bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic analysis of Spanish wheat landraces reveals their variability and potential for breeding
Authors: Pascual Laura , Ruiz Magdalena , López-Fernández Matilde , Pérez-Peña Helena , Benavente Elena , Vázquez José Francisco , Sansaloni Carolina , Giraldo Patricia
Published: February 2020

Background

One of the main goals of the plant breeding in the twenty-first century is the development of crop cultivars that can maintain current yields in unfavorable environments. Landraces that have been grown under varying local conditions include genetic diversity that will be essential to achieve this objective. The Center of Plant Genetic Resources of the Spanish Institute for Agriculture Research maintains a broad collection of wheat landraces. These accessions, which are locally adapted to diverse eco-climatic conditions, represent highly valuable materials for breeding. However, their efficient use requires an exhaustive genetic characterization. The overall aim of this study was to assess the diversity and population structure of a selected set of 380 Spanish landraces and 52 reference varieties of bread and durum wheat by high-throughput genotyping.

Results

The DArTseq GBS approach generated 10 K SNPs and 40 K high-quality DArT markers, which were located against the currently available bread and durum wheat reference genomes. The markers with known locations were distributed across all chromosomes with relatively well-balanced genome-wide coverage. The genetic analysis showed that the Spanish wheat landraces were clustered in different groups, thus representing genetic pools providing a range of allelic variation. The subspecies had a major impact on the population structure of the durum wheat landraces, with three distinct clusters that corresponded to subsp. durum, turgidum and dicoccon being identified. The population structure of bread wheat landraces was mainly biased by geographic origin.

Conclusions

The results showed broader genetic diversity in the landraces compared to a reference set that included commercial varieties, and higher divergence between the landraces and the reference set in durum wheat than in bread wheat. The analyses revealed genomic regions whose patterns of variation were markedly different in the landraces and reference varieties, indicating loci that have been under selection during crop improvement, which could help to target breeding efforts. The results obtained from this work will provide a basis for future genome-wide association studies.
Drought tolerance of the grapevine, Vitis champinii cv. Ramsey, is associated with higher photosynthesis and greater transcriptomic responsiveness of abscisic acid biosynthesis and signaling
Authors: Cochetel Noé , Ghan Ryan , Toups Haley S. , Degu Asfaw , Tillett Richard L. , Schlauch Karen A. , Cramer Grant R.
Published: February 2020

Background

Grapevine is an economically important crop for which yield and berry quality is strongly affected by climate change. Large variations in drought tolerance exist acrossVitisspecies. Some of these species are used as rootstock to enhance abiotic and biotic stress tolerance. In this study, we investigated the physiological and transcriptomic responses to water deficit of four different genotypes that differ in drought tolerance: Ramsey (Vitis champinii), Riparia Gloire (Vitis riparia), Cabernet Sauvignon (Vitis vinifera), and SC2 (Vitis vinifera x Vitis girdiana).

Results

Ramsey was particularly more drought tolerant than the other three genotypes. Ramsey maintained a higher stomatal conductance and photosynthesis at equivalent levels of moderate water deficit. We identified specific and common transcriptomic responses shared among the four differentVitisspecies using RNA sequencing analysis. A weighted gene co-expression analysis identified a water deficit core gene set with the ABA biosynthesis and signaling genes,NCED3,RD29BandABI1as potential hub genes. The transcript abundance of many abscisic acid metabolism and signaling genes was strongly increased by water deficit along with genes associated with lipid metabolism, galactinol synthases and MIP family proteins. This response occurred at smaller water deficits in Ramsey and with higher transcript abundance than the other genotypes. A number of aquaporin genes displayed differential and unique responses to water deficit in Ramsey leaves. Genes involved in cysteine biosynthesis and metabolism were constitutively higher in the roots of Ramsey; thus, linking the gene expression of a known factor that influences ABA biosynthesis to this genotype’s increasedNCED3transcript abundance.

Conclusion

The drought tolerant Ramsey maintained higher photosynthesis at equivalent water deficit than the three other grapevine genotypes. Ramsey was more responsive to water deficit; its transcriptome responded at smaller water deficits, whereas the other genotypes did not respond until more severe water deficits were reached. There was a common core gene network responding to water deficit for all genotypes that included ABA metabolism and signaling. The gene clusters and sub-networks identified in this work represent interesting gene lists to explore and to better understand drought tolerance molecular mechanisms.
Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy
Authors: Jin Bo , Shi Haiming , Zhu Jun , Wu Bangwei , Geshang Quzhen
Published: February 2020

Background

Autophagy plays a crucial role in the pathological process of cardiovascular diseases. However, little is known about the pathological mechanism underlying autophagy regulation in dilated cardiomyopathy (DCM).

Methods

We explored whether up-regulating autophagy could improve cardiac function in mice with experimental DCM through the mTOR-4EBP1 pathway. Animal model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Both up- or down-regulation of autophagy were studied by administration of rapamycin or 3-MA in parallel. Morphology, Western blotting, and echocardiography were applied to confirm the pathological mechanisms.

