bluuebunny/crossref_metadata_2025_split huggingface dataset:
TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus
Authors: Zhang Jiawei , Liu Yu , Zheng Yaling , Luo Yan , Du Yu , Zhao Yao , Guan Jian , Zhang Xiaojie , Fu Jianliang 
Published: January 2020

Abstract
Background
Diabetes mellitus (DM) and chronic cerebral hypoperfusion(CCH)are both risk factors for cognitive impairment. However, whether DM and CCH can synergistically promote cognitive impairment and the related pathological mechanisms remain unknown.

Methods
To investigate the effect of DM and CCH on cognitive function, rats fed with high-fat diet (HFD) and injected with low-dose streptozotocin (STZ) followed by bilateral common carotid artery occlusion (BCCAO) were induced to mimic DM and CCH in vivo and mouse BV2 microglial cells were exposed to hypoxia and/or high glucose to mimic CCH complicated with DM pathologies in vitro. To further explore the underlying mechanism, TREM-2-specific small interfering RNA and TREM-2 overexpression lentivirus were used to knock out and overexpress TREM-2, respectively.

Results
Cognitive deficits, neuronal cell death, neuroinflammation with microglial activation, and TREM-2-MAPK signaling were enhanced when DM was superimposed on CCH both in vivo and in vitro. Manipulating TREM-2 expression levels markedly regulated the p38 MAPK signaling and the inflammatory response in vitro. TREM-2 knockout intensified while TREM-2 overexpression suppressed the p38 MAPK signaling and subsequent pro-inflammatory mediator production under high glucose and hypoxia condition.

Conclusions
These results suggest that TREM-2 negatively regulates p38 MAPK-mediated inflammatory response when DM was synergistically superimposed on CCH and highlight the importance of TREM-2 as a potential target of immune regulation in DM and CCH.
Fractionated carbon ion irradiations of the rat spinal cord: comparison of the relative biological effectiveness with predictions of the local effect model
Authors: Saager Maria , Glowa Christin , Peschke Peter , Brons Stephan , Grün Rebecca , Scholz Michael , Debus Jürgen , Karger Christian P. 
Published: January 2020

Abstract
Background
To determine the relative biological effectiveness (RBE) and α/β-values after fractionated carbon ion irradiations of the rat spinal cord with varying linear energy transfer (LET) to benchmark RBE-model calculations.

Material and methods
The rat spinal cord was irradiated with 6 fractions of carbon ions at 6 positions within a 6 cm spread-out Bragg-peak (SOBP, LET: 16–99 keV/μm). TD50-values (dose at 50% complication probability) were determined from dose-response curves for the endpoint radiation induced myelopathy (paresis grade II) within 300 days after irradiation. Based on TD50-values of 15 MV photons, RBE-values were calculated and adding previously published data, the LET and fractional dose-dependence of the RBE was used to benchmark the local effect model (LEM I and IV).

Results
At six fractions, TD50-values decreased from 39.1 ± 0.4 Gy at 16 keV/μm to 17.5 ± 0.3 Gy at 99 keV/μm and the RBE increased accordingly from 1.46 ± 0.05 to 3.26 ± 0.13. Experimental α/β-ratios ranged from 6.9 ± 1.1 Gy to 44.3 ± 7.2 Gy and increased strongly with LET. Including all available data, comparison with model-predictions revealed that (i) LEM IV agrees better in the SOBP, while LEM I fits better in the entrance region, (ii) LEM IV describes the slope of the RBE within the SOBP better than LEM I, and (iii) in contrast to the strong LET-dependence, the RBE-deviations depend only weakly on fractionation within the measured range.

Conclusions
This study extends the available RBE data base to significantly lower fractional doses and performes detailed tests of the RBE-models LEM I and IV. In this comparison, LEM IV agrees better with the experimental data in the SOBP than LEM I. While this could support a model replacement in treatment planning, careful dosimetric analysis is required for the individual patient to evaluate potential clinical consequences.
Behavioral Economics Incentives to Support HIV Treatment Adherence (BEST): Protocol for a randomized controlled trial in Uganda
Authors: Linnemayr Sebastian , Stecher Chad , Saya Uzaib , MacCarthy Sarah , Wagner Zachary , Jennings Larissa , Mukasa Barbara 
Published: January 2020

Abstract
Background
Many HIV-positive patients do not appropriately adhere to their antiretroviral medication (ART). This leads to higher viral loads and greater probability of HIV transmission. Present bias—a tendency to give in to short-term temptations at the expense of long-term outcomes—is a potential driver of low adherence. In this study we test a novel intervention rooted in behavioral economics that is designed to overcome present bias and increase ART adherence.

