bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of valproic acid on overall survival in patients with high-grade gliomas undergoing temozolomide
Authors: Kuo Yu-Jen , Yang Yao-Hsu , Lee I-Yun , Chen Pau-Chung , Yang Jen-Tsung , Wang Ting-Chung , Lin Martin Hsiu-Chu , Yang Wei-Hsun , Cheng Chun-Yu , Chen Kuo-Tai , Huang Wei-Chao , Lee Ming-Hsueh
Published: July 2020

High-grade gliomas (HGGs) are a rapidly progressive and highly recurrent group of primary brain tumors. Despite aggressive surgical resection with chemoradiotherapy, prognoses remained poor. Valproic acid (VPA), a histone deacetylase inhibitor has shown the potential to inhibit glioma cell growth in vitro through several diverse mechanisms. However clinical studies regarding the effect of VPA on HGGs are limited. This study aimed to investigate whether using VPA in patients with HGGs under temozolomide (TMZ) would lead to a better overall survival (OS).

We used the Taiwan National Health Insurance Research database to conduct this population-based cohort study. A total of 2379 patients with HGGs under TMZ treatment were included and were further classified into VPA (n = 1212, VPA ≥ 84 defined daily dose [DDD]) and non-VPA (n = 1167, VPA < 84 DDD) groups. Each patient was followed from 1998 to 2013 or until death. A Cox proportional hazard regression was performed to evaluate the effect of VPA and OS.

The VPA group had a longer mean OS time compared with the non-VPA group (OS: 50.3 ± 41.0 vs 42.0 ± 37.2 months,P < .001). In patients between 18 and 40 years old, the difference is most significant (OS: 70.5 ± 48.7 vs 55.1 ± 46.0,P = .001). The adjusted hazard ratio is 0.81 (95% confidence interval, 0.72–0.91) for the VPA group relative to the non-VPA group.

VPA at over 84 DDD improved OS in HGGs TMZ treatment.
A modified negative pressure wound therapy for the treatment of refractory wounds
Authors: Xing Dong , Yang Zhaoxu , Cao Can , Dong Zhijie , Wei Jingchao , Zheng Xuehong , Li Wenyi
Published: July 2020

Negative pressure wound therapy (NPWT) is an important therapy for the management of refractory wounds. The aim of this retrospective preliminary study was to introduce a modified NPWT (m-NPWT) and compared the efficacy of it with conventional NPWT (c-NPWT) in the management of refractory wounds.

A total of 127 patients with refractory wounds receiving the NPWT from January 2010 to October 2017 in our hospital were retrospectively reviewed. The demographics and clinical data were collected from medical records and compared between m-NPWT group and c-NPWT group.

There were 65 patients in c-NPWT group and 62 patients in m-NPWT group. No significant difference was observed between 2 groups in antimicrobial use (P = .51), hospitalization time (P = .24), wound-healing rate (P = .44) or complication rate (P = .59). However, patients in m-NPWT group had shorter wound-healing time (24.82 vs 27.66 days, P < .01), less debridement times (1.23 vs 2.08, P < .01), less total cost (3743.93 vs 6344.33 yuan, P < .01) and higher satisfaction rate (56/62 vs 44/65, P = .02) compared to those in c-NPWT group.

The m-NPWT technique was an efficient and safe alternative therapy for refractory wounds.
XPC exon15 Lys939Gln variant increase susceptibility to prostate adenocarcinoma
Authors: Qin Feng , Gao Sheng-Lin , Xu Kai , Su Quan-Xin , Zhang Ze , Shi Li , Zhu Li-Jie , Zhang Li-Feng , Zuo Li
Published: July 2020

Background:

Previous studies have investigated the correlation between xeroderma pigmentosumcomplementation group C (XPC) variants and prostate adenocarcinoma (PA) risk. Nevertheless, research findings remain inconclusive.

Methods:

We conducted a pooled analysis to obtain a more accurate estimation of the relationship on XPC exon15 Lys939Gln polymorphism with susceptibility to PA. Moreover, in silico tools were employed to investigate the effect of XPC expression on PA patients’ survival time.

Results:

A total of 4306 patients and 4779 control subjects were assessed. The overall results indicated that XPC Lys939Gln variant was associated with PA risk (recessive genetic model: odds ratio = 1.15, 95% confidence interval = 1.02–1.30, P
heterogeneity= .044, P = .021, I
2= 45.2), especially in Asian descendants. Population-based studies revealed similar results (odds ratio = 1.15, 95% confidence interval = 1.01–1.32, P
heterogeneity= .146, P = .040, I
2 = 39.0). In silico tools showed that XPC expression in Caucasian patients was lower than in the normal group. No positive association was observed in African patients. PA subjects with high XPC expression had a longer overall survival time than low expression group.

