bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolomics coupled with integrated approaches reveal the therapeutic effects of higenamine combined with [6]-gingerol on doxorubicin-induced chronic heart failure in rats
Authors: Wen Jianxia , Ma Xiao , Niu Ming , Hao Junjie , Huang Ying , Wang Ruilin , Li Ruisheng , Wang Jian , Zhao Yanling 
Published: November 2020

Abstract
Background
This study was aimed to investigate the therapeutic effects and potential mechanism of higenamine combined with [6]-gingerol (HG/[6]-GR) against doxorubicin (DOX)—induced chronic heart failure (CHF) in rats.

Materials and methods
Therapeutic effects of HG/[6]-GR on hemodynamics indices, serum biochemical indicators, histopathology and TUNEL staining of rats were assessed. Moreover, a UHPLC-Q-TOF/MS-based serum metabolic approach was performed to identify the metabolites and possible pathways of HG/[6]-GR on DOX-induced CHF.

Results
HG/[6]-GR had effects on regulating hemodynamic indices, alleviating serum biochemical indicators, improving the pathological characteristics of heart tissue and reducing the apoptosis of myocardial cells. Serum metabolisms analyses indicated that the therapeutic effects of HG and [6]-GR were mainly associated with the regulation of eight metabolites, including acetylphosphate, 3-Carboxy-1-hydroxypropylthiamine diphosphate, coenzyme A, palmitic acid, PE(O-18:1(1Z)/20:4(5Z,8Z,11Z,14Z)), oleic acid, lysoPC(18:1(9Z)), and PC(16:0/16:0). Pathway analysis showed that HG/[6]-GR on CHF treatment was related to twelve pathways, including glycerophospholipid metabolism, fatty acid metabolism, pantothenate and CoA biosynthesis, citrate cycle (TCA cycle), pyruvate metabolism, and arachidonic acid metabolism. Serum metabolites and metabolic pathways regulated by HG/[6]-GR appear to be related to energy metabolism.

Conclusion
Multivariate statistical analysis has provided new insights for understanding CHF and investigating the therapeutic effects and mechanisms of HG/[6]-GR, which influencing the metabolites and pathways related to energy metabolism pathway.
Neurocognition in Congenital Central Hypoventilation Syndrome: influence of genotype and ventilation method
Authors: Trang Ha , Bourgeois Pauline , Cheliout-Heraut Fawzia 
Published: November 2020

AbstractBackgroundCongenital Central Hypoventilation Syndrome (CCHS) is characterized by central hypoventilation due to abnormal autonomic control of breathing and global dysautonomia. Patients harbour heterozygousPHOX-2Bgene mutations which are polyalanine repeats of various lengths in most of the cases. A few previous studies have reported learning difficulties and neuropsychological disorders in patients with CCHS. The aims of the present study were (1) to explore the intellectual abilities of a group of children with CCHS followed up in the centre of reference for CCHS in France using the Wechsler batteries of tests, (2) and to assess whether there was any association between CCHS characteristics and various domains of the intellectual functioning.ResultsThere were 34 consecutive patients (15 males, 19 females) of mean (SD) age of 7.8 (3.8) years, ranging from 4 to 16 years and 6 months. Mean score of full-scale intelligence quotient was 82 (20), being in the low average range. Indexes of working memory and processing speed were significantly lower as compared to the other Wechsler indexes. There were two important findings: (1) full-scale intelligence quotient as well as indexes of verbal comprehension and processing speed were significantly greater in patients with mask ventilation than in those with tracheostomy ventilation (p = 0.012, 0.032 and 0.042 respectively); (2) most interestingly, in the patients with polyalanine repeats mutations, all intellectual indexes negatively correlated with the number of polyalanine expansion, with statistical significance reached for indexes of fluid reasoning and working memory (R = − 0.449,p = 0.032 andR = − 0.562,p = 0.012 respectively).ConclusionsCCHS increased the risk to develop neurocognitive deficiencies, affecting particularly speed of processing and working memory. Our results suggested that both genetics and ventilation method could be also involved in the physiopathology of neurocognitive impairment. Further investigations were required to untangle the complex underlying processes. Neurocognitive assessments should be performed regularly in children with CCHS in order to plan re-education programs, adapt school integration and improve quality of life.
Clinical trials with cannabis medicines—guidance for ethics committees, governance officers and researchers to streamline ethics applications and ensuring patient safety: considerations from the Australian experience
Authors: Martin Jennifer H. , Hill Courtney , Walsh Anna , Efron Daryl , Taylor Kaitlyn , Kennedy Michael , Galettis Rachel , Lightfoot Paul , Hanson Julie , Irving Helen , Agar Meera , Lacey Judith 
Published: November 2020

