bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4
Authors: Qin Shuang , Xu Linping , Yi Ming , Yu Shengnan , Wu Kongming , Luo Suxia 
Published: November 2019

AbstractThe emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.
Leap motion controlled video game-based therapy for upper limb rehabilitation in patients with Parkinson’s disease: a feasibility study
Authors: Fernández-González Pilar , Carratalá-Tejada María , Monge-Pereira Esther , Collado-Vázquez Susana , Sánchez-Herrera Baeza Patricia , Cuesta-Gómez Alicia , Oña-Simbaña Edwin Daniel , Jardón-Huete Alberto , Molina-Rueda Francisco , Balaguer-Bernaldo de Quirós Carlos , Miangolarra-Page Juan Carlos , Cano-de la Cuerda Roberto 
Published: November 2019

Abstract

Background
Non-immersive video games are currently being used as technological rehabilitation tools for individuals with Parkinson’s disease (PD). The aim of this feasibility study was to evaluate the effectiveness of the Leap Motion Controller® (LMC) system used with serious games designed for the upper limb (UL), as well as the levels of satisfaction and compliance among patients in mild-to-moderate stages of the disease.

Methods
A non-probabilistic sampling of non-consecutive cases was performed. 23 PD patients, in stages II-IV of the Hoehn & Yahr scale, were randomized into two groups: an experimental group (n = 12) who received treatment based on serious games designed by the research team using the LMC system for the UL, and a control group (n = 11) who received a specific intervention for the UL. Grip muscle strength, coordination, speed of movements, fine and gross UL dexterity, as well as satisfaction and compliance, were assessed in both groups pre-treatment and post-treatment.

Results
Within the experimental group, significant improvements were observed in all post-treatment assessments, except for Box and Blocks test for the less affected side. Clinical improvements were observed for all assessments in the control group. Statistical intergroup analysis showed significant improvements in coordination, speed of movements and fine motor dexterity scores on the more affected side of patients in the experimental group.

Conclusions
The LMC system and the serious games designed may be a feasible rehabilitation tool for the improvement of coordination, speed of movements and fine UL dexterity in PD patients. Further studies are needed to confirm these preliminary findings.
Important roles of C-terminal residues in degradation of capsid protein of classical swine fever virus
Authors: Chen Yuming , Zhu Erpeng , Fan Shuangqi , Ding Hongxing , Ma Shengming , Zhu Mengjiao , Deng Shaofeng , Chen Jinding , Zhao Mingqiu 
Published: November 2019

Abstract

Background
Capsid (C) protein plays an important role in the replication of classical swine fever virus (CSFV). The ubiquitin proteasome system (UPS) involves in replication of many viruses via modulation of viral proteins. The relationship of CSFV with UPS is poorly understood and the impact of 26S proteasome on C protein has never been reported before.

Methods
In this study, fused C protein with an EGFP tag is expressed in PK-15 and 3D4/2 cells. MG132 and 3-methyladenine (3-MA) are used to detect the roles of 26S proteasome and autophagolysosome in expression levels of C protein. Truncated and mutant C proteins are used to find the exact residues responsible for the degradation of C protein. Immunoprecipitaion is performed to find whether C protein is ubiquitinated or not.

Results
C-EGFP protein expresses in a cleaved form at a low level and is degraded by 26S proteasome which could be partly inhibited by MG132. C-terminal residues play more important roles in the degradation of C protein than N-terminal residues. Residues 260 to 267, especially M260 and L261, are crucial for the degradation. In addition, C-terminal residues 262 to 267 determine cleavage efficiency of C protein.

Conclusions
CSFV C protein is degraded by 26S proteasome in a ubiquitin-independent manner. Last 8 residues at C-terminus of immature C protein play a major role in proteasomal degradation of CSFV C protein and determine the cleavage efficiency of C protein by signal peptide peptidase (SPP). Our findings provide valuable help for fully understanding degradation process of C protein and contribute to fully understanding the role of C protein in CSFV replication.
A newly isolated roseophage represents a distinct member of Siphoviridae family
Authors: Cai Lanlan , Ma Ruijie , Chen Hong , Yang Yunlan , Jiao Nianzhi , Zhang Rui 
Published: November 2019