Conclusion:

Our findings indicated that XPC Lys939Gln variant might contribute to increased PA susceptibility, especially for Asian patients.
The impact of immune checkpoint inhibitors in patients with chronic lymphocytic leukemia (CLL)
Authors: Ntsethe Aviwe , Dludla Phiwayinkosi Vusi , Nyambuya Tawanda Maurice , Ngcobo Siphamandla Raphael , Nkambule Bongani Brian
Published: July 2020

Introduction:

The global burden of chronic lymphocytic leukemia (CLL) has constantly increased over the years, with a current incidence of 3.5 cases per 100,000 people. Although the conventional drugs used to treat CLL patients have been effective treatment failure rate in some of the patients is alarming. Therefore, as a result, novel treatment strategies with improved outcomes such as the blockade of immune checkpoints have emerged. However, consensus on the risk-benefit effects of the using these drugs in patients with CLL is controversial and has not been comprehensively evaluated. This systemic review and meta-analysis provide a comprehensive synthesis of available data assessing adverse events associated with the use of immune checkpoint inhibitors in patients with CLL as well as their influence on the overall survival rate.

Methods:

This protocol for a systematic review and meta-analysis has been prepared in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines. A search strategy will be developed using medical subject headings words in PubMed search engine with MEDLINE database. The search terms will also be adapted for gray literature, Embase, and Cochrane Central Register of Controlled Trials electronic databases. Two reviewers (AN and SRN) will independently screen studies, with a third reviewer consulted in cases of disagreements using a defined inclusion and exclusion criteria. Data items will be extracted using a predefined data extraction sheet. Moreover, the risk of bias and quality of the included studies will be appraised using the Downs and Black checklist and the quality and strengths of evidence across selected studies will be assessed using the Grading of Recommendations Assessment Development and Evaluation approach. The Cochran's Q statistic and the I2 statistics will be used to analyze statistical heterogeneity across studies. If the included studies show substantial level of statistical heterogeneity (I2 > 50%), a random-effects meta-analysis will be performed using R statistical software.

Ethics and dissemination:

The review and meta-analysis will not require ethical approval and the findings will be published in peer-reviewed journals and presented at local and international conferences. This review may help provide clarity on the risk-benefit effects of using immune checkpoint inhibitors in patients with CLL.

Systematic review registration:

International prospective Register of Systematic Reviews (PROSERO) number: CRD42020156926.
Identification of Target Genes in Hypertension and Left Ventricular Remodeling
Authors: Pang Bo , Hu Cong , Wu Guodong , Zhang Yanli , Lin Guangzhu
Published: July 2020

Introduction:

Hypertension occurs profoundly in the world, and left ventricular (LV) remodeling containing functional, structural, and mechanical changes induced by uncontrolled blood pressure is a well-known complication, however the underlying mechanism is still obscure.

Methods:

To determine differences in gene expression profiles of hypertension and LV remodeling consequence to hypertension, Gene Expression Omnibus 2R online tool was used to identify differently expressed genes. Publicly available databases including GeneMANIA, database for annotation, visualization and integrated discovery, search tool for the retrieva predicting associated transcription factors (TF) from annotated affinities interacting genes, Predicting Associated TF from Annotated Affinities, JASPAR and Comparative Toxicogenomics Database (CTD) were accessed to perform an integrated bioinformatic analysis.

Results:

Twenty-one genes (SEC14L3, EML7, PSMD7, PSMA1, GLRX, CNOT10, NBR1, DUSP12, STRAP, SMIM14, RBM8A, TMEM59, TMEM87A,PSMC1, CASP4, ITGB8, DNAJA1, PINK1, PRNP, SAP30L, and EIF3M) were found overexpression in both hypertension and hypertensive LV remodeling. Biological process analysis first revealed that enrichment of these target genes correlated with regulation of cellular amino acid metabolic process, antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent and proteasome complex, 3 different expression genes (DEGs) participate significantly enriched in NFκB, WNT, and MAPK pathways, meanwhile, 47% DEGs displayed similar co-expression characteristics. Furthermore, the transcription factors associated with key DEGs were identified. Finally, the TF (HAND1, E4BP4, ESR1, VBP, ELK-1, POU3F2) associated with LV remodeling in hypertension were confirmed to act a crucial role in correlated heart diseases.

Conclusion:

The present study reveals the targeted genes probably associated with LV remodeling in hypertension by bioinformatics-based analyses, which provides clues for prognosis judgement and pharmacological therapies.
Fatal vascular complications during transradial percutaneous coronary intervention
Authors: Choi SeongIl , Joh Joon Hee , Choe Ju Won
Published: July 2020

Rationale:

Vascular complications of transradial percutaneous coronary intervention (PCI) are rare and usually occur at the access site below the elbow. However, vessels along the tract of the wire or catheter can be injured at any point, causing various types of bleeding complications.

Patient concerns:

A 57-year-old man visited due to chest discomfort. Coronary angiography showed significant stenosis at the distal right coronary artery (RCA). Immediately after the coronary guidewire was passed through the distal RCA, he started a vigorous cough. The voice changed, dyspnea occurred within minutes, and lip cyanosis and stridor were observed. After endotracheal intubation, successful stenting of the distal RCA was achieved. He was extubated at 30 minutes after coronary stenting, but 1-hour post-extubation, his blood pressure suddenly decreased to 70/50 mmHg.

