bluuebunny/crossref_metadata_2025_split huggingface dataset:
Building Meaningful Patient Engagement in Research
Authors: Warren Nathaniel T. , Gaudino James A. , Likumahuwa-Ackman Sonja , Dickerson Kristin , Robbins Lynn , Norman Kathy , Lind John , D’Amato Sele , Foley Perry , Gold Rachel , Bauer Vance , Fields Scott A. , Cohen Deborah J. , Clark Khaya D. , DeVoe Jennifer E. 
Published: August 2018

Background:
Strategies to engage patients to improve and enhance research and clinical care are increasingly being implemented in the United States, yet little is known about best practices for or the impacts of meaningful patient engagement.

Objective:
We describe and reflect on our patient stakeholder groups, engagement framework, experiences, and lessons learned in engaging patients in research, from generating proposal ideas to disseminating findings.

Setting:
The ADVANCE (Accelerating Data Value Across a National Community Health Center Network) clinical data research network is the nation’s largest clinical dataset on the safety net, with outpatient clinical data from 122 health systems (1109 clinics) in 23 states.

Results:
Patients stakeholders codeveloped the ADVANCE engagement framework and its implementation in partnership with network leaders. In phase I of ADVANCE, patients were involved with designing studies (input on primary outcome measures and methods) and usability testing (of the patient portal). In phase II, the network is prioritizing research training, dissemination opportunities, an “ambassador” program to pair more experienced patient stakeholders with those less experienced, and evaluation of engagement activities and impacts.

Discussion:
The ADVANCE framework for patient engagement has successfully involved a diverse group of patients in the design, implementation, and interpretation of comparative effectiveness research. Our experience and framework can be used by other organizations and research networks to support patient engagement activities.
Novel targeted drug delivery systems to minimize systemic immunosuppression in vascularized composite allotransplantation
Authors: Taddeo Adriano , Tsai Catherine , Vögelin Esther , Rieben Robert 
Published: August 2018

Purpose of review
The long-term adverse effects of immunosuppressive treatment, the high rate of acute rejection and the development of chronic rejection are the main factors preventing a wider clinical application of vascularized composite allotransplantation (VCA). Targeted immunosuppression using innovative drug delivery systems (DDS) may help to overcome these hurdles, increasing therapeutic efficacy while reducing systemic toxicity. This review provides a summary of the recently developed strategies for targeted delivery of immunosuppressive drugs in VCA.

Recent findings
Currently, several innovative strategies for targeted immunosuppression have been designed based on the anatomy and function of the target organ. Site-specific DDS have been developed both for directly accessible organs (i.e. skin, eye and lung) and internal organs (i.e. lymph nodes, liver, nervous system, etc.). In preclinical models, DDS designed for sustained, ‘on demand,’ or ‘on cue’ drug release has been shown to promote VCA survival while reducing systemic toxicity. These findings suggest that targeted delivery could increase patient compliance and potentially decrease toxicity in VCA recipients.

Summary
Targeted immunosuppression in VCA represents a promising approach for improving patient compliance and graft survival while reducing off-target toxicity, intensity and frequency of acute rejection episodes and risk of chronic rejection.

Video Abstract

http://links.lww.com/COOT/A1
Long-Term Survivors of Pancreatic Cancer
Authors: Kardosh Adel , Lichtensztajn Daphne Y. , Gubens Matthew A. , Kunz Pamela L. , Fisher George A. , Clarke Christina A. 
Published: August 2018

Objectives
Pancreatic cancer continues to carry a poor prognosis with survival rates that have had minimal improvement over the past 4 decades. We report a population-based, comprehensive analysis of long-term survivors of pancreatic adenocarcinoma diagnosed in the diverse population of California.

Methods
Data from the California Cancer Registry were used to evaluate long-term survival. A total of 70,442 patients diagnosed with pancreatic adenocarcinoma between 1988 and 2009 were identified. Logistic regression was used to identify factors associated with achieving 5-year survival.