Results

Autophagy was activated and autophagosomes were significantly increased in the rapamycin group. The collagen volume fraction (CVF) was decreased in the rapamycin group compared with the DCM group (9.21 ± 0.82% vs 14.38 ± 1.24%, P < 0.01). The expression of p-mTOR and p-4EBP1 were significantly decreased in rapamycin-induced autophagy activation, while the levels were increased by down-regulating autophagy with 3-MA. In the rapamycin group, the LVEF and FS were significantly increased compared with the DCM group (54.12 ± 6.48% vs 45.29 ± 6.68%, P < 0.01; 26.89 ± 4.04% vs 22.17 ± 2.82%, P < 0.05). As the inhibitor of autophagy, 3-MA aggravated the progress of maladaptive cardiac remodeling and declined cardiac function in DCM mice.

Conclusions

The study indicated a possible mechanism for improving cardiac function in mice with experimental DCM by up-regulating autophagy via the mTOR-4EBP1 pathway, which could be a promising therapeutic strategy for DCM.
How were situations of preventive and curative care expenditure for AIDS and medical burden of patients? Research based on "System of Health Accounts 2011"
Authors: Zhan Huan , Wu Qiong , Zang Shuang , Zhou Liangrong , Wang Xin
Published: February 2020

Background

The problem of AIDS response has not only involved public health, but also had a great impact on the family burden.The objective of this study was to estimate the preventive and curative care expenditure(PCE)for AIDS of Hunan Province in 2017 based on System of Health Accounts 2011(SHA2011)by quantity,financing scheme,health provider,health function,and to analyses the factors affecting patients’ medical burden.

Methods

Through stratified multi-stage sampling method, 1336 institutions were surveyed to obtain AIDS prevention and control data, and the official data collected from Health Statistical Yearbook, Health Financial Annual Reports and Government Input Monitoring System were used to estimate the AIDS PCE based on SHA2011. Univariate analyses and ordered logistic regression were used to evaluate the factors affecting the medical burden of AIDS patients.

Results

The AIDS PCE of Hunan Province in 2017 was 266.67 million, mainly flowed to hospitals and disease prevention and control institutions. The proportions of curative care expenditure(CCE) and prevention expenditure were 51.39 and 48.61% respectively. Prevention expenditure were mainly used for traditional prevention methods. All prevention expenditure and 88.52% of CCE were borne by public financing scheme. Family health expenditure accounted for 11.12% of CCE, but there were still some people with heavy burden of treatment. Non insurance, co-infection and length of stay are risk factors to the total hospitalization expenses(Totalexp)and the out-of-pocket payments(OOPs)(all p < 0.05,OR > 1). Taking the age group under 30 as the reference, the partial regression coefficient of the age group over 60 was statistically significant (OR(Totalexp) = 1.809, OR(OOPs) = 0.30).

Conclusion

The financing structure of the PCE for AIDS in Hunan Province was relatively stable and the flow of institutions was reasonable. The functional flow of expenditure embodied the principle of “prevention first”. China should incorporate oral PrEP into the national guidelines as soon as possible to improve the allocation efficiency of AIDS prevention resources. Meantime, several measures should be taken to reduce the medical burden of AIDS patients, including expanding the scope of government assistance, adjusting insurance compensation measures, increasing the rate of patients participating in insurance,encouraging commercial insurance to join the AIDS insurance system,and controlling length of stay in hospital.
Store and neighborhood differences in retailer compliance with a local staple foods ordinance
Authors: Caspi Caitlin E. , Winkler Megan R. , Lenk Kathleen M. , Harnack Lisa J. , Erickson Darin J. , Laska Melissa N.
Published: February 2020

Background

Policies to improve healthy food retail have been recognized as a potential means of reducing diet-related health disparities. The revised 2014 Minneapolis Staple Foods Ordinance instituted minimum stocking standards for healthy, staple foods. The objective of this study was to examine retailer compliance with the policy, and whether compliance varied by neighborhood and store characteristics.

Methods

In this natural experiment, audits were conducted annually pre- and post-ordinance (2014–2017) in 155 small/nontraditional stores in Minneapolis, MN and a comparison city (St. Paul, MN). Compliance measures for 10 product categories included: (1) met requirements for ≥8 categories; (2) 10-point scale (one point for each requirement met); and (3) carried any item in each category. Store characteristics included store size and ownership status. Neighborhood characteristics included census-tract socioeconomic status and low-income/low-access status. Analyses were conducted in 2018.

Results

All compliance measures increased in both Minneapolis and St. Paul from pre- to post-policy; Minneapolis increases were greater only for carrying any item in each category (p < 0.01). In Minneapolis, corporate (vs. independent) stores were generally more compliant. No differences were found by neighborhood characteristics.

Conclusions

Overall trends suggest broad movement among Minneapolis stores towards providing a minimum level of staple foods. Increases were greater in corporate stores. Trends do not suggest neighborhood-level disparities in compliance.

Study registration

ClinicalTrials.gov NCT02774330, retrospectively registered May 17, 2016.
Factors that influence the use of community assets by people with physical disabilities: results of participatory mapping in Envigado, Colombia
Authors: Toro-Hernandez María Luisa , Villa-Torres Laura , Mondragón-Barrera Mónica Alejandra , Camelo-Castillo Wendy
Published: February 2020

Background

Disability is an evolving concept that results from the complex interaction between a person with an impairment and the context in which he/she lives. There is limited understanding on the types, access and use of community assets valuable for people with disabilities, and the role of contextual factors in Colombia. Our goal with this work was to identify the factors at the levels of the socio-ecological framework, and their interaction, that influence the use of community assets among people with physical disabilities and community stakeholders in Envigado, Colombia.