Diagnosis:

Mediastinal widening was newly noted on chest X-ray, and blood hemoglobin was decreased. Contrast-enhanced chest computed tomography showed mediastinal hematoma, tracheal compression, and hemothorax. Contrast extravasation was noted in the terminal branches of the inferior thyroid artery on brachiocephalic angiography.

Interventions:

Successful hemostasis was achieved with endovascular embolization therapy using a Tornado embolization microcoil, Gelfoam gelatin sponge, and Histoacryl glue. The next day, the mediastinal hemorrhage was drained by mediastinoscopy. The endotracheal intubation and ventilator care were maintained for 2 days, and 6 units of packed red blood cells were transfused. Antithrombotics were used to prevent stent thrombosis, and antibiotics to control infection, respectively.

Outcomes:

After successful hemostasis, thrombocytosis and high on-treatment platelet reactivity that disappeared at 2 weeks post-discharge were noted. Follow-up chest imaging showed the normalized mediastinal widening. At 14 months post-discharge, the patient remains healthy.

Lessons:

As life-threating vascular complications, such as brachiocephalic, subclavian vessel dissection, and vessel perforation in the internal mammary, costocervical, and thyrocervical arteries, can occur anytime during transradial PCI, the intervention cardiologist should be well aware of it and have the appropriate countermeasures implemented in the routine procedure.
Hsa_circ_0002320: a novel clinical biomarker for colorectal cancer prognosis
Authors: Yang Ning , Xu Bin , Kong Peng , Han Mei , Li Bing-hui
Published: July 2020

A great many circular RNAs (circRNAs) exist in different types of mammalian cells. Previous studies have verified that a low level of hsa_circ_0002320 is present in gastric cancer and that it might represent a good prognostic indicator. However, its value in colorectal cancer (CRC) is unclear. The aim of this research was to explore the value of hsa_circ_0002320 as a potential diagnostic biomarker for CRC prognosis.

Plasma samples, CRC tissues, and adjacent normal tissues were obtained from 50 patients with CRC, before any treatment, and 100 plasma samples were acquired from healthy individuals. Hsa_circ_0002320 levels in these samples were analyzed by reverse transcription-quantitative polymerase chain reaction. Correlations between hsa_circ_0002320, clinicopathological characteristics, and overall survival (OS) of CRC patients were also investigated. Receiver-operating characteristic (ROC) curve analysis was used to assess the value of hsa_circ_0002320 for CRC diagnosis. Finally, a bioinformatics analysis was performed to verify the effect of hsa_circ_0002320 on CRC prognosis.

Expression levels of hsa_circ_0002320 were significantly decreased in CRC plasma (P < .05). The expression level of hsa_circ_0002320 was significantly correlated with OS time (P < .05). Higher hsa_circ_0002320 reflected significantly greater OS; the HR of high hsa_circ_0002320 was 0.161 (95% CI, 0.066–0.393; P = .000). The area under the ROC curve of hsa_circ_0002320 in CRC was 0.823, which was higher than for the carcinoembryogenic antigen (area under the curve = 0.764). Kaplan-Meier analysis showed that CRC patients with low expression of hsa_circ_0002320 exhibited poorer OS times than those with high expression.

Hsa_circ_0002320 could be a novel, noninvasive diagnostic blood biomarker for CRC prognosis.
The efficacy and safety of fecal microbiota transplantation in the treatment of systemic sclerosis
Authors: Zhang Shixiong , Lv Jingjing , Ren Xuetong , Hao Xinyu , Zhou Pingping , Wang Yangang
Published: July 2020

Background:

Systemic sclerosis (SSc) is 1 of the most complex systemic autoimmune diseases.Accumulating evidence suggests that gut microbiota affect the development and function of the immune system and may play a role in the pathogenesis of autoimmune diseases. This new paradigm raises the possibility that many diseases result, at least partially, from microbiota-related dysfunction. This understanding invites the investigation of fecal microbiota transplantation (FMT) in the treatment of SSc. However, no study has specifically and systematically investigated the efficacy and safety of FMT in the treatment of SSc. Thus, this study will systematically and comprehensively appraise the efficacy and safety of FMT in the treatment of SSc.

Methods:

We will search the following sources without restrictions for date, language, or publication status: PubMed, Web of Science,Cochrane Central Register of Controlled Trials (CENTRAL) Cochrane Library, EMBASE and China National Knowledge Infrastructure. We will apply a combination of Medical Subject Heading (MeSH) and free-text terms incorporating database-specific controlled vocabularies and text words to implement search strategies. We will also search the ongoing trials registered in the World Health Organization's International Clinical Trials Registry Platform. Besides, the previous relevant reviews conducted on FMT for SSc and reference lists of included studies will also be searched.

Results:

This study will provide a reliable basis for the treatment of SSc with FMT.

Conclusions:

The findings will be an available reference to evaluate the efficacy and safety of FMT in the treatment of SSc.

