bluuebunny/crossref_metadata_2025 huggingface dataset:
Illness Cognitions in ALS: New Insights Into Clinical Management of Behavioural Symptoms
Authors: Caga Jashelle , Devenney Emma , Huynh William , Zoing Margaret C. , Ahmed Rebekah M. , Kiernan Matthew C.
Published: September 2021

Timely management of frontotemporal dysfunction associated with amyotrophic lateral sclerosis (ALS) has important prognostic and therapeutic implications. However, there remains a paucity of research on best practise recommendations to guide the development of interventions for cognitive and behavioural symptoms as part of ALS care. Accordingly, a focus on illness perceptions may provide a preliminary framework for managing cognitive and behavioural symptoms. The aim of the present study was to explore the nature of illness perceptions among ALS patients with cognitive and behavioural symptoms. A total of 39 patients were recruited from a specialised ALS clinic. Factor analysis showed three independent and clinically interpretable factors corresponding to “cognitive and emotion related ALS perceptions,” “cognitive- specific ALS perceptions” and “ALS coherence”. Of these factors, greater perceived cognitive and emotional impacts of ALS were associated with an approximate 4-fold increased risk of behavioural changes (p < 0.05). Greater perceived cognitive and emotional impacts of ALS was also associated with more rapid disease progression (p < 0.001). As such, timely provision of intervention addressing perceptions about the impact of ALS on functioning as well as associated emotional distress may optimise clinical management of cognitive and behavioural symptoms of ALS.
On Neurorights
Authors: Ienca Marcello
Published: September 2021

In recent years, philosophical-legal studies on neuroscience (mainly in the fields of neuroethics and neurolaw) have given increasing prominence to a normative analysis of the ethical-legal challenges in the mind and brain sciences in terms of rights, freedoms, entitlements and associated obligations. This way of analyzing the ethical and legal implications of neuroscience has come to be known as “neurorights.” Neurorights can be defined as the ethical, legal, social, or natural principles of freedom or entitlement related to a person’s cerebral and mental domain; that is, the fundamental normative rules for the protection and preservation of the human brain and mind. Although reflections on neurorights have received ample coverage in the mainstream media and have rapidly become a mainstream topic in the public neuroethics discourse, the frequency of such reflections in the academic literature is still relatively scarce. While the prominence of the neurorights debate in public opinion is crucial to ensure public engagement and democratic participation in deliberative processes on this issue, its relatively sporadic presence in the academic literature poses a risk of semantic-normative ambiguity and conceptual confusion. This risk is exacerbated by the presence of multiple and not always reconcilable terminologies. Several meta-ethical, normative ethical, and legal-philosophical questions need to be solved in order to ensure that neurorights can be used as effective instruments of global neurotechnology governance and be adequately imported into international human rights law. To overcome the shortcomings above, this paper attempts to provide a comprehensive normative-ethical, historical and conceptual analysis of neurorights. In particular, it attempts to (i) reconstruct a history of neurorights and locate these rights in the broader history of idea, (ii) outline a systematic conceptual taxonomy of neurorights, (iii) summarize ongoing policy initiatives related to neurorights, (iv) proactively address some unresolved ethico-legal challenges, and (v) identify priority areas for further academic reflection and policy work in this domain.
Reported Hearing Loss in Alzheimer’s Disease Is Associated With Loss of Brainstem and Cerebellar Volume
Authors: Llano Daniel A. , Kwok Susanna S. , Devanarayan Viswanath ,   The Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: September 2021

Multiple epidemiological studies have revealed an association between presbycusis and Alzheimer’s Disease (AD). Unfortunately, the neurobiological underpinnings of this relationship are not clear. It is possible that the two disorders share a common, as yet unidentified, risk factor, or that hearing loss may independently accelerate AD pathology. Here, we examined the relationship between reported hearing loss and brain volumes in normal, mild cognitive impairment (MCI) and AD subjects using a publicly available database. We found that among subjects with AD, individuals that reported hearing loss had smaller brainstem and cerebellar volumes in both hemispheres than individuals without hearing loss. In addition, we found that these brain volumes diminish in size more rapidly among normal subjects with reported hearing loss and that there was a significant interaction between cognitive diagnosis and the relationship between reported hearing loss and these brain volumes. These data suggest that hearing loss is linked to brainstem and cerebellar pathology, but only in the context of the pathological state of AD. We hypothesize that the presence of AD-related pathology in both the brainstem and cerebellum creates vulnerabilities in these brain regions to auditory deafferentation-related atrophy. These data have implications for our understanding of the potential neural substrates for interactions between hearing loss and AD.
Transfer of Perceptual Learning From Local Stereopsis to Global Stereopsis in Adults With Amblyopia: A Preliminary Study
Authors: Chopin Adrien , Silver Michael A. , Sheynin Yasha , Ding Jian , Levi Dennis Michael
Published: September 2021