Methods

Using participatory mapping, a community based participatory approach, we carried out an assessment of community assets identified by people with disabilities and rehabilitation professionals. In-depth interviews (n = 32) informed the design of two participatory mapping activities, one among people with disabilities (n = 5) and a second with rehabilitation professionals (n = 4). Results were presented in a community forum to receive feedback on the findings.

Results

Main findings indicate a chain of contextual factors that limit access and use of assets stemming from the personal (e.g. financial resources, inaccessible housing), interpersonal level (e.g. lack of a personal assistance or aid), and community levels (e.g. lack of accessible public transportation and inaccessible buildings). In most cases these barriers are heightened by system level barriers (e.g. lack of effective enforcement of the legal framework).

Conclusions

Identifying these contextual factors, and their interactions, calls for stronger enforcement of the existing legal framework through articulated work between different stakeholders, so that people with disabilities can enjoy community assets.
Effectiveness and feasibility of a mindful leadership course for medical specialists: a pilot study
Authors: Kersemaekers Wendy M. , Vreeling Kiki , Verweij Hanne , van der Drift Miep , Cillessen Linda , van Dierendonck Dirk , Speckens Anne E. M.
Published: February 2020

Background

Medical specialists experience high levels of stress. This has an impact on their well-being, but also on quality of their leadership. In the current mixed method study, the feasibility and effectiveness of a course Mindful Leadership on burnout, well-being and leadership skills of medical specialists were evaluated.

Methods

This is a non-randomized controlled pre-post evaluation using self-report questionnaires administered at 3 months before (control period), start and end of the training (intervention period). Burn-out symptoms, well-being and leadership skills were assessed with self-report questionnaires. Semi-structured interviews were used to qualitatively evaluate barriers and facilitators for completion of the course.

Results

From September 2014 to June 2016, 52 medical specialists participated in the study. Of these, 48 (92%) completed the course. Compared to the control period, the intervention period resulted in greater reductions of depersonalization (mean difference = − 1.2, p = 0.06), worry (mean difference = − 4.3, p = 0.04) and negative work-home interference (mean difference = − 0.2, p = 0.03), and greater improvements of mindfulness (mean difference = 0.5, p = 0.04), life satisfaction (mean difference = 0.4, p = 0.01) and self-reported ethical leadership (mean difference = 0.1, p = 0.02). Effect sizes were generally small to medium (0.3 to 0.6) and large for life satisfaction (0.8). Appreciation of course elements was a major facilitator and the difficulty of finding time a major barrier for participating.

Conclusions

A ‘Mindful Leadership’ course was feasible and not only effective in reducing burnout symptoms and improving well-being, but also appeared to have potential for improving leadership skills. Mindful leadership courses could be a valuable part of ongoing professional development programs for medical specialists.
Genetic diversity of Plasmodium vivax and Plasmodium falciparum lactate dehydrogenases in Myanmar isolates
Authors: Lee Jinyoung , Kim Tae Im , Lê Hương Giang , Yoo Won Gi , Kang Jung-Mi , Ahn Seong-Kyu , Myint Moe Kyaw , Lin Khin , Kim Tong-Soo , Na Byoung-Kuk
Published: February 2020

Background

Plasmodiumlactate dehydrogenase (pLDH) is a major target in diagnosing the erythrocytic stage of malaria parasites because it is highly expressed during blood-stage parasites and is distinguished from human LDH. Rapid diagnostic tests (RDTs) for malaria use pLDH as a target antigen; however, genetic variations in pLDH within the natural population threaten the efficacy of pLDH-based RDTs.

Methods

Genetic polymorphisms ofPlasmodium vivaxLDH (PvLDH) andPlasmodium falciparumLDH (PfLDH) in Myanmar isolates were analysed by nucleotide sequencing analysis. Genetic polymorphisms and the natural selection of PvLDH and PfLDH were analysed using DNASTAR, MEGA6, and DnaSP ver. 5.10.00 programs. The genetic diversity and natural selection of global PvLDH and PfLDH were also analysed. The haplotype network of global PvLDH and PfLDH was constructed using NETWORK ver. 5.0.0.3. Three-dimensional structures of PvLDH and PfLDH were built with YASARA Structure ver. 18.4.24 and the impact of mutations on structural change and stability was evaluated with SDM ver. 2, CUPSAT and MAESTROweb.

Results

Forty-nine PvLDH and 52 PfLDH sequences were obtained from MyanmarP. vivaxandP. falciparumisolates. Non-synonymous nucleotide substitutions resulting in amino acid changes were identified in both Myanmar PvLDH and PfLDH. Amino acid changes were also identified in the global PvLDH and PfLDH populations, but they did not produce structural alterations in either protein. Low genetic diversity was observed in global PvLDH and PfLDH, which may be maintained by a strong purifying selection.

