bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting mTORC1/2 with OSI‐027 inhibits proliferation and migration of keloid keratinocytes
Authors: Chen Jun , Liu Ke , Liu Yang , Wang Xue , Zhang Zhen 
Published: January 2019

AbstractKeloid is a dermal proliferative disorder characterized by the excessive proliferation and migration of keratinocytes and fibroblasts. Over‐activation of the serine/threonine protein kinase, mammalian target of rapamycin (mTOR), plays a pivotal role in the process. Here, we show that both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) were hyper‐activated in keloid‐derived primary keratinocytes. Further, OSI‐027, an mTOR kinase inhibitor, potently inhibited proliferation and migration of keloid keratinocytes. At the molecular level, OSI‐027 disrupted the assembly of mTORC1 (mTOR–Raptor) and mTORC2 (mTOR–Rictor–mLST8). Further, OSI‐027 almost completely blocked the phosphorylation of the mTORC1 substrates, S6K1, S6 and 4EBP1, and the mTORC2 substrate, AKT, at Ser‐473. The OSI‐027 treatment of keloid keratinocytes showed more effectively inhibited cell proliferation and migration compared to the mTORC1 inhibitor, rapamycin. Moreover, restoring mTORC1 activation by the introduction of the constitutively active S6K1 only partly alleviated OSI‐027‐induced inhibition of keloid keratinocytes. Notably, mTOR2 inhibition by Rictor siRNAs also inhibited keloid keratinocyte proliferation and migration, but less efficiently than OSI‐027. Together, our results imply that concurrent targeting of mTORC1/2 by OSI‐027 potently inhibits the proliferation and the migration of keloid keratinocytes. Thus, OSI‐027 may have translational value for the treatment of keloid.
TGFβ1‐induced cell motility but not cell proliferation is mediated through Cten in colorectal cancer
Authors: Asiri Abdulaziz , Raposo Teresa Pereira , Alfahed Abdulaziz , Ilyas Mohammad 
Published: January 2019

SummaryCten (C‐terminal tensin‐like) is a member of the tensin protein family found in complex with integrins at focal adhesions. It promotes epithelial‐mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although we and others have shown that Cten could be under the regulation of several cytokines and growth factors. Since transforming growth factor beta 1 (TGF‐β1) regulates integrin function and promotes EMT/cell motility, we were prompted to investigate whether TGF‐β1 induces EMT and cell motility through Cten signalling in colorectal cancer. TGF‐β1 signalling was modulated by either stimulation with TGF‐β1 or knockdown of TGF‐β1 in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and on cellular function was tested. The role of Cten as a direct mediator of TGF‐β1 signalling was investigated in a CRC cell line in which the Cten gene had been deleted (SW620ΔCten). When TGF‐β1 was stimulated or inhibited, this resulted in, respectively, upregulation and downregulation of Cten expression and EMT markers (Snail, Rock, N‐cadherin, Src). Cell migration and cell invasion were significantly increased following TGF‐β1 stimulation and lost by TGF‐β1 knockdown. TGF‐β1 stimulation of the SW620ΔCten cell line resulted in selective loss of the effect of TGF‐β1 signalling pathway on EMT and cell motility while the stimulatory effect on cell proliferation was retained. These data suggested Cten may play an essential role in mediating TGF‐β1‐induced EMT and cell motility and may therefore play a role in metastasis in CRC.
The importance of theDSM‐5posttraumatic stress disorder symptoms of cognitions and mood in traumatized children and adolescents: two network approaches
Authors: Bartels Lasse , Berliner Lucy , Holt Tonje , Jensen Tine , Jungbluth Nathaniel , Plener Paul , Risch Elizabeth , Rojas Roberto , Rosner Rita , Sachser Cedric 
Published: January 2019