Results
The overall 5-year survival was 2.5%, with minimal incremental improvements throughout the 3 decades. Age, stage, degree of differentiation, and surgical resection were associated with 5-year survival. Furthermore, younger age and receiving care at a National Cancer Institute–designated cancer center were similarly correlated with 5-year survival regardless of surgical intervention. In addition, we identified stage, differentiation, and adjuvant chemotherapy as significant factors for long-term survival in surgically resected patients. In the unresectable patients, Asian/Pacific islanders and Hispanics were significantly more likely to reach the 5-year milestone than non-Hispanic whites.

Conclusions
Although pancreatic cancer mortality remains high, our study highlights baseline characteristics, treatment, biological factors, and ethnicity that are associated with long-term survival. These findings may serve as a springboard for further investigation.
Application of a Frailty Modeling Approach to Correlated Breastfeeding Duration Data
Authors: Zhao Jian , Zhao Yun , Khanal Vishnu , Lee Andy H. , Binns Colin W. 
Published: August 2018

Background
Correlated breastfeeding duration data are very common in infant feeding research using cohort designs. Intracluster correlation within the same clustering group is expected and needs to be taken into account in statistical analysis; otherwise, the corresponding statistical inferences may be subject to an increased Type I error.

Objectives
The aims of this study were to illustrate the necessity of adjusting for the intracluster correlation in correlated breastfeeding duration data analysis and to demonstrate different frailty modeling approaches.

Methods
An introduction to shared frailty models was presented under the assumption of proportional hazards (PH). Then, two different approaches—the Cox frailty model (semiparametric approach) and the parametric frailty model (parametric approach)—were used to fit the data from a maternal cohort in Nepal as an illustrative example.

Results
For the semiparametric approach, random effects denoting the variations in the hazard of breastfeeding cessation shared by mothers living in the 27 distinct communities were estimated and graphically presented. Compared with the conventional Cox model, Cox frailty model reduced the chance of Type I error occurring, providing a better model fit in the presence of correlated survival data. Among candidate parametric approaches, a Weibull PH model with a gamma frailty term was selected as an appropriate model fitting the breastfeeding data.

Discussion
Shared frailty models can be used in other research areas in the presence of correlated time-to-event data. Model selection depends on the assumption of PH, the specification of the baseline hazard function, and also the study purpose.
PTGER2-β-Catenin Axis Links High Salt Environments to Autoimmunity by Balancing IFNγ and IL-10 in FoxP3+Regulatory T cells
Authors: Sumida Tomokazu , Lincoln Matthew R. , Ukeje Chinonso M. , Rodriguez Donald M. , Akazawa Hiroshi , Noda Tetsuo , Naito Atsuhiko T. , Komuro Issei , Dominguez-Villar Margarita , Hafler David A. 
Published: August 2018

AbstractFoxp3+regulatory T cells (Tregs) are the central component of peripheral immune tolerance. While dysregulation of the Treg cytokine signature has been observed in autoimmune diseases such as multiple sclerosis (MS) and type 1 diabetes, the regulatory mechanisms balancing pro- and anti-inflammatory cytokine production are not known. Here, we identify imbalance between IFNγ and IL-10 as a shared Treg signature, present in patients with MS and under high salt conditions. By performing RNA-seq analysis on human Treg subpopulations, we identify β-catenin as a key regulator that controls the expression of IFNγ and IL-10. The activated β-catenin signature is enriched specifically in IFNγ+Tregs in humans, and this was confirmedin vivowith Treg-specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional, IFNγ-producing, Treg phenotype. Moreover, we identify PTGER2 as a major factor balancing IFNγ and IL-10 production in the context of a high salt environment, with skewed activation of the β-catenin/SGK1/Foxo axis in IFNγ+Tregs. These findings identify a novel molecular mechanism underlying inflammatory Tregs in human autoimmune disease and reveal a new role for a PTGER2-β-catenin loop in Tregs linking environmental high salt conditions to autoimmunity.
Profiling the surface proteome identifies actionable biology for TSC1 mutant cells beyond mTORC1 signaling
Authors: Wei Junnian , Leung Kevin K. , Truillet Charles , Ruggero Davide , Wells James A. , Evans Michael J. 
Published: August 2018