AbstractBackgroundMembers of theRoseobacterlineage are a major group of marine heterotrophic bacteria because of their wide distribution, versatile lifestyles and important biogeochemical roles. Bacteriophages, the most abundant biological entities in the ocean, play important roles in shaping their hosts’ population structures and mediating genetic exchange between hosts. However, our knowledge of roseophages (bacteriophages that infectRoseobacter) is far behind that of their host counterparts, partly reflecting the need to isolate and analyze the phages associated with this ecologically important bacterial clade.MethodsvB_DshS-R4C (R4C), a novel virulent roseophage that infectsDinoroseobacter shibaeDFL12T, was isolated with the double-layer agar method. The phage morphology was visualized with transmission electron microscopy. We characterized R4C in-depth with a genomic analysis and investigated the distribution of the R4C genome in different environments with a metagenomic recruitment analysis.ResultsThe double-stranded DNA genome of R4C consists of 36,291 bp with a high GC content of 66.75%. It has 49 genes with low DNA and protein homologies to those of other known phages. Morphological and phylogenetic analyses suggested that R4C is a novel member of the familySiphoviridaeand is most closely related to phages in the genusCronusvirus. However, unlike theCronusvirusphages, R4C encodes an integrase, implying its ability to establish a lysogenic life cycle. A terminal analysis shows that, like that of λ phage, the R4C genome utilize the ‘cohesive ends’ DNA-packaging mechanism. Significantly, homologues of the R4C genes are more prevalent in coastal areas than in the open ocean.ConclusionsInformation about this newly discovered phage extends our understanding of bacteriophage diversity, evolution, and their roles in different environments.
Sexual risky behavior, cocaine and alcohol use among substance users in an outpatient facility: a cross section study
Authors: Dallelucci Claudia Chaves , Bragiato Emi Carneiro , Areco Kelsy Catherina Nema , Fidalgo Thiago Marques , da Silveira Dartiu Xavier 
Published: November 2019

Abstract

Background
Substance dependence is considered an international health issue and studies that access the characteristic of this population are required to develop public health programs for harm reduction. To this aim, we purpose to to identify, in a population undergo addiction treatment, if the use of substances leads to sexual risky behavior and also check if another variables influences in this behavior.

Method
Observational study of clinical sample collected of adult patients seeking treatment to dependence of alcohol and cocaine. The data collected were: socio-demographic, substance use, sexual behavior and childhood abuse. Risky sexual behaviors were considered: inconsistent use of condoms and presence of multiple sexual partners in the past six months. An exploratory analysis of the association between the variable “risky sexual behavior” and the other variables was performed using Pearson’s chi-square, followed by a multivariate logistic regression analysis.

Results
After analyzing the variables with the presence or absence of risky sexual behavior, were included in the logistic regression the data that presented association with sexual risk behavior, and age appears as an independent factor for risky sexual behaviors. Other factors, such as schooling and unemployment, influence as much as the use of substances in risky sexual behaviors.

Conclusion
Attributing just to the substance use this risky sexual behavior seems too simplistic. Other structural factors such as schooling, work, age and sexual abuse in childhood can influence decision making for safe sex.
Cost-effectiveness analysis (CEA) of IMRT plus C12 boost vs IMRT only in adenoid cystic carcinoma (ACC) of the head and neck
Authors: Jensen A D , Debus Jürgen 
Published: November 2019

AbstractBackgroundParticle therapy provides steep dose gradients to facilitate dose escalation in challenging anatomical sites which has been shown not only to improve local control but also overall survival in patients with ACC. Cost-effectiveness of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost vs IMRT alone was performed in order to objectivise and substantiate more widespread use of this technology in ACC.MethodsPatients with pathologically confirmed ACC received a combination regimen of IMRT plus C12 boost. Patients presenting outside C12 treatment slots received IMRT only. Clinical results were published; economic analysis on patient-level data was carried out from a healthcare purchaser’s perspective based on costs of healthcare utilization. Cost histories were generated from resource use recorded in individual patient charts and adjusted for censoring using the Lin I method. Cost-effectiveness was measured as incremental cost-effectiveness ratio (ICER). Sensitivity analysis was performed regarding potentially differing management of recurrent disease.ResultsThe experimental treatment increased overall costs by € 18,076 (€13,416 – €22,922) at a mean survival benefit of 0.86 years. Despite improved local control, following costs were also increased in the experimental treatment. The ICER was estimated to 26,863 €/LY. After accounting for different management of recurrent disease in the two cohorts, the ICER was calculated to 20,638 €/LY.ConclusionThe combined treatment (IMRT+C12 boost) substantially increased initial and overall treatment cost. In view of limited treatment options in ACC, costs may be acceptable though. Investigations into quality of life measures may support further decisions in the future.
The longitudinal effects of seated isometric yoga on blood biomarkers, autonomic functions, and psychological parameters of patients with chronic fatigue syndrome: a pilot study
Authors: Oka Takakazu , Tanahashi Tokusei , Lkhagvasuren Battuvshin , Yamada Yu 
Published: November 2019