BackgroundThe aim of this study is to provide a better understanding of the central symptoms ofDSM‐5posttraumatic stress disorder (PTSD) in children and adolescents from the perspective of the child and its caregiver. Identifying core symptoms ofPTSDcan help clinicians to understand what may be relevant targets for treatment.PTSDmay present itself differently in children and adolescents compared to adults, and no study so far has investigated theDSM‐5PTSDconceptualization using network analysis.MethodsThe network structure ofDSM‐5PTSDwas investigated in a clinical sample ofn = 475 self‐reports of children and adolescents andn = 424 caregiver‐reports using (a) regularized partial correlation models and (b) a Bayesian approach computing directed acyclic graphs (DAGs).Results(a) The 20DSM‐5PTSDsymptoms were positively connected within the self‐report and the caregiver‐report sample. The most central symptoms werenegative trauma‐related cognitionsandpersistent negative emotional statefor the self‐report andnegative trauma‐related cognitions,intrusive thoughts or memoriesandexaggerated startle responsefor the caregiver‐report. (b) Similarly, symptoms in the negative alterations in cognitions and mood cluster (NACM) have emerged as key drivers of other symptoms in traumatized children and adolescents.ConclusionsAs the symptoms in theDSM‐5NACMcluster were central in our regularized partial correlation networks and also appeared to be the driving forces in theDAGs, these might represent important symptoms withinPTSDsymptomatology and may offer key targets inPTSDtreatment for children and adolescents.
Inhibition of TFEB oligomerization by co‐treatment of melatonin with vorinostat promotes the therapeutic sensitivity in glioblastoma and glioma stem cells
Authors: Sung Gi‐Jun , Kim Sung‐Hak , Kwak Sungmin , Park Seung‐Ho , Song Ji‐Hye , Jung Ji‐Hoon , Kim Hyunhee , Choi Kyung‐Chul 
Published: January 2019

AbstractGlioblastoma (GBM) is the most aggressive malignant glioma and most lethal form of human brain cancer (Clin J Oncol Nurs. 2016;20:S2). GBM is also one of the most expensive and difficult cancers to treat by the surgical resection, local radiotherapy, and temozolomide (TMZ) and still remains an incurable disease. Oncomine platform analysis and Gene Expression Profiling Interactive Analysis (GEPIA) show that the expression of transcription factor EB (TFEB) was significantly increased in GBMs and in GBM patients above stage IV. TFEB requires the oligomerization and localization to regulate transcription in the nucleus. Also, the expression and oligomerization of TFEB proteins contribute to the resistance of GBM cells to conventional chemotherapeutic agents such as TMZ. Thus, we investigated whether the combination of vorinostat and melatonin could overcome the effects of TFEB and induce apoptosis in GBM cells and glioma cancer stem cells (GSCs). The downregulation of TFEB and oligomerization by vorinostat and melatonin increased the expression of apoptosis‐related genes and activated the apoptotic cell death process. Significantly, the inhibition of TFEB expression dramatically decreased GSC tumor‐sphere formation and size. The inhibitory effect of co‐treatment resulted in decreased proliferation of GSCs and induced the expression of cleaved PARP and p‐γH2AX. Taken together, our results definitely demonstrate that TFEB expression contributes to enhanced resistance of GBMs to chemotherapy and that vorinostat‐ and melatonin‐activated apoptosis signaling in GBM cells by inhibiting TFEB expression and oligomerization, suggesting that co‐treatment of vorinostat and melatonin may be an effective therapeutic strategy for human brain cancers.
Sleep Quality and the Stress‐Buffering Role of Religious Involvement: A Mediated Moderation Analysis
Authors: Ellison Christopher G. , Deangelis Reed T. , Hill Terrence D. , Froese Paul 
Published: January 2019

AbstractAlthough several studies have documented an inverse association between stressful events and sleep quality, much less is known about the factors that might moderate or buffer against the adverse effects of psychosocial stress on sleep. Building on previous research, we employ national cross‐sectional survey data from the 2017 Baylor Religion Survey (n= 1,410) to test whether the association between recent stressful events and sleep quality varies according to several dimensions of religious involvement. We also formally assess whether any attenuation of the association between stressful events and sleep quality is at least partially mediated or explained by lower levels of depressive symptoms (mediated moderation). Our moderation analyses indicate that the inverse association between stressful events and sleep quality is in fact attenuated by religious cognitions (secure attachment to God and assurance of salvation), but not religious attendance or private religiousness. We also observe direct evidence of mediated moderation through depressive symptoms for both religious cognitions. Taken together, our results demonstrate that religious cognitions may buffer against stress‐related sleep disturbance by helping people avoid symptoms of depression.
Social Dimensions and Processes in Second Language Acquisition: Multilingual Socialization in Transnational Contexts
Authors: DUFF PATRICIA A. 
Published: January 2019

