bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design and synthesis of HLA-A*02-restricted Hantaan virus multiple-antigenic peptide for CD8+ T cells
Authors: Ma Yan , Tang Kang , Zhang Yusi , Zhang Chunmei , Zhang Yun , Jin Boquan , Ma Ying 
Published: January 2020

Abstract
Background
Hantaan virus (HTNV) can cause hemorrhagic fever with renal syndrome (HFRS) in humans with severe morbidity and high mortality. Although inactivated HFRS vaccines are given annually for prevention in populations, China still has the highest number of HFRS cases and deaths worldwide. Consequently, vaccination for HFRS requires the development of novel, more effective vaccines. Epitope peptide vaccines have been developed rapidly in recent years and are considered a novel approach for the prevention of infection. Specifically, the multiple antigenic peptide (MAP) design with preferable immunogenicity can arouse a satisfactory immune response for vaccination. However, there are few reports on the design and evaluation of MAP for HTNV.

Methods
Three HLA-A*02-restricted 9-mer cytotoxic T lymphocyte (CTL) epitopes on HTNV glycoprotein and one HLA-A*02-restricted 9-mer CTL epitope on the HTNV nucleocapsid, which have been proven to be immunoprotective in our previous study, were selected for the design of HTNV MAP. A four-branched HTNV MAP was evaluated by the IFN-γ-secreting enzyme-linked immunospot assay and proliferation induction capacity of CD8+ T cells and compared with the single HTNV CTL epitope in 17 HLA-A*02+ patients with HFRS. The Mann–Whitney U test was used for comparison of parameters between different subject groups.

Results
The macromolecular HTNV MAP was designed with a polylysine core and four radially branched single CTL epitope chains. Importantly, HTNV MAP could stimulate CD8+ T cell secretion of IFN-γ in HLA-A*02+ patients with HFRS. The frequency of IFN-γ-secreting CD8+ T cells in the MAP stimulation group was significantly higher than that in the single HTNV CTL epitope stimulation groups (P < 0.005). Meanwhile, the activity of IFN-γ-secreting CD8+ T cells in the HTNV MAP group was also higher than that of the single CTL epitope groups (P < 0.05). Moreover, there was a much stronger ability of HTNV MAP to stimulate CD8+ T cell proliferation compared with that of a single HTNV CTL epitope.

Conclusions
The designed HTNV MAP could induce CTL responses ex vivo and may be considered a candidate for the design and development of novel HTNV peptide vaccines.
Tetramethylpyrazine reverses high-glucose induced hypoxic effects by negatively regulating HIF-1α induced BNIP3 expression to ameliorate H9c2 cardiomyoblast apoptosis
Authors: Liu Shih-Ping , Shibu Marthandam Asokan , Tsai Fuu-Jen , Hsu Yuan-Man , Tsai Chang-Hai , Chung Jing-Gung , Yang Jai-Sing , Tang Chih-Hsin , Wang Shulin , Li Qiaowen , Huang Chih-Yang 
Published: January 2020

Abstract
Background
Diabetic patients are highly vulnerable to hypoxic injury, which is associated with hypoxia induced BNIP3 expression that subsequently activate apoptosis. Our previous research show that Tetramethylpyrazine (TMP), a food flavoring agent, represses the hypoxia induced BNIP3 expression attenuate myocardial apoptosis. In this study, we evaluate the effect of TMP to provide protection against hypoxia aggravated high-glucose associated cellular apoptosis.

Methods
The cytoprotective effect of TMP against high glucose induced cellular damages was determined on embryo derived H9c2 cardiomyoblast cells that were subjected to 5% hypoxia for 24 h and subjected to different duration of 33 mM high glucose challenge. Further, the involvement of HIF-1α and BNIP3 in cellular damage and the mechanism of protection of TMP were determined by overexpression and silencing HIF-1α and BNIP3 protein expression.

Results
The results show that hypoxic effects on cell viability aggravates with high glucose challenge and this augmentative effect is mediated through BNIP3 in H9c2 cardiomyoblast cells. However, TMP administration effectively reversed the augmented HIF-1α levels and BNIP3 elevation. TMP improved the survival of H9c2 cells and effectively suppressed apoptosis in H9c2 cells. Further comparison on the effects of TMP on H9c2 cells challenged with high glucose and those challenged with hypoxia show that TMP precisely regulated the hypoxic intensified apoptotic effects in high-glucose condition.