Methods/design
We will enroll 330 HIV-positive patients at Mildmay Hospital in Kampala, Uganda, into a 2-year randomized controlled trial. Participants will be randomized to one of three groups. The first intervention group (T1, n = 110) will be eligible for small lottery prizes based on timely clinic visits and demonstration of viral suppression. Group 2 (T2, n = 110) will be eligible for the same lottery prizes conditional on high adherence measured by a medication event management system (MEMS) cap. The control group (n = 110) will receive the usual standard of care. Adherence will be measured continuously throughout the intervention period and for 12 months post-intervention to evaluate effect persistence. Surveys will be conducted at baseline and then every 6 months. Viral loads will be measured annually. Primary outcomes are whether the viral load is detectable and MEMS-measured adherence. Secondary outcomes are the log-transformed viral load as a continuous measure and a binary measure for whether the person took at least 90% of their ART pills.

Discussion
Our study is one of the first to investigate the effectiveness of lottery incentives for improving ART adherence, and in addition, it compares the relative efficacy of using electronically measured adherence versus viral load to determine lottery eligibility. MEMS caps are relatively costly, whereas viral load testing is now part of routine clinical care in Uganda. BEST will test whether directly incentivizing viral suppression (which can be implemented using readily available clinic data) is as effective as incentivizing electronically measured adherence. Cost-effectiveness analyses of the two implementation modes will also be performed.

Trial registration
ClinicalTrials.gov, NCT03494777. Registered on 11 April 2018.
Enhanced quantitative urine culture technique, a slight modification, in detecting under-diagnosed pediatric urinary tract infection
Authors: Thapaliya Januka , Khadka Priyatam , Thapa Shovana , Gongal Chenu 
Published: January 2020

Abstract
Objectives
The pediatric urinary tract infection (UTI) often remains under-diagnosed or neglected owing to non-specific clinical presentations, patients failing to describe the actual situation and of clinical practice in diagnosis. The study was aimed to determine the etiologies of UTI in children with enhanced quantitative urine culture (EQUC) technique.

Results
Of enrolled 570 pediatric urine samples, the significant growth positivity was higher in EQUC 92 (16.15%) compared to standard urine culture (SUC) 73 (12.80%) technique. 20.6% of the significant isolates as detected with EQUC were missed on the SUC technique. The age group, in range 1–4 years, was more prone to the infection, where E. coli was the commonest pathogen. EQUC detected, probably all isolates, contributing UTI i.e. multidrug-resistant (MDR), extensive drug-resistant (XDR), and extended-spectrum β-lactamase (ESBL) producers, as some of them skipped on the SUC technique. Of total organisms isolated from EQUC, 46% were ESBL producer, 56.5% were MDR, and 1.4% were XDR. However, 40.5% ESBL, 44% MDR but no XDR detected on SUC. Hence a simple modification on conventional culture protocol could be a crucial modification for the detection of etiologies, contributing UTI, and hence to reduce inapt antimicrobial burden.
Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk
Authors: Wang Ting , Maden Sean K. , Luebeck Georg E. , Li Christopher I. , Newcomb Polly A. , Ulrich Cornelia M. , Joo Ji-Hoon E. , Buchanan Daniel D. , Milne Roger L. , Southey Melissa C. , Carter Kelly T. , Willbanks Amber R. , Luo Yanxin , Yu Ming , Grady William M. 
Published: January 2020

Abstract
Background
Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual’s susceptibility to age-related diseases such as CRC.

Methods
We conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual’s chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk.

Results
Each epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10−30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group.

Conclusions
Among the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.
Combining molecular and imaging metrics in cancer: radiogenomics
Authors: Lo Gullo Roberto , Daimiel Isaac , Morris Elizabeth A. , Pinker Katja 
Published: January 2020

Abstract
Background
Radiogenomics is the extension of radiomics through the combination of genetic and radiomic data. Because genetic testing remains expensive, invasive, and time-consuming, and thus unavailable for all patients, radiogenomics may play an important role in providing accurate imaging surrogates which are correlated with genetic expression, thereby serving as a substitute for genetic testing.

Main body
In this article, we define the meaning of radiogenomics and the difference between radiomics and radiogenomics. We provide an up-to-date review of the radiomics and radiogenomics literature in oncology, focusing on breast, brain, gynecological, liver, kidney, prostate and lung malignancies. We also discuss the current challenges to radiogenomics analysis.