It has long been debated whether the analysis of global and local stereoscopic depth is performed by a single system or by separate systems. Global stereopsis requires the visual system to solve a complex binocular matching problem to obtain a coherent percept of depth. In contrast, local stereopsis requires only a simple matching of similar image features. In this preliminary study, we recruited five adults with amblyopia who lacked global stereopsis and trained them on a computerized local stereopsis depth task for an average of 12 h. Three out of five (60%) participants recovered fine global stereoscopic vision through training. Those who recovered global stereopsis reached a learning plateau more quickly on the local stereopsis task, and they tended to start the training with better initial local stereopsis performance, to improve more on local stereopsis with training, and to have less severe amblyopia. The transfer of learning from local stereopsis to global stereopsis is compatible with an interacting two-stage model.
Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease
Authors: Piro Inken , Eckes Anna-Lena , Kasaragod Vikram Babu , Sommer Claudia , Harvey Robert J. , Schaefer Natascha , Villmann Carmen
Published: September 2021

Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC50 value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations.
Novel Molecular Basis for Synapse Formation: Small Non-coding Vault RNA Functions as a Riboregulator of MEK1 to Modulate Synaptogenesis
Authors: Wakatsuki Shuji , Araki Toshiyuki
Published: September 2021

Small non-coding vault RNAs (vtRNAs) have been described as a component of the vault complex, a hollow-and-barrel-shaped ribonucleoprotein complex found in most eukaryotes. It has been suggested that the function of vtRNAs might not be limited to simply maintaining the structure of the vault complex. Despite the increasing research on vtRNAs, little is known about their physiological functions. Recently, we have shown that murine vtRNA (mvtRNA) up-regulates synaptogenesis by activating the mitogen activated protein kinase (MAPK) signaling pathway. mvtRNA binds to and activates mitogen activated protein kinase 1 (MEK1), and thereby enhances MEK1-mediated extracellular signal-regulated kinase activation. Here, we introduce the regulatory mechanism of MAPK signaling in synaptogenesis by vtRNAs and discuss the possibility as a novel molecular basis for synapse formation.
Steering Mast Cells or Their Mediators as a Prospective Novel Therapeutic Approach for the Treatment of Hematological Malignancies
Authors: Mehtani Deeksha , Puri Niti
Published: September 2021

Tumor cells require signaling and close interaction with their microenvironment for their survival and proliferation. In the recent years, Mast cells have earned a greater importance for their presence and role in cancers. It is known that mast cells are attracted towards tumor microenvironment by secreted soluble chemotactic factors. Mast cells seem to exert a pro-tumorigenic role in hematological malignancies with a few exceptions where they showed anti-cancerous role. This dual role of mast cells in tumor growth and survival may be dependent on the intrinsic characteristics of the particular tumor, differences in tumor microenvironment according to tumor type, and the interactions and heterogeneity of mediators released by mast cells in the tumor microenvironment. In many studies, Mast cells and their mediators have been shown to affect tumor survival and growth, prognosis, inflammation, tumor vascularization and angiogenesis. Modulating mast cell accumulation, viability, activity and mediator release patterns may thus be important in controlling these malignancies. In this review, we emphasize on the role of mast cells in lymphoid malignancies and discuss strategies for targeting and steering mast cells or their mediators as a potential therapeutic approach for the treatment of these malignancies.
Targeted Next-Generation Sequencing of Cancer-Related Genes in a Norwegian Patient Cohort With Head and Neck Squamous Cell Carcinoma Reveals Novel Actionable Mutations and Correlations With Pathological Parameters
Authors: Dongre Harsh N. , Haave Hilde , Fromreide Siren , Erland Fredrik A. , Moe Svein Erik Emblem , Dhayalan Sophia Manueldas , Riis Rasmus Kopperud , Sapkota Dipak , Costea Daniela Elena , Aarstad Hans Jorgen , Vintermyr Olav K.
Published: September 2021

Background

Targeted next-generation sequencing (NGS) is increasingly applied in clinical oncology to advance personalized treatment. Despite success in many other tumour types, use of targeted NGS panels for assisting diagnosis and treatment of head and neck squamous cell carcinomas (HNSCC) is still limited.

Aim

The focus of this study was to establish a robust NGS panel targeting most frequent cancer mutations in long-term preserved formalin-fixed paraffin-embedded (FFPE) tissue samples of HNSCC from routine diagnostics.

Materials and Methods

Tumour DNA obtained from archival FFPE tissue blocks of HNSCC patients treated at Haukeland University Hospital between 2003-2016 (n=111) was subjected to mutational analysis using a custom made AmpliSeq Library PLUS panel targeting 31 genes (Illumina). Associations between mutational burden and clinical and pathological parameters were investigated. Mutation and corresponding clinicopathological data from HNSCC were extracted for selected genes from the Cancer Genome Atlas (TCGA) and used for Chi-square and Kaplan-Meier analysis.