AbstractLoss of the TSC1/TSC2 complex leads to constitutively high mTORC1 signaling; however, pharmacological inhibition of mTORC1 in this setting produces a broad spectrum of clinical responses. We report herein several cell surface proteins upregulated by inactivation of TSC1 that present therapeutic alternatives or adjuvants to direct mTORC1 inhibition. A proteomics screen revealed that TSC1 loss most dramatically induced the expression of neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13). The survival of TSC1 null human cancer cells was dependent on NEP expression, and TSC1 mutation sensitized cells to biochemical inhibition of APN. Remarkably, NEP and APN upregulation occurred via a TSC2- and mTORC1-independent mechanism; therefore, the antiproliferative effects of mTORC1 inhibition could be augmented by co-suppression of APN activity.Statement of significanceThese data introduce a non-canonical biological role for TSC1 beyond regulating mTORC1 signaling, which also enabled several immediately translatable therapeutic strategies for clinically problematic cells with TSC1 mutations.
Large-Scale plurimodal networks common to listening, production and reading word-lists: an fmri study combining tasks-induced activation and intrinsic connectivity in 144 right-handers
Authors: Hesling I , Labache L , Joliot M , Tzourio-Mazoyer N 
Published: August 2018

AbstractEven if speech perception and production have been revealed to share a common recruitment of both discrete auditory and motor areas, this overlap being also common to reading and listening, no study has investigated the involvement of larger networks in the three tasks yet. So, we first identified the multimodal bilateral brain areas conjointly activated and asymmetrical during listening, production and reading of word-list using fMRI in 144 healthy right-handers (27 years ± 6 years). Such a selection made it possible to unravel 14 regions of the left hemisphere including motor, premotor and inferior parietal cortical areas. On the right, 7 regions were selected, including the posterior Human Voice Area (pHVA). To characterize the network organization within these 21 regions, we then analysed resting-state functional connectivity in 138 of the same participants. It allowed us to segregate a network of executive areas in relation with task completion from a bilateral WORD_CORE network composed of (1) all left areas supporting the action-perception cycle, in which articulatory gestures are the central motor units on which word perception, production, but also reading, would develop and act together according to the motor theory of speech; (2) the right pHVA, acting as a prosodic integrative area, underpinning the intertwining across hemispheres between prosodic (pHVA) and phonemic (left SMG) processing. The present results show that word processing, whatever the language modality involved, is based on a network of plurimodal areas hosting processes specific to each hemisphere and on their cooperation built upon synchronisation at rest.
A non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease
Authors: Dao Vu Thao-Vi , Elbatreek Mahmoud H. , Deile Martin , Nedvetsky Pavel I. , Güldner Andreas , Ibarra-Alvarado César , Gödecke Axel , Schmidt Harald H.H.W. 
Published: August 2018

AbstractNitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted for example in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase or exogenous NO from NO donor compounds decreased sGC protein and activity. This was not mediated by cGMP as the NO-independent sGC stimulator or direct activation of cGMP-dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent, N-acetyl-L-cysteine did not prevent this feedback. Instead, bothin-vitroandin-vivoand in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC whilst leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP-independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation.
Drosophilasmall ovarygene ensures germline stem cell maintenance and differentiation by silencing transposons and organising heterochromatin
Authors: Jankovics Ferenc , Bence Melinda , Sinka Rita , Faragó Anikó , Bodai László , Pettkó-Szandtner Aladár , Ibrahim Karam , Takács Zsanett , Szarka-Kovács Alexandra Brigitta , Erdélyi Miklós 
Published: August 2018