AbstractBackgroundIn a previous randomized controlled trial, we found that practicing seated isometric yoga regularly for 2 months improved the fatigue of patients with chronic fatigue syndrome (CFS) who are resistant to conventional therapy. The aim of this pilot study was to investigate the possible mechanisms behind this finding by comparing blood biomarkers, autonomic nervous function, and psychological indices before versus after an intervention period of seated isometric yoga practice.MethodsFifteen patients with CFS who did not show satisfactory improvements after at least 6 months of conventional therapy practiced seated isometric yoga (biweekly 20-min sessions with a yoga instructor and daily practice at home) for 2 months. The longitudinal effects of seated isometric yoga on fatigue, blood biomarkers, autonomic function, and psychological state were investigated by comparing the following parameters before and after the intervention period: Fatigue severity was assessed by the Chalder fatigue scale (FS) score. Levels of the blood biomarkers cortisol, DHEA-S, TNF-α, IL-6, prolactin, carnitine, TGF-β1, BDNF, MHPG, HVA, and α-MSH were measured. The autonomic nervous functions assessed were heart rate (HR) and HR variability. Psychological indices included the 20-item Toronto Alexithymia Scale (TAS-20) and the Hospital Anxiety and Depression Scale (HADS).ResultsPracticing seated isometric yoga for 2 months resulted in significant reductions in the Chalder FS (P = 0.002) and HADS-depression (P = 0.02) scores. No significant changes were observed in any other parameter evaluated. The change in Chalder FS score was not correlated with the change in HADS-depression score. However, this change was positively correlated with changes in the serum TNF-α levels (P = 0.048), the high frequency component of HR variability (P = 0.042), and TAS-20 scores (P = 0.001).ConclusionsRegular practice of seated isometric yoga for 2 months reduced the fatigue and depressive symptom scores of patients with CFS without affecting any other parameters we investigated. This study failed to identify the markers responsible for the longitudinal fatigue-relieving effect of seated isometric yoga. However, considering that the reduced fatigue was associated with decreased serum TNF-α level and TAS-20 scores, fatigue improvement might be related to reduced inflammation and improved alexithymia in these patients.Trial registrationUniversity Hospital Medical Information Network (UMIN CTR)UMIN000009646. Registered Dec 27, 2012.
Novel nose poke-based temporal discrimination tasks with concurrent in vivo calcium imaging in freely moving mice
Authors: Marks William D. , Osanai Hisayuki , Yamamoto Jun , Ogawa Sachie K. , Kitamura Takashi 
Published: November 2019

Abstract
The hippocampus has been known to process temporal information as part of memory formation. While time cells have been observed in the hippocampus and medial entorhinal cortex, a number of the behavioral tasks used present potential confounds that may cause some contamination of time cell observations due to animal movement. Here, we report the development of a novel nose poke-based temporal discrimination task designed to be used with in vivo calcium imaging for the analysis of hippocampal time cells in freely moving mice. First, we developed a ten second held nose poke paradigm for use in mice to deliver a purer time metric for the analysis of time cell activity in hippocampus CA1. Second, we developed a temporal discrimination task that involves the association of held nose poke durations of differing lengths with differential spatial cues presented in arms on a linear I-maze. Four of five mice achieved successful temporal discrimination within three weeks. Calcium imaging has been successfully performed in each of these tasks, with time cell activity being detected in the 10s nose poke task, and calcium waves being observed in discrete components of the temporal discrimination task. The newly developed behavior tasks in mice serve as novel tools to accelerate the study of time cell activity and examine the integration of time and space in episodic memory formation.
Proteasomal cysteine deubiquitinase inhibitor b-AP15 suppresses migration and induces apoptosis in diffuse large B cell lymphoma
Authors: Jiang Liling , Sun Yuening , Wang Jinxiang , He Qingyan , Chen Xinmei , Lan Xiaoying , Chen Jinghong , Dou Q. Ping , Shi Xianping , Liu Jinbao 
Published: November 2019