Results

The threshold for sufficient number of reads was attained in 104 (93.7%) cases. Although the specific number of PCR amplified reads detected decreased, the number of NGS-annotated mutations did not significantly change with increased tissue preservation time. In HPV-negative carcinomas, mutations were detected mainly in TP53 (73.3%), FAT1 (26.7%) and FLG (16.7%) whereas in HPV-positive, the common mutations were in FLG (24.3%) FAT1 (17%) and FGFR3 (14.6%) genes. Other less common pathogenic mutations, including well reported SNPs were reproducibly identified. Presence of at least one cancer-specific mutations was found to be positively associated with an extensive desmoplastic stroma (p=0.019), and an aggressive type of invasive front (p=0.035), and negatively associated with the degree of differentiation (p=0.041). Analysis of TCGA data corroborated the association between cancer-specific mutations and tumour differentiation and survival analysis showed that tumours with at least one mutation had shorter disease-free and overall survival (p=0.005).

Conclusions

A custom made targeted NGS panel could reliably detect several specific mutations in archival samples of HNSCCs preserved up to 17 years. Using this method novel associations between mutational burden and clinical and pathological parameters were detected and actionable mutations in HPV-positive HNSCC were discovered.
Miller–Payne Grading and 70-Gene Signature Are Associated With Prognosis of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer After Neoadjuvant Chemotherapy
Authors: Wang Liye , Luo Rongzhen , Lu Qianyi , Jiang Kuikui , Hong Ruoxi , Lee Kaping , Zhang Ping , Zhou Danyang , Wang Shusen , Xu Fei
Published: September 2021

Introduction

HR+/HER2− breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2− non-pCR populations, it is essential to accurate identification new prognostic markers.

Materials and Methods

The study retrospectively analyzed 105 stage II–III patients who were diagnosed with HR+/HER2− BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller–Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.

Results

Among the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1–2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4–5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10–0.80; p = 0.018]. DFS was longer in the good response (MP grades 3–4) group than in the poor response (MP grades 1–2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05–0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9–75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.

Conclusion

The study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.
Statistical Process Control Charts for Monitoring Next-Generation Sequencing and Bioinformatics Turnaround in Precision Medicine Initiatives
Authors: Jain Sneha Rajiv , Sim Wilson , Ng Cheng Han , Chin Yip Han , Lim Wen Hui , Syn Nicholas L. , Kamal Nur Haidah Bte Ahmad , Gupta Mehek , Heong Valerie , Lee Xiao Wen , Sapari Nur Sabrina , Koh Xue Qing , Isa Zul Fazreen Adam , Ho Lucius , O’Hara Caitlin , Ulagapan Arvindh , Gu Shi Yu , Shroff Kashyap , Weng Rei Chern , Lim Joey S. Y. , Lim Diana , Pang Brendan , Ng Lai Kuan , Wong Andrea , Soo Ross Andrew , Yong Wei Peng , Chee Cheng Ean , Lee Soo-Chin , Goh Boon-Cher , Soong Richie , Tan David S.P.
Published: September 2021

Purpose

Precision oncology, such as next generation sequencing (NGS) molecular analysis and bioinformatics are used to guide targeted therapies. The laboratory turnaround time (TAT) is a key performance indicator of laboratory performance. This study aims to formally apply statistical process control (SPC) methods such as CUSUM and EWMA to a precision medicine programme to analyze the learning curves of NGS and bioinformatics processes.

Patients and Methods

Trends in NGS and bioinformatics TAT were analyzed using simple regression models with TAT as the dependent variable and chronologically-ordered case number as the independent variable. The M-estimator “robust” regression and negative binomial regression were chosen to serve as sensitivity analyses to each other. Next, two popular statistical process control (SPC) approaches which are CUSUM and EWMA were utilized and the CUSUM log-likelihood ratio (LLR) charts were also generated. All statistical analyses were done in Stata version 16.0 (StataCorp), and nominal P < 0.05 was considered to be statistically significant.

Results

A total of 365 patients underwent successful molecular profiling. Both the robust linear model and negative binomial model showed statistically significant reductions in TAT with accumulating experience. The EWMA and CUSUM charts of overall TAT largely corresponded except that the EWMA chart consistently decreased while the CUSUM analyses indicated improvement only after a nadir at the 82nd case. CUSUM analysis found that the bioinformatics team took a lower number of cases (54 cases) to overcome the learning curve compared to the NGS team (85 cases).

Conclusion

As NGS and bioinformatics lead precision oncology into the forefront of cancer management, characterizing the TAT of NGS and bioinformatics processes improves the timeliness of data output by potentially spotlighting problems early for rectification, thereby improving care delivery.
Applications of Multi-omics Approaches for Exploring the Molecular Mechanism of Ovarian Carcinogenesis
Authors: Ye Miaomiao , Lin Yibin , Pan Shuya , Wang Zhi-wei , Zhu Xueqiong
Published: September 2021