Conclusion
The results clearly show that flavoring agent-TMP attenuates cytotoxicity amplified by hypoxia challenge in high glucose condition by destabilizing HIF-1α.
Improving quality of care and clinical outcomes for rectal cancer through clinical audits in a multicentre cancer care organisation
Authors: Torras M. G. , Canals E. , Muñoz-Montplet C. , Vidal A. , Jurado D. , Eraso A. , Villà S. , Caro M. , Molero J. , Macià M. , Puigdemont M. , González-Muñoz E. , López A. , Guedea F. , Borras J. M. 
Published: January 2020

Abstract
Introduction
Colorectal cancer treatment requires a complex, multidisciplinary approach. Because of the potential variability, monitoring through clinical audits is advisable. This study assesses the effects of a quality improvement action plan in patients with locally advanced rectal cancer and treated with radiotherapy.

Methods
Comparative, multicentre study in two cohorts of 120 patients each, selected randomly from patients diagnosed with rectal cancer who had initiated radiotherapy with a curative intent. Based on the results from a baseline clinical audit in 2013, a quality improvement action plan was designed and implemented; a second audit in 2017 evaluated its impact.

Results
Standardised information was present on 77.5% of the magnetic resonance imaging (MRI) staging reports. Treatment strategies were similar in all three study centres. Of the patients whose treatment was interrupted, just 9.7% received a compensation dose. There was an increase in MRI re-staging from 32.5 to 61.5%, and a significant decrease in unreported circumferential resection margins following neoadjuvant therapy (ypCRM), from 34.5 to 5.6% (p <  0.001).

Conclusions
The comparison between two clinical audits showed improvements in neoadjuvant radiotherapy in rectal cancer patients. Some indicators reveal areas in need of additional efforts, for example to reduce the overall treatment time.
Involvement of supralemniscal nucleus (B9) 5-HT neuronal system in nociceptive processing: a fiber photometry study
Authors: Moriya Shunpei , Yamashita Akira , Masukawa Daiki , Kambe Yuki , Sakaguchi Junichi , Setoyama Honami , Yamanaka Akihiro , Kuwaki Tomoyuki 
Published: January 2020

AbstractNociception is important perception that has harmful influence on daily life of humans. As to main pain management system, some descending pathways are called descending antinociceptive systems (DAS). As main pathways of DAS, it is well known that dorsal raphe (B6/B7) - rostral ventromedial medulla (B3) - spinal dorsal horn includes serotonergic system. However, possible role of supralemniscal (B9) serotonin (5-HT) cell group in pain management is still open question. In this study, we measured activities of B9 5-HT neuronal cell bodies and B9 5-HT neuron-derived axons located in the locus coeruleus (LC) and ventral tegmental area (VTA), which are also main players of pain management, using fiber photometry system. We introduced the G-CaMP6 in B9 5-HT neurons using transgenic mice carrying a tetracycline-controlled transactivator transgene (tTA) under the control of a tryptophan hydroxylase-2 (TPH2) promoter and site-specific injection of adeno associated virus (AAV-TetO(3G)-G-CaMP6). After confirmation of specific expression of G-CaMP6 in the target population, G-CaMP6 fluorescence intensity in B9 group and LC/VTA groups was measured in awake mice exposed to acute tail pinch and heat stimuli. G-CaMP6 fluorescence intensity rapidly increased by both stimuli in all groups, but not significantly reacted by nonnociceptive control stimuli. The present results clearly indicate that acute nociceptive stimuli cause a rapid increase in the activities of B9-LC/B9-VTA 5-HTergic pathways, suggesting that B9 5-HT neurons play important roles in nociceptive processing.
Myeloid-derived suppressor cells—new and exciting players in lung cancer
Authors: Yang Zhenzhen , Guo Jiacheng , Weng Lanling , Tang Wenxue , Jin Shuiling , Ma Wang 
Published: January 2020

AbstractLung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.
Repurposing chlorpromazine in the treatment of glioblastoma multiforme: analysis of literature and forthcoming steps
Authors: Abbruzzese Claudia , Matteoni Silvia , Persico Michele , Villani Veronica , Paggi Marco G. 
Published: January 2020

Abstract
Background
Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue.

Main body
The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities.

Short conclusions
On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.
Correlation between detergent activity and anti-herpes simplex virus-2 activity of commercially available vaginal gels
Authors: Szöllősi Andrea , Raffai Tímea , Bogdanov Anita , Endrész Valéria , Párducz László , Somogyvári Ferenc , Janovák László , Burián Katalin , Virok Dezső P. 
Published: January 2020

