Lori B. , Rimm Eric B. , Ratanatharathorn Andrew D. , Jha Shaili C. , Koenen Karestan C. , Tworoger Shelley S. , Kubzansky Laura D. 
Published: December 2020

Abstract

Background:
Posttraumatic stress disorder (PTSD) is associated with higher risk of certain chronic diseases, including ovarian cancer, but underlying mechanisms remain unclear. Although prior work has linked menopausal hormone therapy (MHT) use with elevated ovarian cancer risk, little research considers PTSD to likelihood of MHT use. We examined whether PTSD was prospectively associated with greater likelihood of initiating MHT use over 26 years.

Methods:
Using data from the Nurses' Health Study II, with trauma and PTSD (symptoms and onset date) assessed by screener in 2008 and MHT assessed via biennial survey (from 1989), we performed Cox proportional regression models with women contributing person-years from age 36 years. Relevant covariates were assessed at biennial surveys. We considered potential effect modification by race/ethnicity, age at baseline, and period (1989–2002 vs. 2003–2015).

Results:
Over follow-up, 22,352 of 43,025 women reported initiating MHT use. For example, compared with women with no trauma, the HR for initiating MHT was 1.18 for those with trauma/1–3 PTSD symptoms [95% confidence interval (CI), 1.13–1.22] and 1.31 for those with trauma/4–7 PTSD symptoms (95% CI, 1.25–1.36; P trend &lt; 0.001), adjusting for sociodemographic factors. Associations were maintained when adjusting for reproductive factors and health conditions. We found evidence of effect modification by age at baseline.

Conclusions:
Trauma and number of PTSD symptoms were associated with greater likelihood of initiating MHT use in a dose–response manner.

Impact:
MHT may be a pathway linking PTSD to altered chronic disease risk. It is important to understand why women with PTSD initiate MHT use.
Genome Methylation Accurately Predicts Neuroendocrine Tumor Origin: An Online Tool
Authors: Hackeng Wenzel M. , Dreijerink Koen M.A. , de Leng Wendy W.J. , Morsink Folkert H.M. , Valk Gerlof D. , Vriens Menno R. , Offerhaus G. Johan A. , Geisenberger Christoph , Brosens Lodewijk A.A. 
Published: December 2020

Abstract

Purpose:
The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation–based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathologic diagnosis in neuroendocrine tumors.

Experimental Design:
Methylation data was compiled for 69 small intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (neuroendocrine neoplasm identifier, NEN-ID). The model was validated during 3 × 3 nested cross-validation and tested in a local and an external cohort (n = 198 cases).

Results:
NEN-ID predicted the origin of tumor samples with high accuracy (&gt;95%). In addition, the diagnostic approach was determined to be robust across a range of possible confounding experimental parameters, such as tumor purity and array quality. A software infrastructure and online user interface were built to make the model available to the scientific community.

Conclusions:
This DNA methylation–based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID.
MEK-ing the Most of It: Strategies to Co-target Gαq and MAPK in Uveal Melanoma
Authors: Neelature Sriramareddy Sathya , Smalley Keiran S.M. 
Published: December 2020

Abstract
Most uveal melanomas harbor mutations in Gαq and show constitutive MAPK activation. Although MEK inhibition has some efficacy against uveal melanoma, clinical responses are typically poor. The Gαq inhibitor-MEK inhibitor combination showed prolonged suppression of MAPK signaling in preclinical uveal melanoma models and led to improved therapeutic responses.
See related article by Hitchman et al., p. 1476
Cost Effectiveness of Whole Population BRCA Genetic Screening for Cancer Prevention in Israel
Authors: Michaan Nadav , Leshno Moshe , Safra Tamar , Sonnenblick Amir , Laskov Ido , Grisaru Dan 
Published: December 2020

Abstract

With the growing technical ease and reduction in genetic screening costs, whole population BRCA screening may be a feasible option. Our objective was to investigate the cost effectiveness of whole population screening for BRCA mutations in Israel, for varying degrees of BRCA carrier state. Lifetime costs of whole female population screening for BRCA mutation carrier state versus nonscreening were compared using a Markovian process decision analysis model. Model parameters including ovarian and breast cancer risks were obtained from previously published data. Screening and other treatment-related costs were received from the Israeli Ministry of Health pricing list according to specified codes. Quality-adjusted life years were used for cost-effectiveness analysis. Sensitivity analysis was conducted to evaluate model uncertainties, specifically varying degrees of BRCA prevalence. Results show that whole population BRCA screening in Israel is cost effective across a wide range of BRCA prevalence rates with an incremental cost-effectiveness ratio of 81,493 new Israeli Shekels for a BRCA prevalence of 2.5%, increasing to 250,000 new Israeli Shekels for a 0.75% prevalence rate, per quality-adjusted life year gained. Discount rate and population BRCA prevalence and rate of risk reduction salpingo-oophorectomy are the most influential parameters in the model. Whole population screening for BRCA mutations should be offered as part of general health screening strategies by national medical insurance providers, even for non-Ashkenazi Jews. Our algorithm can be applied for other countries, adjusting local costs of screening and treatment.