Ovarian cancer ranks as the fifth most common cause of cancer-related death in females. The molecular mechanisms of ovarian carcinogenesis need to be explored in order to identify effective clinical therapies for ovarian cancer. Recently, multi-omics approaches have been applied to determine the mechanisms of ovarian oncogenesis at genomics (DNA), transcriptomics (RNA), proteomics (proteins), and metabolomics (metabolites) levels. Multi-omics approaches can identify some diagnostic and prognostic biomarkers and therapeutic targets for ovarian cancer, and these molecular signatures are beneficial for clarifying the development and progression of ovarian cancer. Moreover, the discovery of molecular signatures and targeted therapy strategies could noticeably improve the prognosis of ovarian cancer patients.
Targeting PI3K, FGFR, CDK4/6 Signaling Pathways Together With Cytostatics and Radiotherapy in Two Medulloblastoma Cell Lines
Authors: Lukoseviciute Monika , Maier Henrietta , Poulou-Sidiropoulou Eleni , Rosendahl Erika , Holzhauser Stefan , Dalianis Tina , Kostopoulou Ourania N.
Published: September 2021

Objectives

Medulloblastoma (MB) is treated with surgery and chemotherapy, with or without irradiation, but unfortunately >20% of the patients are not cured, and treatment comes with serious long-term side effects, so novel treatments are urgently needed. Phosphoinositide 3-kinases (PI3K), fibroblast growth factor receptors (FGFR), and cyclin-D kinases (CDK) play critical roles in cancer, and especially PI3K is crucial in MB, so here targeted therapies against them were explored.

Methods

MB cell lines DAOY and UW228-3 were exposed to PI3K (BYL719), FGFR (JNJ-42756493), and CDK4/6 (PD-0332991) inhibitors, as single or combined treatments, and their viability, cell confluence, apoptosis, and cytotoxicity were examined. Moreover, the inhibitors were combined with cisplatin, vincristine, or irradiation.

Results

Single treatments with FGFR, PI3K, or CDK4/6 inhibitors decreased viability and proliferation slightly; however, when combining two inhibitors, or the inhibitors with irradiation, sensitivity was enhanced and lower doses could be used. A more complex pattern was obtained when combining the inhibitors with cisplatin and vincristine.

Conclusions

The data suggest that combination treatments with PI3K, FGFR, and CDK4/6 inhibitors for MB could be beneficial and their use should be pursued further. Likewise, their combination with irradiation gave positive effects, while the addition of cisplatin and vincristine resulted in more complex patterns, which need to be investigated further.
Hyperprogressive Disease After Combined Anti-PD-L1 and Anti-CTLA-4 Immunotherapy for MSI-H/dMMR Gastric Cancer: A Case Report
Authors: Varnier Romain , Garrivier Thibaut , Hafliger Emilie , Favre Aymeric , Coutzac Clélia , Spire Clément , Rochefort Pauline , Sarabi Matthieu , Desseigne Françoise , Guibert Pierre , Cattey-Javouhey Anne , Funk-Debleds Pamela , Mastier Charles , Buisson Adrien , Pérol David , Trédan Oliver , Blay Jean-Yves , Phelip Jean-Marc , de la Fouchardiere Christelle
Published: September 2021

Immune checkpoint inhibitors (ICI) have been developed in gastric adenocarcinomas and approved in first-line metastatic setting (in combination with chemotherapy) as well as in pretreated patients. Microsatellite instability-high (MSI-H) tumors are predicted to derive high benefit from ICI but data in gastric locations are limited. Here, we describe the case of a 68-year old patient with stage IV MSI-H gastric adenocarcinoma, referred to our center to receive immunotherapy after failure of standard of care (surgery with perioperative platin-based chemotherapy and paclitaxel plus ramucirumab at disease progression). The patient received one injection of durvalumab and tremelimumab and was hospitalized eighteen days after because of occlusive syndrome. The CT scan showed hyperprogression of the lymph nodes and hepatic lesions, compressing the gastric stump. He died few days later. Molecular analyses did not explain this outcome. To our knowledge, this is one of the first reported cases of hyperprogressive disease after combined ICI for a patient with MSI-H tumor. We review the potential causes and discuss the emerging literature regarding predictive factors of hyperprogression in the particular subset of MSI-H patients. If some data were available in retrospective studies, validation of strong predictive factors is needed to avoid such dramatic evolutions.
Prevalence and Severity of Pain in Cancer Patients in Germany
Authors: Broemer Laura , Hinz Andreas , Koch Uwe , Mehnert-Theuerkauf Anja
Published: September 2021

Pain is a common symptom in cancer patients, restricts daily life activities and reduces survival time. Identification of sociodemographic, medical and psychological correlates of pain among cancer patients in Germany could help identify subgroups most in need of pain management. In this multicenter, epidemiologic cross-sectional study, we assessed pain prevalence and severity, quality of life (QoL) and psychological distress in a sample of 3,745 cancer patients across all tumor entities. In total, 37.9% patients suffered from cancer-related pain and 56.1% suffered from non-specific pain. Younger, female, less educated and unemployed patients reported pain more frequently and more severe pain (p < 0.001). Pain was associated with distress, depression, anxiety, QoL, tumor stage (p < 0.001), and time since diagnosis (p = 0.012). Pain assessment and pain management should be a routine part of cancer treatment and cancer survivorship care plans.
End-of-Life Care Related Distress in the PICU and NICU: A Cross-Sectional Survey in a German Tertiary Center
Authors: Garten Lars , Danke Andrea , Reindl Tobias , Prass Anja , Bührer Christoph
Published: September 2021

Objective: To investigate and compare nurses' perceived care-related distress and experiences in end-of-life situations in neonatal and pediatric intensive care units.