Abstract

Background
The first line therapy for patients with diffuse large B cell (DLBCL) is R-CHOP. About half of DLBCL patients are either refractory to, or will relapse, after the treatment. Therefore, identifying novel drug targets and effective therapeutic agents is urgently needed for improving DLBCL patient survival. b-AP15, a selective small molecule inhibitor of proteasomal USP14 and UCHL5 deubiquitinases (DUBs), has shown selectivity and efficacy in several other types of cancer cells. This is the first study to report the effect of b-AP15 in DLBCL.

Methods
Cell lines of two DLBCL subtypes, Germinal Center B Cell/ GCB (SU-DHL-4, OCI-LY-1, OCI-LY-19) and Activated B Cell/ABC (SU-DHL-2), were used in the current study. Cell viability was measured by MTS assay, proliferation by trypan blue exclusion staining assay, cellular apoptosis by Annexin V-FITC/PI staining and mitochondrial outer membrane permeability assays, the activities of 20S proteasome peptidases by cleavage of specific fluorogenic substrates, and cell migration was detected by transwell assay in these GCB- and ABC-DLBCL cell lines. Mouse xenograft models of SU-DHL-4 and SU-DHL-2 cells were used to determine in vivo effects of b-AP15 in DLBCL tumors.

Results
b-AP15 inhibited proteasome DUB activities and activated cell death pathway, as evident by caspase activation and mitochondria apoptosis in GCB- and ABC- DLBCL cell lines. b-AP15 treatment suppressed migration of GCB- and ABC-DLBCL cells via inhibiting Wnt/β-catenin and TGFβ/Smad pathways. Additionally, b-AP15 significantly inhibited the growth of GCB- and ABC DLBCL in xenograft models.

Conclusions
These results indicate that b-AP15 inhibits cell migration and induces apoptosis in GCB- and ABC-DLBCL cells, and suggest that inhibition of 19S proteasomal DUB should be a novel strategy for DLBCL treatment.
STRA6 exerts oncogenic role in gastric tumorigenesis by acting as a crucial target of miR-873
Authors: Lin Linling , Xiao Jian , Shi Liang , Chen Wangwang , Ge Yugang , Jiang Mingkun , Li Zengliang , Fan Hao , Yang Li , Xu Zekuan 
Published: November 2019

Abstract

Background
Increasing evidence shows that stimulated by retinoic acid 6 (STRA6) participates in regulating multiple cancers. However, the biological roles of STRA6 in gastric cancer (GC) remain unknown. This study aimed to investigate the biological function of STRA6 and reveal the underlying mechanism of its dysregulation in GC.

Methods
The expression level of STRA6 was detected through quantitative real-time PCR and Western blot analysis. The effects of STRA6 on the proliferation of GC cells were studied through CCK-8 proliferation, colony formation and 5-ethynyl-2′-deoxyuridine (EdU) assays. The effects of STRA6 on migration and invasion were detected via wound healing and Transwell assays. Upstream miRNAs, which might regulate STRA6 expression, was predicted through bioinformatics analysis. Their interaction was further confirmed through dual-luciferase reporter assays and rescue experiments.

Results
STRA6 was up-regulated in GC and enhanced the proliferation and metastasis of GC cells in vitro and in vivo. STRA6 knockdown could inhibit the Wnt/β-catenin signalling pathway. STRA6 was confirmed as an miR-873 target, which acted as a tumour suppressor in GC. Rescue assays showed that the repressing effect of miR-873 could be partially reversed by overexpressing STRA6.

Conclusions
STRA6 is down-regulated by miR-873 and plays an oncogenic role by activating Wnt/β-catenin signalling in GC.
The HOTAIR/miR-214/ST6GAL1 crosstalk modulates colorectal cancer procession through mediating sialylated c-Met via JAK2/STAT3 cascade
Authors: Liu Bing , Liu Qianqian , Pan Shimeng , Huang Yiran , Qi Yu , Li Shuangda , Xiao Yang , Jia Li 
Published: November 2019

Abstract

Background
The regulatory non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), emerge as pivotal markers during tumor progression. Abnormal sialylated glycoprotein often leads to the malignancy of colorectal cancer (CRC).