Conclusion

This study extends knowledge for genetic diversity and natural selection of global PvLDH and PfLDH. Although amino acid changes were observed in global PvLDH and PfLDH, they did not alter the conformational structures of the proteins. These suggest that PvLDH and PfLDH are genetically well-conserved in global populations, which indicates that they are suitable antigens for diagnostic purpose and attractive targets for drug development.
circRIP2 accelerates bladder cancer progression via miR-1305/Tgf-β2/smad3 pathway
Authors: Su Yinjie , Feng Weilian , Shi Juanyi , Chen Luping , Huang Jian , Lin Tianxin
Published: February 2020

Background

Increasing evidences indicate that circular RNAs exert critical function in regulating bladder cancer progression. However, the expressive patterns and roles of circular RNAs in bladder cancer remain less investigated.

Methods

circRIP2 was identified and evaluated by RNA-sequencing and qPCR; in vitro effects of circRIP2 were determined by CCK8, clone forming, wound healing and trans-well assays; while mice subcutaneous tumor model was designed for in vivo analysis. Western blot, RNA pulldown assay, miRNA capture and dual luciferase assessment were applied for mechanistic studies.

Results

circRIP2 was identified as a conserved and dramatically repressed circular RNA in bladder cancer. Patients that displayed higher circRIP2 expression negatively associate with the grade, stage, metastasis as well as outcome of bladder cancer. In vitro and in vivo studies suggest that circRIP2 enables to promote bladder cancer progression via inducing EMT. Regarding the mechanism, we performed RNA-sequencing analysis, RNA pulldown with biotin-labeled circRIP2-specific probe, dual luciferase reporter assay. It was found that circRIP2 enables to sponge miR-1305 to elevate Tgf-β2 in bladder cancer, and inducing EMT via Tgf-β2/smad3 pathway. Blocking Tgf-β2 in bladder cancer deprives circRIP2 induced cancer progression and EMT.

Conclusions

Taken together, our study provides the first evidence that circRIP2 expresses differentially in bladder cancer and negatively along with the cancer progression; effective circRIP2 activity accelerates bladder cancer progression via inducing EMT by activating miR-1305/Tgf-β2/smad3 pathway. The research implies that circRIP2 might be a potential biomarker and therapeutic target for bladder cancer patients.
Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA
Authors: Wu Pan , Mo Yongzhen , Peng Miao , Tang Ting , Zhong Yu , Deng Xiangying , Xiong Fang , Guo Can , Wu Xu , Li Yong , Li Xiaoling , Li Guiyuan , Zeng Zhaoyang , Xiong Wei
Published: February 2020

Non-coding RNAs do not encode proteins and regulate various oncological processes. They are also important potential cancer diagnostic and prognostic biomarkers. Bioinformatics and translation omics have begun to elucidate the roles and modes of action of the functional peptides encoded by ncRNA. Here, recent advances in long non-coding RNA (lncRNA) and circular RNA (circRNA)-encoded small peptides are compiled and synthesized. We introduce both the computational and analytical methods used to forecast prospective ncRNAs encoding oncologically functional oligopeptides. We also present numerous specific lncRNA and circRNA-encoded proteins and their cancer-promoting or cancer-inhibiting molecular mechanisms. This information may expedite the discovery, development, and optimization of novel and efficacious cancer diagnostic, therapeutic, and prognostic protein-based tools derived from non-coding RNAs. The role of ncRNA-encoding functional peptides has promising application perspectives and potential challenges in cancer research. The aim of this review is to provide a theoretical basis and relevant references, which may promote the discovery of more functional peptides encoded by ncRNAs, and further develop novel anticancer therapeutic targets, as well as diagnostic and prognostic cancer markers.
A competing-risk nomogram to predict cause-specific death in elderly patients with colorectal cancer after surgery (especially for colon cancer)
Authors: Wang Zhengbing , Wang Yawei , Yang Yan , Luo Yi , Liu Jiangtao , Xu Yingjie , Liu Xuan
Published: February 2020

Background

Clinically, when the diagnosis of colorectal cancer is clear, patients are more concerned about their own prognosis survival. Special population with high risk of accidental death, such as elderly patients, is more likely to die due to causes other than tumors. The main purpose of this study is to construct a prediction model of cause-specific death (CSD) in elderly patients using competing-risk approach, so as to help clinicians to predict the probability of CSD in elderly patients with colorectal cancer.

Methods

The data were extracted from Surveillance, Epidemiology, and End Results (SEER) database to include ≥ 65-year-old patients with colorectal cancer who had undergone surgical treatment from 2010 to 2016. Using competing-risk methodology, the cumulative incidence function (CIF) of CSD was calculated to select the predictors among 13 variables, and the selected variables were subsequently refined and used for the construction of the proportional subdistribution hazard model. The model was presented in the form of nomogram, and the performance of nomogram was bootstrap validated internally and externally using the concordance index (C-index).

Results

Dataset of 19,789 patients who met the inclusion criteria were eventually selected for analysis. The five-year cumulative incidence of CSD was 31.405% (95% confidence interval [CI] 31.402–31.408%). The identified clinically relevant variables in nomogram included marital status, pathological grade, AJCC TNM stage, CEA, perineural invasion, and chemotherapy. The nomogram was shown to have good discrimination after internal validation with a C-index of 0.801 (95% CI 0.795–0.807) as well as external validation with a C-index of 0.759 (95% CI 0.716–0.802). Both the internal and external validation calibration curve indicated good concordance between the predicted and actual outcomes.