Study design: Single-center, cross-sectional survey. Administration of an anonymous self-report questionnaire survey to nurses of two tertiary neonatal intensive care units (NICUs), and two tertiary pediatric intensive care units (PICUs) in Berlin, Germany.

Results: Seventy-three (73/227, response rate 32.2%) nurses completed surveys. Both, NICU (32/49; 65.3%) and PICU (24/24; 100.0%) nurses, reported “staffing shortages” to be the most frequent source of distress in end-of-life situations. However, when asked for the most distressing factor, the most common response by NICU nurses (17/49) was “lack of clearly defined and agreed upon therapeutic goals”, while for PICU nurses (12/24) it was “insufficient time and staffing”. No significant differences were found in reported distress-related symptoms in NICU and PICU nurses. The interventions rated by NICU nurses as most helpful for coping were: “discussion time before the patient's death” (89.6%), “team support” (87.5%), and “discussion time after the patient's death” (87.5%). PICU nurses identified “compassion” (98.8%), “team support”, “personal/private life (family, friends, hobbies)”, and “discussion time after the patient's death” (all 87.5%) as most helpful.

Conclusions: Distress-related symptoms as a result of end-of-life care were commonly reported by NICU and PICU nurses. The most frequent and distressing factors in end-of-life situations might be reduced by improving institutional/organizational factors. Addressing the consequences of redirection of care, however, seems to be a more relevant issue for the relief of distress associated with end-of-life situations in NICU, as compared to PICU nurses.
Vascular Endothelial Function Assessed by Flow-Mediated Vasodilatation in Young Adults Born Very Preterm or With Extremely Low Birthweight: A Regional Cohort Study
Authors: Engan Britt , Engan Mette , Greve Gottfried , Vollsæter Maria , Hufthammer Karl Ove , Leirgul Elisabeth
Published: September 2021

Background: Preterm birth and low birthweight have been associated with increased risk of cardiovascular disease in young adults. Endothelial dysfunction is established as an early marker for development of atherosclerotic cardiovascular disease. Previous studies of endothelial function in young adults born very preterm or with extremely low birthweight have, however, shown diverging results.

Objective: We aimed to evaluate the risk of cardiovascular disease as measured by vascular endothelial function in young adults born very preterm (<29 weeks of gestation) or with extremely low birthweight (<1,000 g), compared with term-born controls.

Methods: This study included 50 young adults born very preterm or with extremely low birthweight and 49 term-born controls born in Norway in the periods 1982–1985, 1991–1992, and 1999–2000 at mean age 28 (±6) years. The endothelial function was assessed by ultrasound measured flow-mediated dilatation (FMD) of the right brachial artery. The arterial diameter was measured at baseline, after release of 5 min of occlusion, and after sublingual administration of nitroglycerine. FMD was reported as absolute and percentage diameter change from baseline and relative to nitroglycerine-induced dilatation.

Results: The participants were mainly normal weight non-smokers, without hypertension, diabetes, or established cardiovascular disease. The cases and controls had mean blood pressure 112/71 (SD 12/9) and 112/69 (SD 11/8) mmHg, body mass index 24.0 (SD 4.2) and 24.4 (SD 4.5) kg/m2, and HbA1c 32.7 (SD 2.5) and 33.0 (SD 2.6) mmol/mol, respectively. For both groups, 4 (8%) were smokers. Mean FMD for the adults born very preterm or with extremely low birthweight was 0.17 mm (95% CI 0.14, 0.21) vs. 0.24 mm (95% CI 0.20, 0.28) for the controls (p = 0.01), corresponding to a percentage increase of 5.4% (95% CI 4.2, 6.6) and 7.6% (95% CI 6.2, 8.9), respectively (p = 0.02). The FMD relative to maximal nitroglycerine-induced dilatation was 20% and 31%, respectively (p = 0.001).

Conclusions: Young adults born very preterm or with extremely low birthweight have significantly lower FMD compared with the term-born controls suggesting an increased risk of cardiovascular disease.
Mefunidone Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice
Authors: Han Yuanyuan , Jiang Mao , He Rongling , Lv Xin , Liao Xiaohua , He Yijun , Zhang Fan , Long Lingzhi , Jiang Guoliang , Peng Zhangzhe , Tao Lijian , Hu Gaoyun , Meng Jie
Published: September 2021