Registration number:

INPLASY202060019.
Compassionate Design: Utilizing Design Thinking to Preserve Sanctity, Dignity, and Personhood When Children Die
Authors: Grossoehme Daniel H. , Mark Melissa S. , Lane Blake , Rednour Allison , Thienprayoon Rachel
Published: July 2020

Introduction:

Greater than 70% of children who die in our institution annually die in an intensive care unit (ICU) setting. Family privacy, visitation policies, and an inability to perform religious rituals in the ICU are barriers to provide children with culturally competent, family-centered care when a child dies. The goal of this project was to profoundly understand family and staff experiences surrounding pediatric death in our institution to identify unique opportunities to design improved, novel delivery models of pediatric end of life (EOL) care.

Methods:

This project utilized a structured process model based on the Vogel and Cagan’s 4-phase integrated new product development process model. The 4 phases are identifying, understanding, conceptualizing, and realizing. We utilized an adaptation of this process model that relies on human-centered and design thinking methodologies in 3 phases: research, ideation, and refinement of a process or product opportunity.

Results:

There were 2 primary results of this project: 5 process and opportunity areas to improve the EOL experience across the hospital, and a set of criteria and considerations for a dedicated EOL space.

Discussion:

Sometimes, the best outcome we can provide for a child and their family is a peaceful, dignified death. This project utilized human-centered design to create improved process outcomes and to design a dedicated EOL space for children who die in the hospital. Offering grieving families quiet, private time with their child in a beautiful, dignified, peaceful location enables the beginning of improved bereavement outcomes for the family and staff.
Vaccinating in the Emergency Department, a Novel Approach to Improve Influenza Vaccination Rates via a Quality Improvement Initiative
Authors: Baumer-Mouradian Shannon H. , Kleinschmidt Abigail , Servi Ashley , Jaworski Brian , Lazarevic Kimberly , Kopetsky Matthew , Nimmer Mark , Hanson Thomas , Gray Matthew P. , Drendel Amy L.
Published: July 2020

Introduction:

Annual influenza vaccination is recommended for all US children 6 months and older to prevent morbidity and mortality. Despite these recommendations, only ~50% of US children are vaccinated annually. Influenza vaccine administration in the pediatric emergency department (ED) is an innovative solution to improve vaccination rates. However, during the 2017–2018 influenza season, only 75 influenza vaccinations were given in this tertiary care ED. We aimed to increase the number of influenza vaccines administered to ED patients from 75 to 1,000 between August 2018 and March 2019.s

Methods:

Process mapping identified potential barriers and solutions. Key interventions included mandatory vaccine screening, creation of a vaccine administration protocol, education for family, provider, and nursing, a revised pharmacy workflow, and weekly staff feedback. Interventions were tested using plan-do-study-act cycles. The process measure was the percent of patients screened for vaccine status. The primary outcome was the number of influenza vaccines administered. The balancing measures were ED length of stay (LOS), wasted vaccines, and financial impact on the institution.

Results:

We included 33,311 children in this study. Screening for vaccine status improved from 0% to 90%. Of those screened, 58% were eligible for vaccination, and 8.5% of eligible patients were vaccinated in the ED. In total, 1,323 vaccines were administered with no significant change in ED LOS (139 min) and no lost revenue to the hospital.

Conclusions:

We implemented an efficient, cost-effective, influenza vaccination program in the pediatric ED and successfully increased vaccinations in a population that might not otherwise receive the vaccine.
The Effect of Interactive Educational Workshops With or Without Standardized Patients on the Clinical Skills of Midwifery Students in Providing Sexual Health Counseling
Authors: Khadivzadeh Talat , Ardaghi Sefat Seighalani Mina , Mirzaii Khadijeh , Mazloum Seyed Reza
Published: July 2020

Background and Objectives

Insufficient skills among health personnel, including midwives, can lead to failure in evaluating and providing sexual health counseling services to clients. Thus, the purpose of this study was to compare the effect of 2 interactive educational workshops with or without standardized patients (SPs) on midwifery students' clinical skills in providing sexual health counseling at Mashhad University of Medical Sciences, Mashhad, Iran, in 2014 to 2015.

Research Methods

In this randomized controlled trial, 62 midwifery students were selected through convenient sampling method and then randomly divided into 2 groups who received 1 of 2 interactive educational workshops, with or without SPs in 10-hour educational programs. The students' skills in providing sexual health counseling were evaluated before and 2 weeks after the education through an Objective Structured Clinical Examination composed of 5 stations using validated checklists. The data were then analyzed using the SPSS Software (Version 16) through descriptive statistics as well as independent t test, paired t test, Mann-Whitney U, χ2, and Fisher exact tests. The level of significance was considered by P < 0.05.

Results

There was no significant difference between the mean scores of students' clinical skills in providing sexual health counseling services in the group educated with or without SPs (22.4 ± 7.0 and 23.0 ± 9.4, P = 0.77). However, 2 weeks after the interventions, the mean scores were 75.8 ± 11.2 and 47.0 ± 8.9, respectively, meaning a significant difference between the study groups (P < 0.0001).