Conclusion

Using the large sample database and competing-risk analysis, a postoperative prediction model for elderly patients with colorectal cancer was established with satisfactory accuracy. The individualized estimates of CSD outcome for the elderly patients were realized.
Hypercholesterolemia negatively influences morphology and molecular markers of epithelial cells within the choroid plexus in rabbits
Authors: Obata Fumiko , Narita Keishi
Published: February 2020

Background

Choroid plexus (CP) is an important tissue not only to produce cerebrospinal fluid (CSF) but also to regulate substances that are secreted into or absorbed from CSF through blood–cerebrospinal fluid barrier (BCSFB) formed by CP epithelial cells (CPECs). CPECs display signs of deterioration in aged and diseased people. However, whether CPECs in hypercholesterolemic animals develop such damage is not known.

Methods

We used cholesterol-fed wild-type or Watanabe hereditary hyperlipidemic (WHHL) rabbits of identical age to determine CPEC changes in terms of morphology and protein expression/localization.

Results

Compared with non-cholesterol-fed control rabbits, prolonged exposure to cholesterol reduced CPEC height and increased lipofuscin levels in CPECs, indicating cellular damage. Expression of aquaporin 1 on the apical membranes of CPECs was diminished in cholesterol-exposed rabbits, implying a reduced CSF-producing function in the CP. The rabbit macrophage-specific antibody (RAM11) immunoreaction became positive in CPECs adjacent to foam cells, indicating an alteration in this cell type.

Conclusion

Cholesterol insults from the circulation (which is reflected by foam-cell accumulation in the CP) induce CPEC dysfunction, and the latter seems to be enhanced by foam cells in hypercholesterolemic rabbits.
SIRT7 depletion inhibits cell proliferation and androgen-induced autophagy by suppressing the AR signaling in prostate cancer
Authors: Ding Mao , Jiang Chen-Yi , Zhang Yu , Zhao Jing , Han Bang-Min , Xia Shu-Jie
Published: February 2020

Background

Sirtuin-7 (SIRT7) is associated with the maintenance of tumorigenesis. However, its functional roles and oncogenic mechanisms in prostate cancer (PCa) are poorly understood. Here, we investigated the roles and underlying molecular mechanisms of SIRT7 in PCa cell growth and androgen-induced autophagy.

Methods

The LNCap and 22Rv1 PCa cell lines were subjected to quantitative reverse transcription (RT)-PCR to characterize their genes encoding SIRT7, AR, and SMAD4. The proteins produced from these genes were quantified by western blotting and immunoprecipitation analysis. SIRT7-depleted cells were produced by transfection with plasmid vectors bearing short hairpin RNAs against SIRT7. The proliferation of each cell line was assessed by CCK8 and EdU assays. Autophagic flux was tracked by mRFP–GFP–LC3 adenovirus under an immunofluorescence microscope. Apoptosis was evaluated by flow cytometry. Tumors were induced in mouse axillae by injection of the cell lines into mice. Tumor morphology was examined by immunohistochemistry and relative tumor growth and metastases were compared by a bioluminescence-based in vivo imaging system.

Results

SIRT7 depletion significantly inhibited cell proliferation, androgen-induced autophagy, and invasion in LNCap and 22Rv1 cells (in vitro) and mouse xenograft tumors induced by injection of these cells (in vivo). SIRT7 knockdown also increased the sensitivity of PCa cells to radiation. Immunohistochemical analysis of 93 specimens and bioinformatic analysis revealed that SIRT7 expression was positively associated with androgen receptor (AR). Moreover, the AR signal pathway participated in SIRT7-mediated regulation of PCa cell proliferation, autophagy, and invasion. SIRT7 depletion downregulated the AR signal pathway by upregulating the level of SMAD4 protein in PCa cells.

Conclusion

SIRT7 plays an important role in the development and progression of human PCa and may be a promising prognostic marker for prostate cancer.
Prevention of doxorubicin-induced Cardiotoxicity by pharmacological non-hypoxic myocardial preconditioning based on Docosahexaenoic Acid (DHA) and carvedilol direct antioxidant effects: study protocol for a pilot, randomized, double-blind, controlled trial (CarDHA trial)
Authors: Carrasco Rodrigo , Ramirez María Cristina , Nes Kjersti , Schuster Andrés , Aguayo Rubén , Morales Marcelo , Ramos Cristobal , Hasson Daniel , Sotomayor Camilo G. , Henriquez Pablo , Cortés Ignacio , Erazo Marcia , Salas Claudio , Gormaz Juan G.
Published: February 2020

Background

Anthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes. Carvedilol, a β-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the β-blocker effect, could prevent related cardiotoxicity. However, carvedilol’s antioxidant effects are probably not enough to prevent cardiotoxicity manifestations in certain cases. We hypothesize that breast cancer patients taking carvedilol as well as a non-hypoxic myocardial preconditioning based on docosahexaenoic acid (DHA), an enhancer of cardiac endogenous antioxidant capacity, will develop less subclinical cardiotoxicity manifestations than patients randomized to double placebo.