AbstractSelf-renewal and differentiation of stem cells is one of the fundamental biological phenomena relying on proper chromatin organisation. In our study, we describe a novel chromatin regulator encoded by theDrosophila small ovary (sov)gene. We demonstrate thatsovis required in both the germline stem cells (GSCs) and the surrounding somatic niche cells to ensure GSC survival and differentiation.Sovmaintains niche integrity and function by repressing transposon mobility, not only in the germline, but also in the soma. Protein interactome analysis of Sov revealed a physical interaction between Sov and HP1a. In the germ cell nuclei, Sov co-localises with HP1a, suggesting that Sov affects transposon repression as a component of the heterochromatin. In a position effect variegation assay, we found a dominant genetic interaction betweensovand HP1a, indicating their functional cooperation in promoting the spread of heterochromatin. Anin vivotethering assay and FRAP analysis revealed that Sov enhances heterochromatin formation by supporting the recruitment of HP1a to the chromatin. We propose a model in whichsovmaintains GSC niche integrity by regulating piRNA-mediated transposon silencing as a heterochromatin regulator.Summary statementSmall ovarymaintains the integrity of the stem cell niche by regulating piRNA-mediated transposon silencing acting as a key component of the heterochromatin.
DOT1L inhibition reveals a distinct class of enhancers dependent on H3K79 methylation
Authors: Godfrey Laura , Crump Nicholas T. , Thorne Ross , Lau I-Jun , Repapi Emmanouela , Dimou Dimitra , Telenius Jelena M. , Oudelaar A. Marieke , Downes Damien J. , Vyas Paresh , Hughes Jim R. , Milne Thomas A. 
Published: August 2018

SummaryEnhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to identify and subcategorize enhancers. Here we identify a distinct subset of enhancers in leukemia cells that are functionally dependent upon H3K79me3. Using the DOT1L inhibitor, EPZ-5676, we show that loss of H3K79me3 at these H3K79me3 enhancer elements (KEEs) leads to reduced chromatin accessibility, histone acetylation and transcription factor binding. We then use Capture-C, a high-resolution chromosome conformation capture technique, to show that H3K79me3 is required for KEE interactions with the promoter as well as transcription of the associated genes. Together these data implicate H3K79me3 in having a functional role at a subset of active enhancers where it helps maintain histone acetylation and chromatin accessibility, potentially by promoting phase-separated condensates.
(-)-Epigallocatechin-3-gallate inhibition of Epstein-Barr virus lytic replication involves latent membrane protein 1-mediated MAPK signaling pathways
Authors: Li Hongde , Luo Xiangjian , Hu Jianmin , Liu Sufang , Li Namei , Tang Min , Weng Xinxiang , Yi Wei , Gao Jinghe , Bode Ann M. , Dong Zigang , Cao Ya 
Published: August 2018

AbstractEBV lytic replication has been shown to be important for carcinogenesis. Latent membrane protein 1 (LMP1) plays an important role in the viral latent infection and is abundantly expressed after EBV entry into the lytic cycle. However, the biological significance of LMP1 continuous expression in EBV lytic cycle is still not completely understood. We found that LMP1 promotes EBV reactivation by activating the downstream MAPK signaling in both AGS-EBV and B95.8 cells. In AGS-EBV cells, LMP1 induces EBV the initiation of the EBV lytic cycle in a p53 dependent manner. Activation of c-Jun by LMP1 through JNKs appears to be involved in EBV reactivation in p53 mutant B95.8 cells. We also demonstrated that EGCG, an anti-EBV agent, inhibits LMP1 expression and the activation of the downstream MAPK signaling pathways, followed by downregulation of EBV lytic protein expression level. Together, this study provides the first evidence that LMP1 promotes EBV reactivation via activation of the MAPK signaling pathways. Our findings further demonstrate that the mechanisms underlying EGCG inhibition of the EBV lytic replication involve the suppression of LMP1-mediated MAPK signaling pathways.Summary statementThis study definitely confirms the role of LMP1 in EBV reactivation and further explores the mechanism by which EGCG inhibits EBV lytic replication.
Alteration of the social and spatial organization of the vector of Chagas disease,Triatoma infestans, by the parasiteTrypanosoma cruzi
Authors: Depickère Stéphanie , Ramírez-Ávila Gonzalo Marcelo , Deneubourg Jean-Louis 
Published: August 2018