AbstractWith cannabis medicines now obtaining legal status in many international jurisdictions (generally on the authorisation of a medical professional), a rapid increase in consumer demand for access to cannabis as a therapeutic option in the treatment and management of a range of indications is being noted. Despite this accessibility, knowledge on optimal use is lacking. Further drug development and clinical trials at regulatory standards are necessary both if a better understanding of the efficacy of cannabis medicines, optimal product formulation and indication-specific dosing is needed and to ensure the broader quality and safety of cannabis medicines in the clinical setting.To enable this, clinical, academic and public calls for the undertaking of rigorous clinical trials to establish an evidence base for the therapeutic use of cannabis medicines have been made internationally. While this commitment to undertake human studies with cannabis medicines is welcomed, it has highlighted unique challenges, notably in the review stages of ethics and governance. This often results in lengthy delays to approval by Human Research Ethics Committees (herein ‘HREC’, Australia’s nomenclature for Institutional Review Boards) and trial commencement. A principal concern in these cases is that in contrast to clinical trials using other more conventional pharmaceutical products, trials of cannabis medicines in humans often involve the use of an investigational product prior to some (or any) of the preclinical and pharmaceutical safety issues being established. This paucity of data around product safety, potential drug interactions, continuity of supply, shelf life and product storage results in apprehension by HRECs and governance bodies to endorse trials using cannabis medicines.This manuscript draws from the experiences of Australian researchers and staff involved in clinical trials of cannabis medicines to describe some of the common difficulties that may be faced in the HREC approval process. It also presents practical advice aimed to assist researchers, HRECs and governance officers navigate this complex terrain. While the authors’ experiences are situated within the Australian setting, many of the barriers described are applicable within the international context and thus, the solutions that have been proposed are typically adaptive for use within other jurisdictions.
An integrative approach to identify sand fly vectors of leishmaniasis in Ethiopia by morphological and molecular techniques
Authors: Pareyn Myrthe , Dvorak Vit , Halada Petr , Van Houtte Natalie , Girma Nigatu , de Kesel Wim , Merdekios Behailu , Massebo Fekadu , Leirs Herwig , Volf Petr 
Published: November 2020

AbstractBackgroundEthiopia is affected by human leishmaniasis caused by severalLeishmaniaspecies and transmitted by a variety of sand fly vectors of the genusPhlebotomus. The sand fly fauna in Ethiopia is highly diverse and some species are closely related and similar in morphology, resulting in difficulties with species identification that requires deployment of molecular techniques. DNA barcoding entails high costs, requires time and lacks reference sequences for many Ethiopian species. Yet, proper species identification is pivotal for epidemiological surveillance as species differ in their actual involvement in transmission cycles. Recently, protein profiling using MALDI-TOF mass spectrometry has been introduced as a promising technique for sand fly identification.MethodsIn our study, we used an integrative taxonomic approach to identify most of the important sand fly vectors of leishmaniasis in Ethiopia, applying three complementary methods: morphological assessment, sequencing analysis of two genetic markers, and MALDI-TOF MS protein profiling.ResultsAlthough morphological assessment resulted in some inconclusive identifications, both DNA- and protein-based techniques performed well, providing a similar hierarchical clustering pattern for the analyzed species. Both methods generated species-specific sequences or protein patterns for all species except forPhlebotomus pediferandP. longipes, the two presumed vectors ofLeishmania aethiopica, suggesting that they may represent a single species,P. longipesParrot & Martin. All three approaches also revealed that the collected specimens ofAdleriussp. differ fromP.(Adlerius)arabicus, the only species ofAdleriuscurrently reported in Ethiopia, and molecular comparisons indicate that it may represent a yet undescribed new species.ConclusionsOur study uses three complementary taxonomical methods for species identification of taxonomically challenging and yet medically import Ethiopian sand flies. The generated MALDI-TOF MS protein profiles resulted in unambiguous identifications, hence showing suitability of this technique for sand fly species identification. Furthermore, our results contribute to the still inadequate knowledge of the sand fly fauna of Ethiopia, a country severely burdened with human leishmaniasis.Graphical Abstract
Comparison of maximal lactate steady state with anaerobic threshold determined by various methods based on graded exercise test with 3-minute stages in elite cyclists
Authors: Płoszczyca Kamila , Jazic Dominik , Piotrowicz Zofia , Chalimoniuk Małgorzata , Langfort Józef , Czuba Miłosz 
Published: November 2020