Methods/design

We designed a pilot, randomized controlled, two-arm clinical trial with 32 patients to evaluate the effects of non-hypoxic cardiac preconditioning (DHA) plus carvedilol on subclinical cardiotoxicity in breast cancer patients undergoing anthracycline treatment. The trial includes four co-primary endpoints: changes in left ventricular ejection fraction (LVEF) determined by cardiac magnetic resonance (CMR); changes in global longitudinal strain (GLS) determined by two-dimensional echocardiography (ECHO); elevation in serum biomarkers (hs-cTnT and NT-ProBNP); and one electrocardiographic variable (QTc interval). Secondary endpoints include other imaging, biomarkers and the occurrence of major adverse cardiac events during follow-up. The enrollment and follow-up for clinical outcomes is ongoing.

Discussion

We expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and non-hypoxic myocardial preconditioning with DHA to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo.

Trial registration

ISRCTN registry, ID:ISRCTN69560410. Registered on 8 June 2016.
University College London/University of Gothenburg PhD course “Biomarkers in neurodegenerative diseases” 2019—course organisation
Authors: Khatun Ayesha , Paterson Ross W. , Schöll Michael
Published: February 2020

Biomarkers are increasingly employed for effective research into neurodegenerative diseases. They have become essential for reaching an accurate clinical diagnosis, monitoring disease, and refining entry criteria for participation in clinical treatment trials, and will be key in measuring target engagement and treatment outcome in disease-modifying therapies. Emerging techniques and research combining different biomarker modalities continue to strengthen our understanding of the underlying pathology and the sequence of pathogenic events. Given recent advances, we are now at a pivotal stage in biomarker research. PhD students working in the field of neurodegenerative disease require a working knowledge of a range of biomarkers available and their limitations, to correctly interpret scientific literature and to design and conduct successful research studies themselves. Here, we outline the University College London/University of Gothenburg “Biomarkers in neurodegenerative diseases course”, the first initiative of its kind aimed to bring together both experts and PhD students from all areas within the field of neurodegeneration, to provide comprehensive knowledge of biomarker research for the next generation of scientists.
Acute generalized exanthematous pustulosis simulating toxic epidermal necrolysis: case presentation and literature review
Authors: Copaescu Ana-Maria , Bouffard Danielle , Masse Marie-Soleil
Published: February 2020

Background

Acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions. These rare conditions differ in clinical presentation, pathological features, treatment and prognosis, but overlap has been described implying a challenging clinical management.

Case presentation

We describe a case of overlap between TEN and AGEP probably secondary to beta-lactams in a 77-year-old patient treated for a complicated cholangitis. We review the diagnosis and the management of these two conditions. The diagnosis of TEN was suggested by the initial clinical presentation with severe hemodynamic instability, skin detachment, positive Nikolsky sign and mucosal involvement. However, the skin biopsy as well as the rapid improvement of the skin lesions were discriminative for AGEP. This indicated an overlap presentation. Unfortunately, the patient refused allergy investigations in order to find the culprit drug. Medical photographs, proper physical examination and histopathological results are integrated.

Conclusion

Despite clinical features indicating a diagnosis of TEN, histopathology was conclusive for AGEP thus indicating a possible clinical-pathological overlap between the two conditions, a scarcely described situation in the medical literature. To our knowledge, this is one of the few cases that portrays a TEN–AGEP overlap probably secondary to Piperacillin Tazobactam. Understanding the immunological implications of these conditions can help us better distinguish and manage these severe reactions.
Cancer/testis antigens expression during cultivation of melanoma and soft tissue sarcoma cells
Authors: Danilova Anna , Misyurin Vsevolod , Novik Aleksei , Girdyuk Dmitry , Avdonkina Natalia , Nekhaeva Tatiana , Emelyanova Natalia , Pipia Nino , Misyurin Andrey , Baldueva Irina
Published: February 2020

Background

Autologous dendritic cells (DC) loaded with tumor-associated antigens (TAAs) are a promising approach for anticancer immunotherapy. Polyantigen lysates appear to be an excellent source of TAAs for loading onto the patient’s dendritic cells. Cancer/testis antigens (CTA) are expressed by a wide range of tumors, but are minimally expressed on normal tissues, and could serve as a universal target for immunotherapy. However, CTA expression levels can vary significantly in patients with the same tumor type. We proposed that patients who do not respond to DC-based therapy may have distinct features of the CTA expression profile on tumor cells.

Patients and methods

We compared the gene expression of the principal families CTA in 22 melanoma and 27 soft tissue and bone sarcomas cell lines (STBS), received from patients and used for DC vaccine preparation.

Results

The majority (47 of 49, 95.9%) cell lines showed CTA gene activity. The incidence of gene expression of GAGE, NYESO1, MAGEA1, PRAME’s was significantly different (adj. p < 0.05) between melanoma and sarcoma cell lines. The expression of the SCP1 gene was detected neither in melanoma cells nor in the STBS cells. Clustering by the gene expression profile revealed four different expression patterns. We found three main patterns types: hyperexpression of multiple CTA, hyperexpression of one CTA with almost no expression of others, and no expression of CTA. All clusters types exist in melanoma and sarcoma cell lines. We observed dependence of killing efficacy from the PRAME (rho = 0.940, adj. p < 0.01) expression during real-time monitoring with the xCELLigence system of the interaction between melanoma or sarcoma cells with the T-lymphocytes activated by the lysate of selected allogenous melanoma cell lines with high expression of CTA.