Conclusions

Although both teaching methods could promote clinical skills among the midwifery students, the effect of interactive workshop with SPs was much significantly stronger.
Noninvasive Discrimination of Low and High-risk Pancreatic Intraductal Papillary Mucinous Neoplasms
Authors: Roth Susanne , Bose Promita , Alhamdani Mohamed S. S. , Mustafa Shakhawan A. , Tjaden Christine , Zamzow Katharina , Hinz Ulf , Michalski Christoph W. , Neoptolemos John P. , Hoheisel Jörg D. , Büchler Markus W. , Hackert Thilo
Published: July 2020

Objective:

To propose a noninvasive diagnostic approach, which allows reliable distinction between low- and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMNs).

Background:

IPMNs are identifiable precursor lesions of pancreatic cancer, of which surgical resection is warranted prior to the development of invasive carcinoma, but low-grade IPMNs should not be unnecessarily resected. However, diagnostic tools that preoperatively enable accurate risk stratification of IPMNs are missing.

Methods:

This single-center, retrospective cohort study included 56 patients who underwent surgical resection for IPMN including 18 low-risk (low-grade) and 38 high-risk (high-grade/invasive carcinoma) IPMNs, from whom clinical features and serum samples were prospectively obtained. An antibody microarray platform was used to analyze the serum proteome. Based on serum markers and selected clinical characteristics support vector machine models were constructed to predict the risk of IPMN malignancy.

Results:

A serum protein signature discriminating low- and high-risk IPMN patients was identified. Combinations of established clinical features and the newly identified serum biomarkers correctly distinguished low- and high-risk IPMNs in 93% on 1000-fold cross-validation.

Conclusions:

This study highlights the synergistic predictive value of combining a novel serum protein signature with conventional clinical characteristics to risk-stratify IPMN patients. If these findings are supported by larger validation studies, they might enable more rational decision-making in clinical management of IPMN patients in conjunction with clinical guidelines.
The Relationship Between Lymph Node Ratio and Survival Benefit With Adjuvant Chemotherapy in Node-positive Esophageal Adenocarcinoma
Authors: Raman Vignesh , Jawitz Oliver K. , Farrow Norma E. , Voigt Soraya L. , Rhodin Kristen E. , Yang Chi-Fu J. , Turner Megan C. , D’Amico Thomas A. , Harpole David H. , Tong Betty C.
Published: July 2020

Background:

We hypothesized that the ratio of positive lymph nodes to total assessed lymph nodes (LNR) is an indicator of cancer burden in esophageal adenocarcinoma and may identify patients who may most benefit from AC.

Objective:

The aim of this study was to discern whether there is a threshold LNR above which AC is associated with a survival benefit in this population.

Methods:

The 2004–2015 National Cancer Database was queried for patients who underwent upfront, complete resection of pT1-4N1–3M0 esophageal adenocarcinoma. The primary outcome, overall survival, was examined using multivariable Cox proportional hazards models employing an interaction term between LNR and AC.

Results:

A total of 1733 patients were included: 811 (47%) did not receive AC whereas 922 (53%) did. The median LNR was 20% (interquartile range 9–40). In a multivariable Cox model, the interaction term between LNR and receipt of AC was significant (P = 0.01). A plot of the interaction demonstrated that AC was associated with improved survival beyond a LNR of about 10%–12%. In a sensitivity analysis, the receipt of AC was not associated with improved survival in patients with LNR <12% (hazard ratio 1.02; 95% confidence interval 0.72–1.44) but was associated with improved survival in those with LNR ≥12% (hazard ratio 0.65; 95% confidence interval 0.50–0.79).

Conclusions:

In this study of patients with upfront, complete resection of node-positive esophageal adenocarcinoma, AC was associated with improved survival for LNR ≥12%. LNR may be used as an adjunct in multidisciplinary decision-making about adjuvant therapies in this patient population.
Recent therapeutic prospects for Machado–Joseph disease
Authors: Costa Maria do Carmo
Published: July 2020

Purpose of review

Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a fatal, dominantly inherited, neurodegenerative disease caused by expansion of a CAG repeat in the coding region of the ATXN3 gene. No disease-modifying treatment is yet available for MJD/SCA3. This review discusses recently developed therapeutic strategies that hold promise as future effective treatments for this incurable disease.

Recent findings

As a result of the exploration of multiple therapeutic approaches over the last decade, the MJD/SCA3 field is finally starting to see options for disease-modifying treatments for this disease come into view on the horizon. Recently developed strategies include DNA-targeted and RNA-targeted therapies, and approaches targeting protein quality control pathways and cellular homeostasis.

While still in preclinical testing stages, antisense oligonucleotides, short hairpin RNAs and citalopram all show promise to reaching testing in clinical trials for MJD/SCA3. Two pharmacological approaches in early stages of development, the slipped-CAG DNA binding compound naphthyridine-azaquinolone and autophagosome-tethering compounds, also show potential therapeutic capacity for MJD/SCA3. Overall, a handful of therapeutic options are currently showing potential as future successful treatments for fatal MJD/SCA3.
MRI of neurodegeneration with brain iron accumulation
Authors: Lehéricy Stéphane , Roze Emmanuel , Goizet Cyril , Mochel Fanny
Published: July 2020

Purpose of review

The diagnosis of neurodegeneration with brain iron accumulation (NBIA) typically associates various extrapyramidal and pyramidal features, cognitive and psychiatric symptoms with bilateral hypointensities in the globus pallidus on iron-sensitive magnetic resonance images, reflecting the alteration of iron homeostasis in this area. This article details the contribution of MRI in the diagnosis by summarizing and comparing MRI patterns of the various NBIA subtypes.