AbstractInsects of Triatominae subfamily are vectors of the parasiteTrypanosoma cruzi, the etiological agent of Chagas disease affecting millions of people in Latin America. Some of these vector species, likeTriatoma infestans, live in the human neighborhood, aggregating in walls or roof cracks during the day and going out to feed on animal or human blood at night. Except for their feeding specialization, these insects share this cycle of activities with many gregarious arthropod species. The understanding of how sex andT. cruziinfection affect their aggregation and geotaxis behavior is essential for understanding the spatial organization of the insects and the parasite dispersion. Experiments with non-infected and infected adults ofT. infestansshow that the insects presented a high negative geotaxis and aggregative behavior. Males had a higher negative geotaxis and a higher aggregation level than females. The aggregation level and the negative geotaxis were stronger in infected insects than in non-infected ones, the difference between sexes being maintained. The importance of these results is discussed in term of parasitic manipulation, dispersion of the vector and strategy of its monitoring.
Accurate Reference-Free Somatic Variant-Calling by Integrating Genomic, Sequencing and Population Data
Authors: Sun Ren X. , Lalansingh Christopher M. , Espiritu Shadrielle Melijah G. , Yao Cindy Q. , Yamaguchi Takafumi N. , Prokopec Stephenie D. , Szyca Lesia , Houlahan Kathleen E. , Heisler Lawrence E. , Black Morgan , Li Constance H. , Barrett John W. , Nichols Anthony C. , Boutros Paul C. 
Published: August 2018

ABSTRACTThe detection of somatic single nucleotide variants (SNVs) is critical in both research and clinical applications. Studies of human cancer typically use matched normal (reference) samples from a distant tissue to increase SNV prediction accuracy. This process both doubles sequencing costs and poses challenges when reference samples are not readily available, such as for many cell-lines. To address these challenges, we created S22S: an approach for the prediction of somatic mutations without need for matched reference tissue. S22S takes underlying sequence data, augments them with genomic background context and population frequency information, and classifies SNVs as somatic or non-somatic. We validated S22S using primary tumor/normal pairs from four tumor types, spanning two different sequencing technologies. S22S robustly identifies somatic SNVs, with the area under the precision recall curve reaching 0.97 in kidney clear cell carcinoma, comparable to the best tumor/normal analysis pipelines. S22S is freely available at http://labs.oicr.on.ca/Boutros-lab/software/s22s.
Rift Valley fever virus induces fetal demise through direct placental infection
Authors: McMillen Cynthia M. , Arora Nitin , Boyles Devin A. , Albe Joseph R. , Kujawa Michael R. , Bonadio Jeffrey F. , Coyne Carolyn B. , Hartman Amy L. 
Published: August 2018

AbstractRift Valley fever virus (RVFV) infections in pregnant livestock are associated with high rates of fetal demise and have been linked to miscarriage in pregnant women. To address how acute RVFV infection during pregnancy causes detrimental effects on the fetus, we developed an immunocompetent pregnant rodent model of RVFV infection. We found that pregnant rats were more susceptible to RVFV-induced death than their non-pregnant counterparts and that RVFV infection resulted in intrauterine fetal death and severe congenital abnormalities, even in pups from infected asymptomatic pregnant rats. Virus distribution in infected dams was widespread, with a previously unrecognized preference for infection, replication, and tissue damage in the placenta. In human mid-gestation placental tissue, RVFV directly infected placental chorionic villi, with replication detected in the outermost syncytial layer. Our work identifies direct placental infection by RVFV as a mechanism for vertical transmission and points to the teratogenic potential of this virus in humans. This is the first time vertical transmission of RVFV has been shown in species other than livestock. This study highlights the potential impact of a future epidemic of this emerging mosquito-borne virus.