AbstractObjectiveHerpes simplex virus-2 (HSV-2) infections are almost exclusively sexually transmitted. The presence of vaginal gels during sexual activity may have a significant positive or negative impact on viral transmission. Therefore we investigated three off-the-shelf vaginal lubricants and one pH restoring gel to evaluate their impact on HSV-2 replication.ResultsHeLa cells were infected with untreated virions and virions incubated with the particular gels. The accumulation of viral genomes was monitored by quantitative PCR (qPCR) method at 24 h post infection. Two of the tested gels had no significant effect on HSV-2 replication at the maximum applied concentration, while two had a strong inhibitory effect (~ 98% reduction of replication). The replication inhibitory effect was observed at various multiplicity of infection (MOI 0.4–6.4) and the two inhibitory gels were also capable of inhibiting the HSV-2 induced cytopathic effect on HeLa cells. The surface tension decreasing activity—an indication of detergent activity—was strongly correlated with the anti-HSV-2 activity of the gels (R2: 0.88). Our results indicate that off-the-shelf vaginal gels have a markedly different anti-HSV-2 activity that may influence HSV-2 transmission.
Bradycardia and syncope as sole manifestations of a cranial lesion: a case report
Authors: Pchejetski Dmitri , Kenbaz Mojiba , Alshaker Heba , Jesudason Kiruparajan 
Published: January 2020

Abstract
Background
Bradycardia and syncope are known sequelae of brain lesions. However, in the absence of neurological signs and symptoms, bradycardia and syncope are often investigated purely from the cardiovascular perspective and central nervous system-related causes may be easily overlooked during differential diagnosis.

Case presentation
Here we report a case of a 69-year-old Caucasian man who presented to the emergency department after a fall. He had 1-year history of syncope and bradycardia with frequent ectopic beats shown on his electrocardiogram. He had no neurological symptoms. He was previously investigated as an out-patient and a diagnosis of idiopathic bradycardia with ventricular ectopic beats was made. On admission, cardiovascular investigations could not reveal the cause of his bradycardia. Computed tomography and magnetic resonance imaging scans of his head showed a localized mass in left basal ganglia consistent with infiltrating glioma.

Conclusion
To the best of our knowledge this is the first case report demonstrating central nervous system-related bradycardia and syncope without other neurological symptoms. This case will serve as a useful reminder to general practitioners, accident and emergency doctors, and cardiologists.
Simulation and multi-objective optimization to improve the final shape and process efficiency of a laser-based material accumulation process
Authors: Bänsch Eberhard , Luttmann Andreas , Montalvo-Urquizo Jonathan , Schmidt Alfred , Villarreal-Marroquín Maria G. 
Published: January 2020

AbstractCommon goals of modern production processes are precision and efficiency. Typically, they are conflicting and cannot be optimized at the same time. Multi-objective optimization methods are able to compute a set of good parameters, from which a decision maker can make a choice for practical situations. For complex processes, the use of physical experiments and/or extensive process simulations can be too costly or even unfeasible, so the use of surrogate models based on few simulations is a good alternative.In this work, we present an integrated framework to find optimal process parameters for a laser-based material accumulation process (thermal upsetting) using a combination of meta-heuristic optimization models and finite element simulations. In order to effectively simulate the coupled system of heat equation with solid-liquid phase transitions and melt flow with capillary free surface in three space dimensions for a wide range of process parameters, we introduce a new coupled numerical 3d finite element method. We use a multi-objective optimization method based on surrogate models. Thus, with only few direct simulations necessary, we are able to select Pareto sets of process parameters which can be used to optimize three or six different performance measures.
Dissecting the factors shaping fish skin microbiomes in a heterogeneous inland water system
Authors: Krotman Yaron , Yergaliyev Timur M. , Alexander Shani Rivka , Avrahami Yosef , Szitenberg Amir 
Published: January 2020

AbstractBackgroundFish skin microbiomes are rarely studied in inland water systems, in spite of their importance for fish health and ecology. This is mainly because fish species distribution often covaries with other biotic and abiotic factors, complicating the study design. We tackled this issue in the northern part of the Jordan River system, in which a few fish species geographically overlap, across steep gradients of water temperature and salinity.ResultsUsing 16S rRNA metabarcoding, we studied the water properties that shape the skin bacterial communities, and their interaction with fish taxonomy. To better characterise the indigenous skin community, we excluded bacteria that were equally abundant in the skin samples and in the water samples, from our analysis of the skin samples. With this in mind, we found alpha diversity of the skin communities to be stable across sites, but higher in benthic loaches, compared to other fish. Beta diversity was found to be different among sites and to weakly covary with the dissolved oxygen, when treated skin communities were considered. In contrast, water temperature and conductivity were strong factors explaining beta diversity in the untreated skin communities. Beta diversity differences between co-occurring fish species emerged only for the treated skin communities. Metagenomics predictions highlighted the microbiome functional implications of excluding the water community contamination from the fish skin communities. Finally, we found that human-induced eutrophication promotes dysbiosis of the fish skin community, with signatures relating to fish health.ConclusionsConsideration of the background water microbiome when studying fish skin microbiomes, across varying fish species and water properties, exposes patterns otherwise undetected and highlight among-fish-species differences. We suggest that sporadic nutrient pollution events, otherwise undetected, drive fish skin communities to dysbiosis. This finding is in line with a recent study, showing that biofilms capture sporadic pollution events, undetectable by interspersed water monitoring.
Personalized CT‐based radiomics nomogram preoperative predicting Ki‐67 expression in gastrointestinal stromal tumors: a multicenter development and validation cohort
Authors: Zhang Qing‐Wei , Gao Yun‐Jie , Zhang Ran‐Ying , Zhou Xiao‐Xuan , Chen Shuang‐Li , Zhang Yan , Liu Qiang , Xu Jian‐Rong , Ge Zhi‐Zheng 
Published: January 2020