Methods
Differential levels of HOTAIR and ST6GAL1 are analyzed by qRT-PCR. Functionally, CRC cell proliferation, aggressiveness and apoptosis are measured through relevant experiments, including CCK8 assay, colony formation assay, transwell assay, western blot and flow cytometry. Dual-luciferase reporter gene assay and RIP assay confirm the direct interaction between HOTAIR and miR-214. The lung metastasis, liver metatstasis and xenografts nude mice models are established to show the in vivo effect of HOATIR.

Results
Here, differential levels of HOTAIR and ST6GAL1 are primarily observed in CRC samples and cells. Upregulated HOTAIR and ST6GAL1 are crucial predictors for poor CRC prognosis. Altered level of ST6GAL1 modulates CRC malignancy. Furthermore, ST6GAL1 and HOTAIR are confirmed as the direct targets of miR-214, and ST6GAL1 is regulated by HOTAIR via sponging miR-214. ST6GAL1 induces the elevated metabolic sialylation of c-Met, which is co-mediated by HOTAIR and miR-214. Sialylated c-Met affects the activity of JAK2/STAT3 pathway. The regulatory role of HOTAIR/miR-214/ST6GAL1 axis also impacts CRC procession. In addition, HOTAIR mediates lung metastasis, liver metastasis and tumorigenesis in vivo. ShHOTAIR and AMG-208 are combined to inhibit tumorigenesis for successful drug development.

Conclusion
The HOTAIR/miR-214/ST6GAL1 axis commands the CRC malignancy by modifying c-Met with sialylation and activating JAK2/STAT3 pathway. Our study presents novel insights into CRC progression and provided prospective therapeutic target for CRC.
A novel non-invasive method to detect excessively high respiratory effort and dynamic transpulmonary driving pressure during mechanical ventilation
Authors: Bertoni Michele , Telias Irene , Urner Martin , Long Michael , Del Sorbo Lorenzo , Fan Eddy , Sinderby Christer , Beck Jennifer , Liu Ling , Qiu Haibo , Wong Jenna , Slutsky Arthur S. , Ferguson Niall D. , Brochard Laurent J. , Goligher Ewan C. 
Published: November 2019

Abstract

Background
Excessive respiratory muscle effort during mechanical ventilation may cause patient self-inflicted lung injury and load-induced diaphragm myotrauma, but there are no non-invasive methods to reliably detect elevated transpulmonary driving pressure and elevated respiratory muscle effort during assisted ventilation. We hypothesized that the swing in airway pressure generated by respiratory muscle effort under assisted ventilation when the airway is briefly occluded (ΔPocc) could be used as a highly feasible non-invasive technique to screen for these conditions.

Methods
Respiratory muscle pressure (Pmus), dynamic transpulmonary driving pressure (ΔPL,dyn, the difference between peak and end-expiratory transpulmonary pressure), and ΔPocc were measured daily in mechanically ventilated patients in two ICUs in Toronto, Canada. A conversion factor to predict ΔPL,dyn and Pmus from ΔPocc was derived and validated using cross-validation. External validity was assessed in an independent cohort (Nanjing, China).

Results
Fifty-two daily recordings were collected in 16 patients. In this sample, Pmus and ΔPL were frequently excessively high: Pmus exceeded 10 cm H2O on 84% of study days and ΔPL,dyn exceeded 15 cm H2O on 53% of study days. ΔPocc measurements accurately detected Pmus > 10 cm H2O (AUROC 0.92, 95% CI 0.83–0.97) and ΔPL,dyn > 15 cm H2O (AUROC 0.93, 95% CI 0.86–0.99). In the external validation cohort (n = 12), estimating Pmus and ΔPL,dyn from ΔPocc measurements detected excessively high Pmus and ΔPL,dyn with similar accuracy (AUROC ≥ 0.94).

Conclusions
Measuring ΔPocc enables accurate non-invasive detection of elevated respiratory muscle pressure and transpulmonary driving pressure. Excessive respiratory effort and transpulmonary driving pressure may be frequent in spontaneously breathing ventilated patients.