Conclusion
Radiomics and radiogenomics are promising to increase precision in diagnosis, assessment of prognosis, and prediction of treatment response, providing valuable information for patient care throughout the course of the disease, given that this information is easily obtainable with imaging. Larger prospective studies and standardization will be needed to define relevant imaging biomarkers before they can be implemented into the clinical workflow.
Study of breast implants mammography examinations for identification of suitable image quality criteria
Authors: Sá dos Reis Cláudia , Gremion Isabelle , Richli Meystre Nicole 
Published: January 2020

Abstract
Purpose
To characterise the mammography technique used in breast cancer screening programmes for breast implants (BI) and to identify if the image quality (IQ) criteria available in literature are applicable to BI imaging.

Methods
The study was conducted in two phases: literature review to find IQ criteria used in mammography combining keywords in several sources; and assessment of 1207 BI mammograms using the criteria that was identified previously to see if they were achieved or not. An observation grid was used to collect information about positioning, beam energy, compression force, and exposure mode. Descriptive statistics and Student’s t test and χ2 test were performed according to the nature of the variables.

Results
Forty-seven out of 2188 documents were included in the analysis, with 13 items identified to assess the quality of positioning, 4 for sharpness, 3 for artefacts, and 2 for exposure parameters. After applying the criteria to BI mammograms, retroglandular fat was not included in 37.3% of the images. The “Pectoral-Nipple-Line” criterion was achieved in 35% of MLO/ML images. The placement of the implant (subpectoral/subglandular) or performing the Eklund had significant influence on the visible anatomy (p = < 0.005), alongside whether the breast was aligned to the detector’s centre.

Conclusions
Some of the criteria used to assess standard mammograms were not applicable to BI due to implant overlap. The alignment of the image with the detector’s centre seems to have an impact on the amount of visible tissue. Further studies are necessary to define the appropriate protocol, technique, and suitable quality criteria to assess BI mammograms.
Imaging indications and findings in evaluation of lung transplant graft dysfunction and rejection
Authors: Bin Saeedan Mnahi , Mukhopadhyay Sanjay , Lane C. Randall , Renapurkar Rahul D. 
Published: January 2020

AbstractLung transplantation is a treatment option in end-stage lung disease. Complications can develop along a continuum in the immediate or longer post-transplant period, including surgical and technical complications, primary graft dysfunction, rejection, infections, post-transplant lymphoproliferative disorder, and recurrence of the primary disease. These complications have overlapping clinical and imaging features and often co-exist. Time of onset after transplant is helpful in narrowing the differential diagnosis. In the early post transplantation period, imaging findings are non-specific and need to be interpreted in the context of the clinical picture and other investigations. In contrast, imaging plays a key role in diagnosing and monitoring patients with chronic lung allograft dysfunction. The goal of this article is to review primary graft dysfunction, acute rejection, and chronic rejection with emphasis on the role of imaging, pathology findings, and differential diagnosis.
Alteration of fatty acid oxidation by increased CPT1A on replicative senescence of placenta-derived mesenchymal stem cells
Authors: Seok Jin , Jung Hyun Sook , Park Sohae , Lee Jung Ok , Kim Chong Jai , Kim Gi Jin 
Published: January 2020

Abstract
Background
Human placenta-derived mesenchymal stem cells (PD-MSCs) are powerful sources for cell therapy in regenerative medicine. However, a limited lifespan by senescence through mechanisms that are well unknown is the greatest obstacle. In the present study, we first demonstrated the characterization of replicative senescent PD-MSCs and their possible mitochondrial functional alterations.

Methods
Human PD-MSCs were cultured to senescent cells for a long period of time. The cells of before passage number 8 were early cells and after passage number 14 were late cells. Also, immortalized cells of PD-MSCs (overexpressed hTERT gene into PD-MSCs) after passage number 14 were positive control of non-senescent cells. The characterization and mitochondria analysis of PD-MSCs were explored with long-term cultivation.

Results
Long-term cultivation of PD-MSCs exhibited increases of senescent markers such as SA-β-gal and p21 including apoptotic factor, and decreases of proliferation, differentiation potential, and survival factor. Mitochondrial dysfunction was also observed in membrane potential and metabolic flexibility with enlarged mitochondrial mass. Interestingly, we founded that fatty acid oxidation (FAO) is an important metabolism in PD-MSCs, and carnitine palmitoyltransferase1A (CPT1A) overexpressed in senescent PD-MSCs. The inhibition of CPT1A induced a change of energy metabolism and reversed senescence of PD-MSCs.