Abstract
Background
The maximal lactate steady state (MLSS) is defined as the highest workload that can be maintained for a longer period of time without continued blood lactate (LA) accumulation. MLSS is one of the physiological indicators of aerobic performance. However, determination of MLSS requires the performance of a series of constant-intensity tests during multiple laboratory visits. Therefore, attempts are made to determine MLSS indirectly by means of anaerobic threshold (AT) evaluated during a single graded exercise test (GXT) until volitional exhaustion. The aim of our study was to verify whether AT determined by maximal deviation (Dmax), modified maximal deviation (ModDmax), baseline LA concentration + 1 mmol/l (+ 1 mmol/l), individual anaerobic threshold (IAT), onset of blood lactate accumulation (OBLA4mmol/l) and V-slope methods based on GXT with 3-min stages provide valid estimates of MLSS in elite cyclists.

Methods
Twelve elite male cyclists (71.3 ± 3.6 ml/kg/min) completed GXT (the increase by 40 W every 3 min) to establish the AT (by Dmax, ModDmax, + 1 mmol/l, IAT, OBLA4mmol/l and V-slope methods). Next, a series of 30-min constant-load tests to determine MLSS was performed. Agreement between the MLSS and workload (WR) at AT was evaluated using the Bland–Altman method.

Results
The analysis revealed a very high (rs > 0.90, p < 0.001) correlation between WRMLSS and WRDmax and WRIAT. The other AT methods were highly (rs > 0.70) correlated with MLSS except for OBLA4mmol/l (rs = 0.67). The Bland-Altman analysis revealed the highest agreement with MLSS for the Dmax, IAT and + 1 mmol/l methods. Mean difference between WRMLSS and WRDmax, WRIAT and WR+1mmol/l was 1.7 ± 3.9 W, 4.3 ± 7.9 W and 6.7 ± 17.2 W, respectively. Furthermore, the WRDmax and WRIAT had the lowest limits of agreement with the WRMLSS. The ModDmax and OBLA4mmol/l methods overestimated MLSS by 31.7 ± 18.5 W and 43.3 ± 17.8 W, respectively. The V-slope method underestimated MLSS by 36.2 ± 10.9 W.

Conclusions
The AT determined by Dmax and IAT methods based on the cycling GXT with 3-min stages provides a high agreement with the MLSS in elite cyclists. Despite the high correlation with MLSS and low mean difference, the AT determined by + 1 mmol/l method may highly overestimate or underestimate MLSS in individual subjects. The individual MLSS cannot be properly estimated by V-slope, ModDmax and OBLA4mmol/l methods.
5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers
Authors: Liu Siyu , de Medeiros Marcell Costa , Fernandez Evan M. , Zarins Katie R. , Cavalcante Raymond G. , Qin Tingting , Wolf Gregory T. , Figueroa Maria E. , D’Silva Nisha J. , Rozek Laura S. , Sartor Maureen A. 
Published: November 2020

Abstract
Background
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied.

Results
We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(−) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(−) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(−) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(−) oral cavity cell lines.