AbstractSocial aspects of second language acquisition (SLA) and the contexts in which people attempt to learn and use languages and seek to become integrated within new and changing cultures have been examined for decades from various theoretical perspectives. In this article, I present some of the ways in which ‘social’ experience is being theorized in SLA and in broader fields that intersect with SLA, such as linguistic anthropology. I then discuss how the Douglas Fir Group (DFG, 2016) originally portrayed the many interlinking factors affecting SLA in our multilingual world on several analytic levels and suggest ways of perhaps reconceptualizing the model while retaining its powerful heuristic value. Next, I describe language socialization research as 1 productive social approach and provide examples of research in 2 transnational domains—study abroad and heritage language learning—that demonstrate a multiscalar approach to examining social dimensions of language development and use. The article ends with a discussion of transdisciplinarity in SLA research. I suggest possibilities for team‐based research projects that aim to understandcasesfrom multiple, integrated perspectives on different scales of analysis, and then provide a brief reflection on some of the troubling political ideologies that SLA researchers who embrace multilingualism must now confront on a daily basis.
Genotype and rhizobium inoculation modulate the assembly of soybean rhizobacterial communities
Authors: Zhong Yongjia , Yang Yongqing , Liu Peng , Xu Ruineng , Rensing Christopher , Fu Xiangdong , Liao Hong 
Published: January 2019

AbstractRhizosphere bacterial communities are vital for plants, yet the composition of rhizobacterial communities and the complex interactions between roots and microbiota, or between microbiota, are largely unknown. In this study, we investigated the structure and composition of rhizobacterial communities in two soybean cultivars and their recombinant inbred lines contrasting in nodulation through 16S rRNA amplicon sequencing in two years of field trials. Our results demonstrate that soybean plants are able to select microbes from bulk soils at the taxonomic and functional level. Soybean genotype significantly influenced the structure of rhizobacterial communities and resulted in dramatically different co‐occurrence networks of rhizobacterial communities between different genotypes of soybean plants. Furthermore, the introduction of exogenous rhizobia through inoculation altered soybean rhizobacterial communities in genotype‐dependent manner. Rhizobium inoculation not only stimulated the proliferation of potential beneficial microbes but also increased connections in rhizobacterial networks and changed the hub microbes, all of which led to the association of distinctive bacterial communities. Taken together, we demonstrated that the assembly of soybean rhizobacterial communities was determined by both genotype and the introduction of exogenous rhizobia. These findings bolster the feasibility of root microbiome engineering through inoculation of specific microbial constituents.
Unscheduled bleeding with hormone replacement therapy
Authors: Dave Fulva Gajjar , Adedipe Tolu , Disu Stewart , Laiyemo Raphael 
Published: January 2019

Key content

Menopause is now considered as a mid‐life event. Hormone replacement therapy (HRT) is justified when menopausal symptoms adversely affect the quality of life of the individual woman.

Management of unscheduled bleeding with HRT remains a clinical challenge and leads to pressure on resources. The aim should be to exclude endometrial pathology and to regulate the bleeding pattern so that the woman's concerns are addressed and compliance maintained.

The mechanisms which underlie this unscheduled bleeding are poorly understood.

Appropriate counselling should be offered at the outset.

Learning objectives

To gain knowledge of the most appropriate HRT regimens used in perimenopausal, postmenopausal and hysterectomised women to minimise unscheduled bleeding.

To learn how to tailor the treatment regimen to the individual woman's situation.

Ethical issues

The lack of clinical evidence for managing unscheduled bleeding should be acknowledged.

Should clinicians initiate expensive and invasive investigations in all women with unscheduled bleeding on HRT or only select those with significant risk factors?
Fracture distribution on the Swift Reservoir Anticline, Montana: Implications for structural and lithological controls on fracture intensity
Authors: Watkins Hannah , Bond Clare E. , Cawood Adam J. , Cooper Mark A. , Warren Marian J. 
Published: January 2019