Conclusions
These findings suggest that alteration of FAO by increased CPT1A plays an important role in mitochondrial dysfunction and senescence of PD-MSCs during long-term cultivation.
Age-dependent impairment of adipose-derived stem cells isolated from horses
Authors: Alicka Michalina , Kornicka-Garbowska Katarzyna , Kucharczyk Katarzyna , Kępska Martyna , Rӧcken Michael , Marycz Krzysztof 
Published: January 2020

Abstract
Background
Progressive loss of cell functionality caused by an age-related impairment in cell metabolism concerns not only mature specialized cells but also its progenitors, which significantly reduces their regenerative potential. Adipose-derived stem cells (ASCs) are most commonly used in veterinary medicine as an alternative treatment option in ligaments and cartilage injuries, especially in case of high-value sport horses. Therefore, the main aim of this study was to identify the molecular alternations in ASCs derived from three age-matched horse groups: young (< 5), middle-aged (5–15), and old (> 15 years old).

Methods
ASCs were isolated from three age-matched horse groups using an enzymatic method. Molecular changes were assessed using qRT-PCR, ELISA and western blot methods, flow cytometry-based system, and confocal and scanning electron microscopy.

Results
Our findings showed that ASCs derived from the middle-aged and old groups exhibited a typical senescence phenotype, such as increased percentage of G1/G0-arrested cells, binucleation, enhanced β-galactosidase activity, and accumulation of γH2AX foci, as well as a reduction in cell proliferation. Moreover, aged ASCs were characterized by increased gene expression of pro-inflammatory cytokines and miRNAs (interleukin 8 (IL-8), IL-1β, tumor necrosis factor α (TNF-α), miR-203b-5p, and miR-16-5p), as well as apoptosis markers (p21, p53, caspase-3, caspase-9). In addition, our study revealed that the protein level of mitofusin 1 (MFN1) markedly decreased with increasing age. Aged ASCs also displayed a reduction in mRNA levels of genes involved in stem cell homeostasis and homing, like TET-3, TET-3 (TET family), and C-X-C chemokine receptor type 4 (CXCR4), as well as protein expression of DNA methyltransferase (DNMT1) and octamer transcription factor 3/4 (Oct 3/4). Furthermore, we observed a higher splicing ratio of XBP1 (X-box binding protein 1) mRNA, indicating elevated inositol-requiring enzyme 1 (IRE-1) activity and, consequently, increased endoplasmic reticulum (ER) stress. We also observed reduced levels of glucose transporter 4 (GLUT-4) and insulin receptor (INSR) which indicated impaired insulin sensitivity.

Conclusions
Obtained data suggest that ASCs derived from horses older than 5 years old exhibited several molecular alternations which markedly limit their regenerative capacity. The results provide valuable information that allows for a better understanding of the molecular events occurring in ASCs in the course of aging and may help to identify new potential drug targets to restore their regenerative potential.

Graphical abstract
Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products
Authors: Laggner Maria , Gugerell Alfred , Bachmann Christiane , Hofbauer Helmut , Vorstandlechner Vera , Seibold Marcus , Gouya Lechner Ghazaleh , Peterbauer Anja , Madlener Sibylle , Demyanets Svitlana , Sorgenfrey Dirk , Ostler Tobias , Erb Michael , Mildner Michael , Ankersmit Hendrik Jan 
Published: January 2020

Abstract
Background
The recent concept of secretome-based tissue regeneration has profoundly altered the field of regenerative medicine and offers promising novel therapeutic options. In contrast to medicinal products with a single active substance, cell-derived secretomes comprise pleiotropic bioactive ingredients, representing a major obstacle for reproducible drug product efficacy and warranting patient safety. Good manufacturing practice (GMP)-compliant production guarantees high batch-to-batch consistency and reproducible efficacy of biological medicinal products, but different batches of cellular secretomes produced under GMP have not been compared yet, and suitable quality control parameters have not been established. To this end, we analyzed diverse biological and functional parameters of different batches produced under GMP of the secretome obtained from γ-irradiated peripheral blood mononuclear cells with proven tissue regenerative properties in infarcted myocardium, stroke, spinal cord injury, and skin wounds.

Methods
We quantified key secretome ingredients, including cytokines, lipids, and extracellular vesicles, and functionally assessed potency in tube formation assay, ex vivo aortic ring sprouting assay, and cell-based protein and reporter gene assays. Furthermore, we determined secretome stability in different batches after 6 months of storage at various ambient temperatures.

Results
We observed that inter-batch differences in the bioactive components and secretome properties were small despite considerable differences in protein concentrations and potencies between individual donor secretomes. Stability tests showed that the analytical and functional properties of the secretomes remained stable when lyophilisates were stored at temperatures up to + 5 °C for 6 months.

Conclusions
We are the first to demonstrate the consistent production of cell-derived, yet cell-free secretome as a biological medicinal product. The results from this study provide the basis for selecting appropriate quality control parameters for GMP-compliant production of therapeutic cell secretomes and pave the way for future clinical trials employing secretomes in tissue regenerative medicine.