Conclusion
Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancer-related processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups.
Are neuropsychiatric symptoms in dementia linked to CSF biomarkers of synaptic and axonal degeneration?
Authors: Bloniecki Victor , Zetterberg Henrik , Aarsland Dag , Vannini Patrizia , Kvartsberg Hlin , Winblad Bengt , Blennow Kaj , Freund-Levi Yvonne 
Published: November 2020

Abstract
Background
The underlying disease mechanism of neuropsychiatric symptoms (NPS) in dementia remains unclear. Cerebrospinal fluid (CSF) biomarkers for synaptic and axonal degeneration may provide novel neuropathological information for their occurrence. The aim was to investigate the relationship between NPS and CSF biomarkers for synaptic (neurogranin [Ng], growth-associated protein 43 [GAP-43]) and axonal (neurofilament light [NFL]) injury in patients with dementia.

Methods
A total of 151 patients (mean age ± SD, 73.5 ± 11.0, females n = 92 [61%]) were included, of which 64 had Alzheimer’s disease (AD) (34 with high NPS, i.e., Neuropsychiatric Inventory (NPI) score > 10 and 30 with low levels of NPS) and 18 were diagnosed with vascular dementia (VaD), 27 with mixed dementia (MIX), 12 with mild cognitive impairment (MCI), and 30 with subjective cognitive impairment (SCI). NPS were primarily assessed using the NPI. CSF samples were analyzed using enzyme-linked immunosorbent assays (ELISAs) for T-tau, P-tau, Aβ1–42, Ng, NFL, and GAP-43.

Results
No significant differences were seen in the CSF levels of Ng, GAP-43, and NFL between AD patients with high vs low levels of NPS (but almost significantly decreased for Ng in AD patients < 70 years with high NPS, p = 0.06). No significant associations between NPS and CSF biomarkers were seen in AD patients. In VaD (n = 17), negative correlations were found between GAP-43, Ng, NFL, and NPS.

Conclusion
Our results could suggest that low levels of Ng may be associated with higher severity of NPS early in the AD continuum (age < 70). Furthermore, our data may indicate a potential relationship between the presence of NPS and synaptic as well as axonal degeneration in the setting of VaD pathology.
Preoperative accelerated radiotherapy combined with chemotherapy in a defined cohort of patients with high risk soft tissue sarcoma: a Scandinavian Sarcoma Group study
Authors: Hall Kirsten Sundby , Bruland Øyvind S. , Bjerkehagen Bodil , Lidbrink Elisabet , Jebsen Nina , Hagberg Hans , Papworth Karin , Hagberg Oskar , Trovik Clement , Bauer Henrik , Eriksson Mikael 
Published: November 2020

Abstract
Background
We recently reported outcomes from a Scandinavian Sarcoma Group adjuvant study (SSG XX group A) conducted on localized and operable high risk soft tissue sarcoma (STS) of the extremities and trunk wall. SSG XX, group B, comprised of patients in a defined cohort with locally advanced STS considered at high risk for intralesional surgery. These patients received preoperative accelerated radiotherapy, together with neoadjuvant and adjuvant chemotherapy. Herein we report the results of this group B.

Methods
Twenty patients with high-grade, locally advanced and deep STS located in lower extremities (n = 12), upper extremities (5) or trunk wall (3) were included. The median age was 59 years and 14 patients were males. The treatment regimen consisted of 6 cycles of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2), with three cycles given neoadjuvantly, and preoperative radiotherapy (1, 8 Gyx2/daily to 36 Gy) between cycles 2 and 3. After a repeated MRI surgery was then conducted, and the remaining 3 chemotherapy cycles were given postoperatively at 3 weeks intervals. Survival data, local control, toxicity of chemotherapy and postoperative complications are presented.

Results
Median follow-up time for metastasis-free survival (MFS) was 2.8 years (range 0.3–10.4). The 5-year MFS was 49.5% (95% confidence interval [CI] 31.7–77.4). The median follow-up time was 5.4 years (range 0.3–10.4) for overall survival (OS). The 5-year OS was 64.0% (95% CI 45.8–89.4). The median tumour size was 13 cm, with undifferentiated pleomorphic sarcoma (n = 10) and synovial sarcoma (n = 6) diagnosed most frequently. All patients completed surgery. Resection margins were R0 in 19 patients and R1 in 1 patient. No patients had evidence of disease progression preoperatively. Three patients experienced a local recurrence, in 2 after lung metastases had already been diagnosed. Eleven patients (55%) had postoperative wound problems (temporary in 8 and persistent in 3).