Recent findings

MRI almost always shows characteristic changes combining iron accumulation and additional neuroimaging abnormalities. Iron-sensitive MRI shows iron deposition in the basal ganglia, particularly in bilateral globus pallidus and substantia nigra. Other regions may be affected depending on the NBIA subtypes including the cerebellum and dentate nucleus, the midbrain, the striatum, the thalamus, and the cortex. Atrophy of the cerebellum, brainstem, corpus callosum and cortex, and white matter changes may be associated and worsen with disease duration. Iron deposition can be quantified using R2∗ or quantitative susceptibility mapping.

Recent MRI advances allow depicting differences between the various subtypes of NBIA, providing a useful analytical framework for clinicians. Standardization of protocols for image acquisition and analysis may help improving the detection of imaging changes associated with NBIA and the quantification of iron deposition.
Transcriptional response of Fusarium oxysporum and Neocosmospora solani challenged with amphotericin B or posaconazole
Authors: Castillo-Castañeda A. , Cañas-Duarte S. J. , Guevara-Suarez M. , Guarro J. , Restrepo S. , Celis Ramírez A. M.
Published: July 2020

Some species of fusaria are well-known pathogens of humans, animals and plants. Fusarium oxysporum and Neocosmospora solani (formerly Fusarium solani) cause human infections that range from onychomycosis or keratitis to severe disseminated infections. In general, these infections are difficult to treat due to poor therapeutic responses in immunocompromised patients. Despite that, little is known about the molecular mechanisms and transcriptional changes responsible for the antifungal resistance in fusaria. To shed light on the transcriptional response to antifungals, we carried out the first reported high-throughput RNA-seq analysis for F. oxysporum and N. solani that had been exposed to amphotericin B (AMB) and posaconazole (PSC). We detected significant differences between the transcriptional profiles of the two species and we found that some oxidation-reduction, metabolic, cellular and transport processes were regulated differentially by both fungi. The same was found with several genes from the ergosterol synthesis, efflux pumps, oxidative stress response and membrane biosynthesis pathways. A significant up-regulation of the C-22 sterol desaturase (ERG5), the sterol 24-C-methyltransferase (ERG6) gene, the glutathione S-transferase (GST) gene and of several members of the major facilitator superfamily (MSF) was demonstrated in this study after treating F. oxysporum with AMB. These results offer a good overview of transcriptional changes after exposure to commonly used antifungals, highlights the genes that are related to resistance mechanisms of these fungi, which will be a valuable tool for identifying causes of failure of treatments.
Single source of pangolin CoVs with a near identical Spike RBD to SARS-CoV-2
Authors: Chan Yujia Alina , Zhan Shing Hei
Published: July 2020

Multiple publications have independently described pangolin CoV genomes from the same batch of smuggled pangolins confiscated in Guangdong province in March, 2019. We analyzed the three metagenomic datasets that sampled this batch of pangolins and found that the two complete pangolin CoV genomes, GD_1 by Xiao et al.Natureand MP789 by Liu et al.PLoS Pathogens, were both built primarily using the 2019 dataset first described by Liu et al.Viruses. Other publications, such as Zhang et al.Current Biologyand Lam et al.Nature, have also relied on this same dataset by Liu et al.Virusesfor their assembly of the Guangdong pangolin CoV sequences and comparisons to SARS-CoV-2. To our knowledge, all of the published pangolin CoV genome sequences that share a highly similar Spike receptor binding domain with SARS-CoV-2 originate from this singular batch of smuggled pangolins. This raises the question of whether pangolins are truly reservoirs or hosts of SARS-CoV-2-related coronaviruses in the wild, or whether the pangolins may have contracted the CoV from another host species during trafficking. Our observations highlight the importance of requiring authors to publish their complete genome assembly pipeline and all contributing raw sequence data, particularly those supporting epidemiological investigations, in order to empower peer review and independent analysis of the sequence data. This is necessary to ensure both the accuracy of the data and the conclusions presented by each publication.
SARS-CoV-2 infection induces germinal center responses with robust stimulation of CD4 T follicular helper cells in rhesus macaques
Authors: Elizaldi Sonny R. , Lakshmanappa Yashavanth Shaan , Roh Jamin W. , Schmidt Brian A. , Carroll Timothy D. , Weaver Kourtney D. , Smith Justin C. , Deere Jesse D. , Dutra Joseph , Stone Mars , Sammak Rebecca Lee , Olstad Katherine J. , Reader J. Rachel , Ma Zhong-Min , Nguyen Nancy K. , Watanabe Jennifer , Usachaenko Jodie , Immareddy Ramya , Yee JoAnn L. , Weiskopf Daniela , Sette Alessandro , Hartigan-O’Connor Dennis , McSorley Stephen J. , Morrison John H. , Tran Nam K. , Simmons Graham , Busch Michael P , Kozlowski Pamela A. , Van Rompay Koen K.A. , Miller Christopher J. , Iyer Smita S.
Published: July 2020