Conclusion

Our results demonstrate that one can use lysates from allogeneic melanoma cell lines as a source of CTA for DC load during the production of anticancer vaccines for the STBS treatment. Patterns of CTA expression should be evaluated as biomarkers of response in prospective clinical trials.
Impulsive stochastic fractional differential equations driven by fractional Brownian motion
Authors: Abouagwa Mahmoud , Cheng Feifei , Li Ji
Published: February 2020

In this research, we study the existence and uniqueness results for a new class of stochastic fractional differential equations with impulses driven by a standard Brownian motion and an independent fractional Brownian motion with Hurst index $1/2< H<1$1/2<H<1 under a non-Lipschitz condition with the Lipschitz one as a particular case. Our analysis depends on an approximation scheme of Carathéodory type. Some previous results are improved and extended.
Thermodynamic and ecological preselection of synthetic fuel intermediates from biogas at farm sites
Authors: Peters Ralf , Decker Maximilian , Eggemann Lea , Schemme Steffen , Schorn Felix , Breuer Janos Lucian , Weiske Stefan , Pasel Joachim , Samsun Remzi Can , Stolten Detlef
Published: February 2020

Background

Synthetic fuels based on renewable hydrogen and CO2are a currently highly discussed piece of the puzzle to defossilize the transport sector. In this regard, CO2can play a positive role in shaping a sustainable future. Large potentials are available as a product of biogas production, however occurring in small scales and in thin spatial distributions. This work aims to evaluate suitable synthetic fuel products to be produced at farm sites.

Methods

A thermodynamic analysis to assess the energetic efficiency of synthesis pathways and a qualitative assessment of product handling issues is carried out.

Results

Regarding the technical and safety-related advantages in storage, liquid products are the superior option for fuel production at decentralized sites. Due to the economy of scale, multi-stage synthesis processes lose economic performance with rising complexity. A method was shown which covers a principle sketch of all necessary reaction, separation steps, and all compression and heat exchanger units. The figures showed that methanol and butanol are the most suitable candidates in contrast to OME3-5for implementation in existing transportation and fuel systems. These results were underpin by a Gibbs energy analysis.

Conclusions

As long as safety regulations are met and the farm can guarantee safe storage and transport, farm-site production for all intermediates can be realized technically. Ultimately, this work points out that the process must be kept as simple as possible, favoring methanol production at farm site and its further processing to more complicated fuels in large units for several fuel pathways.
The physiology of movement
Authors: Goossens Steven , Wybouw Nicky , Van Leeuwen Thomas , Bonte Dries
Published: February 2020

Movement, from foraging to migration, is known to be under the influence of the environment. The translation of environmental cues to individual movement decision making is determined by an individual’s internal state and anticipated to balance costs and benefits. General body condition, metabolic and hormonal physiology mechanistically underpin this internal state. These physiological determinants are tightly, and often genetically linked with each other and hence central to a mechanistic understanding of movement. We here synthesise the available evidence of the physiological drivers and signatures of movement and review (1) how physiological state as measured in its most coarse way by body condition correlates with movement decisions during foraging, migration and dispersal, (2) how hormonal changes underlie changes in these movement strategies and (3) how these can be linked to molecular pathways.

We reveale that a high body condition facilitates the efficiency of routine foraging, dispersal and migration. Dispersal decision making is, however, in some cases stimulated by a decreased individual condition. Many of the biotic and abiotic stressors that induce movement initiate a physiological cascade in vertebrates through the production of stress hormones. Movement is therefore associated with hormone levels in vertebrates but also insects, often in interaction with factors related to body or social condition. The underlying molecular and physiological mechanisms are currently studied in few model species, and show –in congruence with our insights on the role of body condition- a central role of energy metabolism during glycolysis, and the coupling with timing processes during migration. Molecular insights into the physiological basis of movement remain, however, highly refractory. We finalise this review with a critical reflection on the importance of these physiological feedbacks for a better mechanistic understanding of movement and its effects on ecological dynamics at all levels of biological organization.
Electroencephalography-based neurofeedback as treatment for post-traumatic stress disorder: A systematic review and meta-analysis
Authors: Steingrimsson Steinn , Bilonic Gorana , Ekelund Ann-Catrin , Larson Tomas , Stadig Ida , Svensson Mikael , Vukovic Iris Sarajlic , Wartenberg Constanze , Wrede Olof , Bernhardsson Susanne
Published: February 2020

Background

Post-traumatic stress disorder (PTSD) is debilitating for patients and society. There are a number of treatment methods albeit not all patients respond to these and an interesting method using electroencephalography-based neurofeedback (EEG-NF) has become more prominent in recent years. This systematic review aimed to assess whether EEG-NF, compared with sham NF, other treatment, or no treatment, is effective for PTSD. Primary outcomes were self-harm, PTSD symptoms, level of functioning and health-related quality of life.

Methods

Systematic literature searches for randomized controlled trials (RCTs) were conducted in six databases. Random effects meta-analysis was performed. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation.