Idiopathic pulmonary fibrosis (IPF) is one of the most common and devastating interstitial lung diseases with poor prognosis. Currently, few effective drugs are available for IPF. Hence, we sought to explore the role of mefunidone (MFD), a newly synthesized drug developed by our team, in lung fibrosis. In this study, MFD was found to attenuate bleomycin (BLM) -induced lung fibrosis and inflammation in mice according to Ashcroft and alveolitis scoring. The protein contents and total cell counts in bronchoalveolar lavage fluids of BLM-treated mice were also lowered by MFD. Moreover, the elevation of TGF-β/Smad2 and phosphorylation of MAPK pathways was repressed by MFD. Additionally, MFD attenuated the swelling and vacuolization of mitochondria, lowered the ratio of apoptotic cells, restored the mitochondrial membrane potential, and reversed the expression of cleaved-caspase 3, Bcl-2 and Bax. Meanwhile, the level of epithelial marker, E-cadherin, was restored by MFD, while the levels of mesenchymal markers such as Snail and vimentin were down-regulated by MFD. Besides, MFD inhibited the expression of fibronectin and α-smooth muscle actin in TGF-β treated normal human lung fibroblasts. Thus, our findings suggested that MFD could ameliorate lung fibrosis, cell apoptosis and EMT potentiallyviasuppression of TGF-β/Smad2 and MAPK pathways.
Anti-Inflammatory Properties of Statin-Loaded Biodegradable Lecithin/Chitosan Nanoparticles: A Step Toward Nose-to-Brain Treatment of Neurodegenerative Diseases
Authors: Clementino Adryana Rocha , Marchi Cinzia , Pozzoli Michele , Bernini Franco , Zimetti Francesca , Sonvico Fabio
Published: September 2021

Nasal delivery has been indicated as one of the most interesting alternative routes for the brain delivery of neuroprotective drugs. Nanocarriers have emerged as a promising strategy for the delivery of neurotherapeutics across the nasal epithelia. In this work, hybrid lecithin/chitosan nanoparticles (LCNs) were proposed as a drug delivery platform for the nasal administration of simvastatin (SVT) for the treatment of neuroinflammatory diseases. The impact of SVT nanoencapsulation on its transport across the nasal epithelium was investigated, as well as the efficacy of SVT-LCNs in suppressing cytokines release in a cellular model of neuroinflammation. Drug release studies were performed in simulated nasal fluids to investigate SVT release from the nanoparticles under conditions mimicking the physiological environment present in the nasal cavity. It was observed that interaction of nanoparticles with a simulated nasal mucus decreased nanoparticle drug release and/or slowed drug diffusion. On the other hand, it was demonstrated that two antibacterial enzymes commonly present in the nasal secretions, lysozyme and phospholipase A2, promoted drug release from the nanocarrier. Indeed, an enzyme-triggered drug release was observed even in the presence of mucus, with a 5-fold increase in drug release from LCNs. Moreover, chitosan-coated nanoparticles enhanced SVT permeation across a human cell model of the nasal epithelium (×11). The nanoformulation pharmacological activity was assessed using an accepted model of microglia, obtained by activating the human macrophage cell line THP-1 with the Escherichia coli–derived lipopolysaccharide (LPS) as the pro-inflammatory stimulus. SVT-LCNs were demonstrated to suppress the pro-inflammatory signaling more efficiently than the simple drug solution (−75% for IL-6 and −27% for TNF-α vs. −47% and −15% at 10 µM concentration for SVT-LCNs and SVT solution, respectively). Moreover, neither cellular toxicity nor pro-inflammatory responses were evidenced for the treatment with the blank nanoparticles even after 36 h of incubation, indicating a good biocompatibility of the nanomedicine components in vitro. Due to their biocompatibility and ability to promote drug release and absorption at the biointerface, hybrid LCNs appear to be an ideal carrier for achieving nose-to-brain delivery of poorly water-soluble drugs such as SVT.
Combined Therapy With Avastin, a PAF Receptor Antagonist and a Lipid Mediator Inhibited Glioblastoma Tumor Growth
Authors: Cruz Flores Valerie A. , Menghani Hemant , Mukherjee Pranab K. , Marrero Luis , Obenaus Andre , Dang Quan , Khoutorova Larissa , Reid Madigan M. , Belayev Ludmila , Bazan Nicolas G.
Published: September 2021

Glioblastoma multiforme (GBM) is an aggressive, highly proliferative, invasive brain tumor with a poor prognosis and low survival rate. The current standard of care for GBM is chemotherapy combined with radiation following surgical intervention, altogether with limited efficacy, since survival averages 18 months. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the dysregulation of numerous signaling pathways. Recently emerging therapies to precisely modulate tumor angiogenesis, inflammation, and oxidative stress are gaining attention as potential options to combat GBM. Using a mouse model of GBM, this study aims to investigate Avastin (suppressor of vascular endothelial growth factor and anti-angiogenetic treatment), LAU-0901 (a platelet-activating factor receptor antagonist that blocks pro-inflammatory signaling), Elovanoid; ELV, a novel pro-homeostatic lipid mediator that protects neural cell integrity and their combination as an alternative treatment for GBM. Female athymic nude mice were anesthetized with ketamine/xylazine, and luciferase-modified U87MG tumor cells were stereotactically injected into the right striatum. On post-implantation day 13, mice received one of the following: LAU-0901, ELV, Avastin, and all three compounds in combination. Bioluminescent imaging (BLI) was performed on days 13, 20, and 30 post-implantation. Mice were perfused for ex vivo MRI on day 30. Bioluminescent intracranial tumor growth percentage was reduced by treatments with LAU-0901 (43%), Avastin (77%), or ELV (86%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 72, 92, and 96%, respectively. Additionally, tumor reduction was confirmed by MRI on day 30, which shows a decrease in tumor volume by treatments with LAU-0901 (37%), Avastin (67%), or ELV (81.5%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 69, 78.7, and 88.6%, respectively. We concluded that LAU-0901 and ELV combined with Avastin exert a better inhibitive effect in GBM progression than monotherapy. To our knowledge, this is the first study that demonstrates the efficacy of these novel therapeutic regimens in a model of GBM and may provide the basis for future therapeutics in GBM patients.
Effects of Extreme Weight Loss on Cardiometabolic Health in Children With Metabolic Syndrome: A Metabolomic Study
Authors: Liu Jingxin , Zhu Lin , Liao Jing , Liu Xiaoguang
Published: September 2021