CD4 T follicular helper (Tfh) cells are important for the generation of long-lasting and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfhcells and stimulates the germinal center response is an important question as we investigate vaccine options for the current pandemic. Here we report that, following infection with SARS-CoV-2, adult rhesus macaques exhibited transient accumulation of activated, proliferating Tfhcells in their peripheral blood on a transitory basis. The CD4 helper cell responses were skewed predominantly toward a Th1 response in blood, lung, and lymph nodes, reflective of the interferon-rich cytokine environment following infection. We also observed the generation of germinal center Tfhcells specific for the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, and a corresponding early appearance of antiviral serum IgG antibodies but delayed or absent IgA antibodies. Our data suggest that a vaccine promoting Th1-type Tfh responses that target the S protein may lead to protective immunity.
The Role of Alcohol Consumption on Acetaminophen Induced Liver Injury: Implications from A Mathematical Model
Authors: Ghosh Aditi , Berger Isaac , Remien Christopher H. , Mubayi Anuj
Published: July 2020

Acetaminophen (APAP) overdose is one of the predominant causes of drug induced acute liver injury in the U.S and U.K. Clinical studies show that ingestion of alcohol may increase the risk of APAP induced liver injury. Chronic alcoholism may potentiate APAP hepatotoxicity and this increased risk of APAP toxicity is observed when APAP is ingested even shortly after alcohol is cleared from the body. However, clinical reports also suggest that acute alcohol consumption may have a protective effect against hepatotoxicity by inhibiting microsomal acetaminophen oxidation and thereby reducing N-acetyl-p-benzoquinone imine (NAPQI) production. The aim of this study is to model this dual role of alcohol to determine how the timing of alcohol ingestion affects APAP metabolism and resulting liver injury and identify mechanisms of APAP induced liver injury. The mathematical model is developed to capture condition of a patient of single time APAP overdose who may be an acute or chronic alcohol user. The analysis suggests that the risk of APAP-induced hepatotoxicity is increased if APAP is ingested shortly after alcohol is cleared from the body in chronic alcohol users. A protective effect of acute consumption of alcohol is also observed in patients with APAP overdose. For example, simultaneous ingestion of alcohol and APAP overdose or alcohol intake after or before few hours of APAP overdose may result in less APAP-induced hepatotoxicity when compared to a single time APAP overdose. The rate of hepatocyte damage in APAP overdose patients depends on trade-off between induction and inhibition of CYP enzyme.
Functional and structural characterization of H105Y mutation in MtrR protein ofNeisseria gonorrhoeae
Authors: Sachdev Divya , Kumari Indu , Chopra Madhu , Singh Laishram R. , Saluja Daman
Published: July 2020

MtrR is a negative regulator of MtrCDE efflux pump. Various N-Terminal and C-Terminal mutations have been reported in different multidrug resistant clinical isolates ofNeisseria gonorrhoeaeacross the world. Mutations in N-terminal region of MtrR, are known to abrogate its binding with the promoter thereby providing an evidence that this region encodes for DNA binding domain. In contrast, mechanism of action of mutations in C-terminal, known to play a role in protein dimerization and has site for ligand binding, is left unexplored. In the present study, usingin silicoapproach, we observed that H105Y mutation affects the conformation of the protein and its binding with penicillin. Purified, recombinant wild type and mutant MtrR were compared for their binding to promoter region and various antibiotics. Fluorescence spectroscopy, CD spectroscopy and dynamic light scattering assay with wild type and mutant MtrR suggested decreased binding of H105Y MtrR with its promoter without affecting protein dimerization, but due to altered conformation of mutant dimer. Ourin silicoresults also suggest altered conformation of the mutant dimer protein leading to difference in the posture of homodimer formed and hence altered binding with DNA. Mutant protein also showed stronger binding with various antibiotics: penicillin, ceftriaxone and ofloxacin. Binding of drugs also leads to altered conformation of the protein which may lead to its decreased binding with the promoter DNA.

Importance

Mutations in MtrR, a transcriptional repressor of MtrCDE efflux pump have been reported in various multi-drug resistantNeisseria gonorrhoeaeacross the world. We identified that a C-terminal mutation H105Y, outside the DNA binding domain of MtrR, decreases the binding of MtrR with its promoter. We identified that the mutation alters the structure of the dimer, as well as enhances the antibiotic binding. We envisage that the altered structure of MtrR affects its DNA binding thereby increasing efflux of antibiotics and increased resistance. These findings could be used as a guide to design novel drugs that should either not bind to MtrR or could surpass the conformational change and decreased DNA binding.
Continuous flexibility analysis of SARS-CoV-2 Spike prefusion structures
Authors: Melero Roberto , Sorzano Carlos Oscar S. , Foster Brent , Vilas José-Luis , Martínez Marta , Marabini Roberto , Ramírez-Aportela Erney , Sanchez-Garcia Ruben , Herreros David , del Caño Laura , Losana Patricia , Fonseca-Reyna Yunior C. , Conesa Pablo , Wrapp Daniel , Chacon Pablo , McLellan Jason S. , Tagare Hemant D. , Carazo Jose-Maria
Published: July 2020