Results

Four RCTs were included (123 participants). Suicidal thoughts were significantly reduced after EEG-NF compared with a waiting list in a small study. PTSD symptoms were assessed in all studies with different instruments. Results were consistently in favor of EEG-NF with large effect sizes (standardized mean difference −2.30 (95% confidence interval: −4.37 to −0.24). One study reported significantly improved level of executive functioning and one study a reduction in use of psychotropic medication. Complications were scarcely reported. Certainty of evidence was assessed as very low for the four assessed outcomes.

Conclusions

Based on four RCTs, with several study limitations and imprecision, it is uncertain whether EEG-NF reduces suicidal thoughts, PTSD symptoms, medication use, or improves function. Although all studies showed promising results, further studies are needed to increase the certainty of evidence.
Pemetrexed plus erlotinib as a salvage treatment in high EGFR-expressing metastatic colorectal cancer patients following failure of standard chemotherapy: A phase II single-arm prospective study.
Authors: Byeon Seonggyu , Kim Seung Tae , Hong Jung Yong , Lee Jeeyun , Park Joon Oh , Lim Ho-Yeong , Kang Won Ki , Park Young Suk
Published: February 2020

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Background: We conducted a single-arm, phase II study to evaluate the combination of pemetrexed and erlotinib as a salvage treatment in high EGFR-expressing (2+ or 3 on immunohistochemistry (IHC)) metastatic colorectal cancer (CRC) patients who failed to show a benefit after standard chemotherapy. Methods: We investigated pemetrexed and erlotinib (pemetrexed 500 mg/m2 on Day 1 and erlotinib 100 mg/m2 on Days 1–21) as a salvage treatment, given every three weeks, until disease progression or intolerable toxicity. The primary outcome was overall response rate (RR). Results: From May 2017 to April 2018, 29 metastatic CRC patients with high EGFR expression who previously received the standard therapies were enrolled into this trial. The regimen was well tolerated. Skin rash, vomiting, fatigue, and anorexia were common toxic effects but were mostly manageable and controllable side effects of only grades 1 or 2. In intent-to-treat analysis, three partial responses (PRs) were observed in enrolled patients, revealing an overall RR of 10.3%. This value supported the statistical hypothesis of this study. Fifteen patients had stable disease and the disease control rate (DCR) was 62.1%. All three patients who achieved a PR had an expression of EGFR 3+ in a tumor. Among eight patients with a tumor expressing an EGFR value of 3+, the RR and DCR were 37.5% and 75.0%, respectively. Conclusions: This phase II trial using pemetrexed and erlotinib in metastatic CRC with high EGFR expression met the primary endpoint of tumor response. Clinical trial information: NCT03086538.
Clinical impact of primary tumor location in patients with metastatic colorectal cancer (mCRC) treated with regorafenib or trifluridine/tipiracil as later-line.
Authors: Nakajima Hiromichi , Fukuoka Shota , Moriwaki Toshikazu , Masuishi Toshiki , Takashima Atsuo , Kumekawa Yosuke , Kajiwara Takeshi , Yamazaki Kentaro , Komoda Masato , Makiyama Akitaka , Denda Tadamichi , Hatachi Yukimasa , Suto Takeshi , Sugimoto Naotoshi , Enomoto Masanobu , Ishikawa Toshiaki , Kashiwada Tomomi , Oki Eiji , Gosho Masahiko , Shimada Yasuhiro
Published: February 2020

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Background: In the recent years, primary tumor location (PTL) is considered as an important prognostic and predictive factor in first-line treatment of mCRC. Although regorafenib (REG) and trifluridine/tipiracil (TFTD) have been available recently, the prognostic value of PTL in later-line with these agents is not well understood. TFTD improved survival regardless of PTL in the RECOURSE trial, while REG did not show survival benefit in the patients (pts) with rectal cancer in the CORRECT trial. Methods: We retrospectively evaluated pts with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were ECOG PS of 0–2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF and anti-EGFR therapy (if KRAS wild type), and no prior use of REG and TFTD. The impact of PTL on overall survival (OS) were evaluated using Cox proportional hazards models based on baseline characteristics and propensity score matching. Results: A total of 550 pts (223 pts in the REG group, 327 pts in the TFTD group; 122 pts in the right-sided, 428 pts in the left-sided) were included in this study. Although the right-sided pts was significantly shorter OS compared with the left-sided pts by univariate analysis (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.63-0.99, P = 0.04), multivariate analysis revealed that PTL was not an independent prognostic factor (HR 0.88, 95% CI 0.69-1.1, P = 0.26). The similar results were obtained in each treatment group. In subgroup analysis according to PTL, OS were comparable between REG and TFTD groups regardless of PTL (HR 0.93, 95% CI 0.62-1.39 in the right-sided; HR 1.08, 95% CI 0.83-1.39 in the left-sided [excluding rectum]; and HR 1.01, 95% CI 0.62-1.62 in the rectal cancer pts). These results were similar in sensitivity analysis using propensity score-matching. Conclusions: In the present study, PTL is not a prognostic factor in patient with mCRC treated with either REG or TFTD as later-line. No difference in OS was observed between REG and TFTD groups irrespective of PTL.