Objectives: To evaluate the effect of extreme weight loss programs on circulating metabolites and their relationship with cardiometabolic health in children with metabolic syndrome.

Methods: This study was a quasi-experimental design with a pretest and post-test. Thirty children with metabolic syndrome and aged 10–17years were recruited to an extreme weight loss program (i.e., exercise combined with diet control). The primary outcomes included plasma metabolites, body composition, and cardiometabolic risk factors. A total of 324 metabolites were quantitatively detected by an ultra-performance liquid chromatography coupled to tandem mass spectrometry system, and the variable importance in the projection (VIP) value of each metabolite was calculated by the orthogonal projection to latent structures discriminant analysis. The fold change (FC) and p value of each metabolite were used to screen differential metabolites with the following values: VIP>1, p value<0.05, and |log2FC|>0.25. Pathway enrichment and correlation analyses between metabolites and cardiometabolic risk factors were also performed.

Result: A large effect size was observed, presenting a weight loss of −8.9kg (Cohen’s d=1.00, p<0.001), body mass index reduction of −3.3kg/m2 (Cohen’s d=1.47, p<0.001), and body fat percent reduction of −4.1 (%) (Cohen’s d=1.22, p<0.001) after the intervention. Similar improvements were found in total cholesterol (Cohen’s d=2.65, p<0.001), triglycerides (Cohen’s d=2.59, p<0.001), low-density lipoprotein cholesterol (Cohen’s d=2.81, p<0.001), glucose metabolism, and blood pressure. A total of 59 metabolites were changed after the intervention (e.g., aminoacyl-tRNA biosynthesis, glycine, serine, and threonine metabolism; nitrogen metabolism, tricarboxylic acid cycle, and phenylalanine, tyrosine, and tryptophan biosynthesis). The changes in metabolites (e.g., amino acids, fatty acids, organic acids, and carnitine) were related to lipid metabolism improvement (p<0.05). Organic acids and carnitines were associated with changes in the body composition (p<0.05).

Conclusion: Exercise combined with dietary control improved the body composition and cardiometabolic health in children with metabolic syndrome, and these changes may be related to plasma metabolites.
High-Intensity Interval Training for Heart Failure Patients With Preserved Ejection Fraction (HIT-HF)-Rational and Design of a Prospective, Randomized, Controlled Trial
Authors: Gasser Benedikt A. , Boesing Maria , Schoch Raphael , Brighenti-Zogg Stefanie , Kröpfl Julia M. , Thesenvitz Elke , Hanssen Henner , Leuppi Jörg D. , Schmidt-Trucksäss Arno , Dieterle Thomas
Published: September 2021

Background: The pathophysiology of HF with preserved ejection fraction (HFpEF) has not yet been fully understood and HFpEF is often misdiagnosed. Remodeling and fibrosis stimulated by inflammation appear to be main factors for the progression of HFpEF. In contrast to patients with HF with reduced ejection fraction, medical treatment in HFpEF is limited to relieving HF symptoms. Since mortality in HFpEF patients remains unacceptably high with a 5-year survival rate of only 30%, new treatment strategies are urgently needed. Exercise seems to be a valid option. However, the optimal training regime still has to be elucidated. Therefore, the aim of the study is to investigate the effects of a high-intensity interval (HIT) training vs. a moderate continuous training (MCT) on exercise capacity and disease-specific mechanisms in a cohort of patients with HFpEF.

Methods: The proposed study will be a prospective, randomized controlled trial in a primary care setting including 86 patients with stable HFpEF. Patients will undergo measurements of exercise capacity, disease-specific blood biomarkers, cardiac and arterial vessel structure and function, total hemoglobin mass, metabolic requirements, habitual physical activity, and quality of life (QoL) at baseline and follow-up. After the baseline visit, patients will be randomized to the intervention or control group. The intervention group (n = 43) will attend a supervised 12-week HIT on a bicycle ergometer combined with strength training. The control group (n = 43) will receive an isocaloric supervised MCT combined with strength training. After 12 weeks, study measurements will be repeated in all patients to quantify the effects of the intervention. In addition, telephone interviews will be performed at 6 months, 1, 2, and 3 years after the last visit to assess clinical outcomes and QoL.