AbstractBackground and AimTo develop and validate radiomic prediction models using contrast‐enhanced computed tomography (CE‐CT) to preoperatively predict Ki‐67 expression in gastrointestinal stromal tumors (GISTs).MethodA total of 339 GIST patients from four centers were categorized into the training, internal validation, and external validation cohort. By filtering unstable features, minimum redundancy, maximum relevance, Least Absolute Shrinkage and Selection Operator (LASSO) algorithm, a radiomic signature was built to predict the malignant potential of GISTs. Individual nomograms of Ki‐67 expression incorporating the radiomic signature or clinical factors were developed using the multivariate logistic model and evaluated regarding its calibration, discrimination, and clinical usefulness.ResultsThe radiomic signature, consisting of 6 radiomic features had AUC of 0.787 [95% confidence interval (CI) 0.632–0.801], 0.765 (95% CI 0.683–0.847), and 0.754 (95% CI 0.666–0.842) in the prediction of high Ki‐67 expression in the training, internal validation and external validation cohort, respectively. The radiomic nomogram including the radiomic signature and tumor size demonstrated significant calibration, and discrimination with AUC of 0.801 (95% CI 0.726–0.876), 0.828 (95% CI 0.681–0.974), and 0.784 (95% CI 0.701–0.868) in the training, internal validation and external validation cohort respectively. Based on the Decision curve analysis, the radiomics nomogram was found to be clinically significant and useful.ConclusionsThe radiomic signature from CE‐CT was significantly associated with Ki‐67 expression in GISTs. A nomogram consisted of radiomic signature, and tumor size had maximum accuracy in the prediction of Ki‐67 expression in GISTs. Results from our study provide vital insight to make important preoperative clinical decisions.
DNA damage accumulates and responses are engaged in human ALS brain and spinal motor neurons and DNA repair is activatable in iPSC-derived motor neurons with SOD1 mutations
Authors: Kim Byung Woo , Jeong Ye Eun , Wong Margaret , Martin Lee J. 
Published: January 2020

AbstractDNA damage is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, relationships between DNA damage accumulation, DNA damage response (DDR), and upper and lower motor neuron vulnerability in human ALS are unclear; furthermore, it is unknown whether epigenetic silencing of DNA repair pathways contributes to ALS pathogenesis. We tested the hypotheses that DNA damage accumulates in ALS motor neurons along with diminished DDR, and that DNA repair genes undergo hypermethylation. Human postmortem CNS tissue was obtained from ALS cases (N = 34) and age-matched controls without neurologic disease (N = 15). Compared to age-matched controls, abasic sites accumulated in genomic DNA of ALS motor cortex and laser capture microdissection-acquired spinal motor neurons but not in motor neuron mitochondrial DNA. By immunohistochemistry, DNA damage accumulated significantly in upper and lower motor neurons in ALS cases as single-stranded DNA and 8-hydroxy-deoxyguanosine (OHdG) compared to age-matched controls. Significant DDR was engaged in ALS motor neurons as evidenced by accumulation of c-Abl, nuclear BRCA1, and ATM activation. DNA damage and DDR were present in motor neurons at pre-attritional stages and throughout the somatodendritic attritional stages of neurodegeneration. Motor neurons with DNA damage were also positive for activated p53 and cleaved caspase-3. Gene-specific promoter DNA methylation pyrosequencing identified the DNA repair genesOgg1,Apex1,PnkpandAptxas hypomethylated in ALS. In human induced-pluripotent stem cell (iPSC)-derived motor neurons with familial ALS SOD1 mutations, DNA repair capacity was similar to isogenic control motor neurons. Our results show that vulnerable neurons in human ALS accumulate DNA damage, and contrary to our hypothesis, strongly activate and mobilize response effectors and DNA repair genes. This DDR in ALS motor neurons involves recruitment of c-Abl and BRCA1 to the nucleus in vivo, and repair of DNA double-strand breaks in human ALS motor neurons with SOD1 mutations in cell culture.