Abstract
Where primary porosity and permeability of a rock are unfavourable for hydrocarbon production, fractures can improve reservoir potential by enhancing permeability. Higher fracture intensity may create a better-connected fracture network, improving fractured-reservoir quality. Investigations into the controls on fracture intensity commonly conclude that either structural or lithological factors have the greatest influence on fracture abundance. We use the Swift Reservoir Anticline in northwestern Montana to investigate how fracture intensity varies throughout the structure and determine that although structural factors do influence fracture intensity, lithology is the main control at outcrop.
The Swift Reservoir Anticline exposes bedding surfaces of the Mississippian Castle Reef Formation dolomite. Field data indicates that fracture intensity is highest in the fold forelimb, decreasing into the backlimb except in outcrops of coarse dolomite where fracture intensity is low, regardless of structural position. Field fracture intensity correlates with whole-rock quartz, kaolinite and porosity percentages. We suggest porosity and composition influence bulk-rock mechanical properties, which, in turn, control the fracture intensity at outcrop. Fracture intensity has a stronger relationship with lithological than structural factors, therefore we suggest that the key to predicting fracture intensity in the subsurface here is understanding how lithology varies spatially.
Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia
Authors: Wang Wen-Tao , Han Cai , Sun Yu-Meng , Chen Zhen-Hua , Fang Ke , Huang Wei , Sun Lin-Yu , Zeng Zhan-Cheng , Luo Xue-Qun , Chen Yue-Qin 
Published: January 2019

Abstract

Purpose:
Despite many attempts to understand mixed-lineage leukemia (MLL leukemia), effective therapies for this disease remain limited. We identified a lysosome-associated membrane protein (LAMP) family member, LAMP5, that is specifically and highly expressed in patients with MLL leukemia. The purpose of the study was to demonstrate the functional relevance and clinical value of LAMP5 in the disease.

Experimental Design:
We first recruited a large cohort of leukemia patients to validate LAMP5 expression and evaluate its clinical value. We then performed in vitro and in vivo experiments to investigate the functional relevance of LAMP5 in MLL leukemia progression or maintenance.

Results:
LAMP5 was validated as being specifically and highly expressed in patients with MLL leukemia and was associated with a poor outcome. Functional studies showed that LAMP5 is a novel autophagic suppressor and protects MLL fusion proteins from autophagic degradation. Specifically targeting LAMP5 significantly promoted degradation of MLL fusion proteins and inhibited MLL leukemia progression in both an animal model and primary cells. We further revealed that LAMP5 is a direct target of the H3K79 histone methyltransferase DOT1L. Downregulating LAMP5 with a DOT1L inhibitor enhanced the selective autophagic degradation of MLL oncoproteins and extended survival in vivo; this observation was especially significant when combining DOT1L inhibitors with LAMP5 knockdown.

Conclusions:
This study demonstrates that LAMP5 serves as a “bodyguard” for MLL fusions to evade degradation and is the first to link H3K79 methylation to autophagy regulation, highlighting the potential of LAMP5 as a therapeutic target for MLL leukemia.
The Clonal Evolution of Metastatic Osteosarcoma as Shaped by Cisplatin Treatment
Authors: Brady Samuel W. , Ma Xiaotu , Bahrami Armita , Satas Gryte , Wu Gang , Newman Scott , Rusch Michael , Putnam Daniel K. , Mulder Heather L. , Yergeau Donald A. , Edmonson Michael N. , Easton John , Alexandrov Ludmil B. , Chen Xiang , Mardis Elaine R. , Wilson Richard K. , Downing James R. , Pappo Alberto S. , Raphael Benjamin J. , Dyer Michael A. , Zhang Jinghui 
Published: January 2019

Abstract

To investigate the genomic evolution of metastatic pediatric osteosarcoma, we performed whole-genome and targeted deep sequencing on 14 osteosarcoma metastases and two primary tumors from four patients (two to eight samples per patient). All four patients harbored ancestral (truncal) somatic variants resulting in TP53 inactivation and cell-cycle aberrations, followed by divergence into relapse-specific lineages exhibiting a cisplatin-induced mutation signature. In three of the four patients, the cisplatin signature accounted for &gt;40% of mutations detected in the metastatic samples. Mutations potentially acquired during cisplatin treatment included NF1 missense mutations of uncertain significance in two patients and a KIT G565R activating mutation in one patient. Three of four patients demonstrated widespread ploidy differences between samples from the sample patient. Single-cell seeding of metastasis was detected in most metastatic samples. Cross-seeding between metastatic sites was observed in one patient, whereas in another patient a minor clone from the primary tumor seeded both metastases analyzed. These results reveal extensive clonal heterogeneity in metastatic osteosarcoma, much of which is likely cisplatin-induced.