Prevention Relevance:
Whole population BRCA mutation screening in Israel is cost effective across a wide prevalence rate and should be offered as part of general health screening strategies by national medical insurance providers for cancer prevention.
Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune–Tumor Interactions: Engage, Expand, Enable
Authors: Fabian Kellsye P. , Malamas Anthony S. , Padget Michelle R. , Solocinski Kristen , Wolfson Benjamin , Fujii Rika , Abdul Sater Houssein , Schlom Jeffrey , Hodge James W. 
Published: December 2020

Abstract
Immunotherapy of immunologically cold solid tumors may require multiple agents to engage immune effector cells, expand effector populations and activities, and enable immune responses in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology agents, namely, (i) a tumor antigen–targeting adenovirus-based vaccine (Ad-CEA) and an IL15 superagonist (N-803) to activate tumor-specific T cells, (ii) OX40 and GITR agonists to expand and enhance the activated effector populations, and (iii) an IDO inhibitor (IDOi) to enable effector-cell activity in the TME. Flow cytometry, T-cell receptor (TCR) sequencing, and RNA-sequencing (RNA-seq) analyses showed that in the CEA-transgenic murine colon carcinoma (MC38-CEA) tumor model, Ad-CEA + N-803 combination therapy resulted in immune-mediated antitumor effects and promoted the expression of costimulatory molecules on immune subsets, OX40 and GITR, and the inhibitory molecule IDO. Treatment with Ad-CEA + N-803 + OX40 + GITR + IDOi, termed the pentatherapy regimen, resulted in the greatest inhibition of tumor growth and protection from tumor rechallenge without toxicity. Monotherapy with any of the agents had little to no antitumor activity, whereas combining two, three, or four agents had minimal antitumor effects. Immune analyses demonstrated that the pentatherapy combination induced CD4+ and CD8+ T-cell activity in the periphery and tumor, and antitumor activity associated with decreased regulatory T-cell (Treg) immunosuppression in the TME. The pentatherapy combination also inhibited tumor growth and metastatic formation in 4T1 and LL2-CEA murine tumor models. This study provides the rationale for the combination of multimodal immunotherapy agents to engage, enhance, and enable adaptive antitumor immunity.
Intravenous Hydrogen Therapy With Intracisternal Magnesium Sulfate Infusion in Severe Aneurysmal Subarachnoid Hemorrhage
Authors: Takeuchi Satoru , Kumagai Kosuke , Toyooka Terushige , Otani Naoki , Wada Kojiro , Mori Kentaro 
Published: December 2020

Background and Purpose:
Poor-grade subarachnoid hemorrhage still has a poor prognosis. This randomized controlled clinical trial evaluated intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy in patients with poor-grade subarachnoid hemorrhage.

Methods:

Thirty-seven patients with poor-grade subarachnoid hemorrhage were randomized to Mg+H
2
, Mg, and control groups. Mg and Mg+H
2
groups received intracisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days. Mg+H
2
group also received intravenous hydrogen-rich solution infusion for 14 days. Primary outcome measures were occurrence of delayed cerebral ischemia and cerebral vasospasm. Secondary outcome measures were modified Rankin Scale and Karnofsky performance status at 3 and 12 months, Barthel index at 12 months, and serum and cerebrospinal fluid malondialdehyde and neuron-specific enolase.

Results:

Serum neuron-specific enolase levels were significantly lower in the Mg+H
2
group from days 3 to 14 than in the control group. Cerebrospinal fluid neuron-specific enolase levels were also significantly lower in the Mg+H
2
group from days 3 to 7 than in the control group. Incidences of cerebral vasospasm and delayed cerebral ischemia were significantly higher in the control group than in other groups. Modified Rankin Scale and Karnofsky performance status did not significantly differ between the three groups at 3 months. Modified Rankin Scale scores 0 to 2 were more common in the Mg and Mg+H
2
groups at 1 year. Barthel index was higher in the Mg+H
2
group than in the control group.

Conclusions:
Intracisternal magnesium sulfate infusion started immediately after surgery reduces the incidence of cerebral vasospasm and delayed cerebral ischemia and improves clinical outcomes without complications in patients with poor-grade subarachnoid hemorrhage. Intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy decreases serum malondialdehyde and neuron-specific enolase and improves Barthel index, indicating hydrogen has additional effects.

Registration:

URL:
https://www.umin.ac.jp/ctr/index.htm
. Unique identifier: UMIN000014696.