Conclusions
Preoperative chemotherapy and radiotherapy were associated with temporary wound-healing problems. Survival outcomes, local control and toxicities were deemed satisfactory when considering the locally advanced sarcoma disease status at primary diagnosis.
Trial registration This study was registered at ClinicalTrials.gov Identifier NCT00790244 and with European Union Drug Regulating Authorities Clinical Trials No. EUDRACT 2007-001152-39
Molecular characterization of HEXOKINASE1 in plant innate immunity
Authors: Jing Wu , Uddin Shahab , Chakraborty Rupak , Van Anh Duong Thu , Macoy Donah Mary , Park Si On , Ryu Gyeong Ryul , Kim Young Hun , Cha Joon‑Yung , Kim Woe-Yeon , Kim Min Gab 
Published: November 2020

AbstractHexokinase1 (HXK1) is an Arabidopsis glucose sensor that has a variety of roles during plant growth and devlopment, including during germination, flowering, and senescence. HXK1 also acts as a positive regulator of plant immune responses. Previous research suggested that HXK1 might influence plant immune responses via responses to glucose. Plant immune responses are governed by two main pathways: PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI). PTI involves the recognition of Pathogen-Associated Molecular Patterns (PAMPs) and leads to increased callose formation and accumulation of pathogenesis response (PR) proteins. ETI acts in response to effectors secreted by Gram-negative bacteria. During ETI, the membrane-localized protein RPM1-interacting protein 4 (RIN4) becomes phosphorylated in reponse to interactions with effectors and mediates the downstream response. In this study, the effects of glucose on plant immune responses against infection with Pseudomonas syringae pv. tomato DC3000 and other P. syringae strains were investigated in the presence and absence of HXK1. Infiltration of leaves with glucose prior to infection led to decreases in bacterial populations and reductions in disease symptoms in wild-type Arabidopsis plants, indicating that glucose plays a role in plant immunity. Both PTI and ETI responses were affected. However, these effects were not observed in a hxk1 mutant, indicating that the effects of glucose on plant immune responses were mediated by HXK1-related pathways.
Assessing preventive health behaviors from COVID-19: a cross sectional study with health belief model in Golestan Province, Northern of Iran
Authors: Shahnazi Hossein , Ahmadi-Livani Maryam , Pahlavanzadeh Bagher , Rajabi Abdolhalim , Hamrah Mohammad Shoaib , Charkazi Abdurrahman 
Published: November 2020

AbstractBackgroundCoronavirus disease 2019 (COVID-19) is a new viral disease that has caused a pandemic in the world. Due to the lack of vaccines and definitive treatment, preventive behaviors are the only way to overcome the disease. Therefore, the present study aimed to determine the preventive behaviors from the disease based on constructs of the health belief model.MethodsIn the present cross-sectional study during March 11–16, 2020, 750 individuals in Golestan Province of Iran were included in the study using the convenience sampling and they completed the questionnaires through cyberspace. Factor scores were calculated using the confirmatory factor analysis. The effects of different factors were separately investigated using the univariate analyses, including students samplet-test, ANOVA, and simple linear regression. Finally, the effective factors were examined by the multiple regression analysis at a significant level of 0.05 and through Mplus 7 and SPSS 16.ResultsThe participants’ mean age was 33.9 ± 9.45 years; and 57.1% of them had associate and bachelor's degrees. Multiple regression indicated that the mean score of preventive behavior from COVID-19 was higher in females than males, and greater in urban dwellers than rural dwellers. Furthermore, one unit increase in the standard deviation of factor scores of self-efficacy and perceived benefits increased the scores of preventive behavior from COVID-19 by 0.22 and 0.17 units respectively. On the contrary, one unit increase in the standard deviation of factor score of perceived barriers and fatalistic beliefs decreased the scores of the preventive behavior from COVID-19 by 0.36 and 0.19 units respectively.ConclusionsResults of the present study indicated that female gender, perceived barriers, perceived self-efficacy, fatalistic beliefs, perceived interests, and living in city had the greatest preventive behaviors from COVID-19 respectively. Preventive interventions were necessary among males and villagers.