Implications:
The extent and consequences of chemotherapy-induced damage in pediatric cancers is unknown. We found that cisplatin treatment can potentially double the mutational burden in osteosarcoma, which has implications for optimizing therapy for recurrent, chemotherapy-resistant disease.
Long-Term Prognosis of Patients with Obscure Gastrointestinal Bleeding: A Retrospective Cohort Study
Authors: Arai Makoto , Matsumura Tomoaki , Ohta Yuki , Kiyono Soichiro , Hayashi Masahiro , Taida Takashi , Saito Keiko , Okimoto Kenichiro , Maruoka Daisuke , Nakagawa Tomoo , Katsuno Tatsuro , Kato Naoya , Takiguchi Yuichi 
Published: January 2019

Aims: We evaluated the long-term prognosis of patients with obscure gastrointestinal bleeding (OGIB) who underwent capsule endoscopy (CE). Methods: In our hospital, 429 patients underwent CE between November 2007 and March 2012. Among them, 259 patients underwent CE as the first examination for OGIB and were then followed at 77 clinics and hospitals. The clinical characteristics were investigated, including age, gender, overt/occult bleeding, the use of antithrombotic drugs and NSAIDs, complications (liver cirrhosis and hemodialysis), and CE. We asked the medical institutions for their survival data as of August 2017 (> 5 years after CE). Results: The prognoses of 240 patients (92.6%) were analyzed. The average follow-up period was 55.7 (1–115) months. During the follow-up period, 57 patients (23.8%) died and the survival rates were 90.5% at 1 year, 81.7% at 3 years, and 74.7% at 5 years. Age 65 years or older and liver cirrhosis were predictive factors for a poor prognosis. Rebleeding occurred in 42 patients (17.9%) and small bowel cancer and gastrointestinal stromal tumor were found at 12 and 21 months after CE, respectively. Conclusions: Patients with OGIB showed a poor prognosis, especially those who were elderly or who had liver cirrhosis.
Central Arterial Stiffness Is Associated With Structural Brain Damage and Poorer Cognitive Performance: The ARIC Study
Authors: Palta Priya , Sharrett A. Richey , Wei Jingkai , Meyer Michelle L. , Kucharska‐Newton Anna , Power Melinda C. , Deal Jennifer A. , Jack Clifford R. , Knopman David , Wright Jacqueline , Griswold Michael , Tanaka Hirofumi , Mosley Thomas H. , Heiss Gerardo 
Published: January 2019

Background
Central arterial stiffening and increased pulsatility, with consequent cerebral hypoperfusion, may result in structural brain damage and cognitive impairment.

Methods and Results

We analyzed a cross‐sectional sample of
ARIC
‐
NCS
(Atherosclerosis Risk in Communities–Neurocognitive Study) participants (aged 67–90 years, 60% women) with measures of cognition (n=3703) and brain magnetic resonance imaging (n=1255). Central arterial hemodynamics were assessed as carotid‐femoral pulse wave velocity and pressure pulsatility (central pulse pressure). We derived factor scores for cognitive domains. Brain
magnetic resonance imaging
using 3‐Tesla scanners quantified lacunar infarcts; cerebral microbleeds; and volumes of white matter hyperintensities, total brain, and the Alzheimer disease signature region. We used logistic regression, adjusted for demographics,
apolipoprotein E
ɛ4, heart rate, mean arterial pressure, and select cardiovascular risk factors, to estimate the odds of lacunar infarcts or cerebral microbleeds. Linear regression, additionally adjusted for intracranial volume, estimated the difference in log‐transformed volumes of
white matter hyperintensities
, total brain, and the
Alzheimer disease
signature region. We estimated the mean difference in cognitive factor scores across quartiles of carotid‐femoral pulse wave velocity or
central pulse pressure
using linear regression. Compared with participants in the lowest carotid‐femoral pulse wave velocity quartile, participants in the highest quartile of carotid‐femoral pulse wave velocity had a greater burden of
white matter hyperintensities
(
P
=0.007 for trend), smaller total brain volumes (−18.30 cm
3
; 95%
CI
, −27.54 to −9.07 cm
3
), and smaller
Alzheimer disease
signature region volumes (−1.48 cm
3
; 95%
CI
, −2.27 to −0.68 cm
3
). These participants also had lower scores in executive function/processing speed (β=−0.04
z
score; 95%
CI
, −0.07 to −0.01
z
score) and general cognition (β=−0.09
z
score; 95%
CI
, −0.15 to −0.03
z
score). Similar results were observed for
central pulse pressure
.

Conclusions
Central arterial hemodynamics were associated with structural brain damage and poorer cognitive performance among older adults.