Discussion: We anticipate clinically significant changes in exercise capacity, expressed as VO2peak, as well as in disease-specific mechanisms following HIT compared to MCT. Moreover, the study is expected to add important knowledge on the pathophysiology of HFpEF and the clinical benefits of a training intervention as a novel treatment strategy in HFpEF patients, which may help to improve both QoL and functional status in affected patients.

Trial registration:ClinicalTrials.gov, identifier: NCT03184311, Registered 9 June 2017.
Clostridium butyricum Supplement Can Ameliorate the Intestinal Barrier Roles in Broiler Chickens Experimentally Infected With Clostridium perfringens
Authors: Xu Xiao , Yang Shunli , Olajide Joshua Seun , Qu Zigang , Gong Zhenxing , Wang Jing , Zhang Yanbing , Wang Heng , Xiong Ling , Zhang Kun , Zhou Enmin , Cai Jianping
Published: September 2021

Necrotic enteritis (NE), caused by Clostridium perfringens, is an economically important disease in the broiler. Among normal flora in the broiler intestinal region, Clostridium butyricum has been identified as a probiotic agent that reduces the susceptibility of broilers to C. perfringens. However, the effects of C. butyricum supplement on broiler intestinal integrity during NE are largely unknown. In this study, we investigated the effects of C. butyricum on the growth performance, intestinal morphology and barrier function, and the functions of immune-related cytokines under NE in broilers. Chickens were divided into five groups: control group (NC), supplement C. butyricum only group (CB), NE-infected group (PC), supplement C. butyricum from Day 14 (NECB1) to Day 22 NE-infected group, and supplement C. butyricum from Day 1 (NECB2) to Day 22 NE-infected group. The results showed that there were significantly decreased average daily weight gain and increased feed conversion rate in the infected group (PC) compared with the C. butyricum-supplemented groups (NECB1 and NECB2) through the diet. Histopathological observation on the Hematoxylin–Eosin staining avian small intestine sections revealed that supplementation of C. butyricum (NECB1 and NECB2) could increase the intestinal villus height/crypt depth and lessen the intestinal damage under NE. ELISA and Limulus test showed that broilers infected with NE (PC) had higher serum IgA and lipopolysaccharide content; however, after C. butyricum supplementation (NECB1 and NECB2), they returned to a normal level. Furthermore, real-time PCR and Western blot results indicated that compared with PC, supplementing C. butyricum (NECB1 and NECB2) could initialize the expressions of genes related to the intestinal barrier-associated molecules (such as CLDN-1, CLDN-3, OCLN, MUC2, ZO-1, and CLDN5), cytokines (such as IL-10, IL-6, and TGFB1), and C. perfringens plc gene expression. Moreover, the results detected by the Ussing chamber suggested that C. butyricum (NECB1 and NECB2) could amend the decrease in conductivity value and short-circuit current value caused by NE. In addition, NECB2 significantly reduced the upregulation of fluorescein isothiocyanate–dextran flux caused by the NE disease. In conclusion, these findings suggest that dietary supplementation of C. butyricum in broilers with NE improved chicken growth performance, intestinal integrity and barrier function, and immunological status. Notably, no statistical difference was observed with the addition of C. butyricum on day 1 or day 14.
Validity and Reliability of a Phone App and Stopwatch for the Measurement of 505 Change of Direction Performance: A Test-Retest Study Design
Authors: Chen Zhili , Bian Chao , Liao Kaifang , Bishop Chris , Li Yongming
Published: September 2021

Purpose: The aim of this study was to explore the validity and reliability of a phone app [named: change of direction (COD) timer] and stopwatches for the measurement of COD performance.

Methods: Sixty-two youth basketball players (age: 15.9±1.4yrs., height: 178.8±11.0cm, and body mass: 70.0±14.1kg) performed six trials of 505 COD test (with the left side being the plant leg first, then the right side). The completion time was measured simultaneously via timing gates (with error correction processing algorithms), the phone app, and stopwatches.

Results: There was an almost perfect correlation and agreement between timing gates and COD timer (r=0.978; SEE=0.035s; and LoA=−0.08~0.06s), but a lower correlation and agreement between timing gates and stopwatch (r=0.954; SEE=0.050s; and LoA=−0.17~0.04s) with statistical significance in completion time (ES=1.29, 95%CI: 1.15–1.43, p<0.01). The coefficient of variation revealed similar level of dispersion between the three timing devices (timing gates: 6.58%; COD timer: 6.32%; and stopwatch: 6.71%). Inter-observer reliability (ICC=0.991) and test-retest reliability (ICC=0.998) were excellent in COD timer, while the inter-observer reliability was lower (ICC=0.890) in the stopwatches.

Conclusion: In the 505 COD test, the COD timer was able to provide a valid and reliable measurement. On the contrary, stopwatch was not recommended because of large error. Thus, if timing gates are unavailable, practitioners can adopt the COD timer app to assess 505 COD speed times.