With the help of novel processing workflows and algorithms, we have obtained a better understanding of the flexibility and conformational dynamics of the SARS-CoV-2 spike in the prefusion state. We have re-analyzed previous cryo-EM data combining 3D clustering approaches with ways to explore a continuous flexibility space based on 3D Principal Component Analysis. These advanced analyses revealed a concerted motion involving the receptor-binding domain (RBD), N-terminal domain (NTD), and subdomain 1 and 2 (SD1 & SD2) around the previously characterized 1-RBD-up state, which have been modeled as elastic deformations. We show that in this dataset there are not well-defined, stable, spike conformations, but virtually a continuum of states moving in a concerted fashion. We obtained an improved resolution ensemble map with minimum bias, from which we model by flexible fitting the extremes of the change along the direction of maximal variance. Moreover, a high-resolution structure of a recently described biochemically stabilized form of the spike is shown to greatly reduce the dynamics observed for the wild-type spike. Our results provide new detailed avenues to potentially restrain the spike dynamics for structure-based drug and vaccine design and at the same time give a warning of the potential image processing classification instability of these complicated datasets, having a direct impact on the interpretability of the results.
Striatal cholinergic interneuron numbers are increased in a rodent model of dystonic cerebral palsy
Authors: Gandham Sushma , Tak Yearam , Aravamuthan Bhooma R.
Published: July 2020

Neonatal brain injury leading to cerebral palsy (CP) is the most common cause of childhood dystonia, a painful and functionally debilitating movement disorder. Rare monogenic etiologies of dystonia have been associated with striatal cholinergic interneuron (ChI) pathology. However it is unclear whether striatal ChI pathology is also associated with dystonia following neonatal brain injury. We used unbiased stereology to estimate striatal ChI and parvalbumin-positive GABAergic interneuron (PVI) numbers in a rodent model of neonatal brain injury that demonstrates electrophysiological markers of dystonia and spasticity. Striatal ChI numbers are increased following neonatal brain injury while PVI numbers are unchanged. These numbers do not correlate with electrophysiologic measures of dystonia severity. This suggests that striatal ChI pathology, though present, may not be the primary pathophysiologic contributor to dystonia following neonatal brain injury. Increased striatal ChI numbers could instead represent a passenger or protective phenomenon in the setting of dystonic CP.
DeepCDR: a hybrid graph convolutional network for predicting cancer drug response
Authors: Liu Qiao , Hu Zhiqiang , Jiang Rui , Zhou Mu
Published: July 2020

Motivation

Accurate prediction of cancer drug response (CDR) is challenging due to the uncertainty of drug efficacy and heterogeneity of cancer patients. Strong evidences have implicated the high dependence of CDR on tumor genomic and transcriptomic profiles of individual patients. Precise identification of CDR is crucial in both guiding anti-cancer drug design and understanding cancer biology.

Results

In this study, we present DeepCDR which integrates multi-omics profiles of cancer cells and explores intrinsic chemical structures of drugs for predicting cancer drug response. Specifically, DeepCDR is a hybrid graph convolutional network consisting of a uniform graph convolutional network (UGCN) and multiple subnetworks. Unlike prior studies modeling hand-crafted features of drugs, DeepCDR automatically learns the latent representation of topological structures among atoms and bonds of drugs. Extensive experiments showed that DeepCDR outperformed state-of-the-art methods in both classification and regression settings under various data settings. We also evaluated the contribution of different types of omics profiles for assessing drug response. Furthermore, we provided an exploratory strategy for identifying potential cancer-associated genes concerning specific cancer types. Our results highlighted the predictive power of DeepCDR and its potential translational value in guiding disease-specific drug design.

Availability

DeepCDR is freely available athttps://github.com/kimmo1019/DeepCDR

Contact

ruijiang@tsinghua.edu.cn;muzhou@sensebrain.site

Supplementary information

Supplementary data are available atBioinformaticsonline.
Subjective visibility report is facilitated by conscious predictions only
Authors: Alilović Josipa , Slagter Heleen A. , van Gaal Simon
Published: July 2020

Predictions in the visual domain have been shown to modulate conscious access. Yet, little is known about how predictions may do so and to what extent they need to be consciously implemented to be effective. To address this, we administered an attentional blink (AB) task in which target 1 (T1) identity predicted target 2 (T2) identity, while participants rated their perceptual awareness of validly versus invalidly predicted T2s (Experiment 1 & 2) or reported T2 identity (Experiment 3). Critically, we tested the effects of conscious and non-conscious predictions, after seen and unseen T1s, on T2 visibility. We found that valid predictions increased subjective visibility reports and discrimination of T2s, but only when predictions were generated by a consciously accessed T1, irrespective of the timing at which the effects were measured (short vs. longs lags). These results further our understanding of the intricate relationship between predictive processing and consciousness.
Whole genome survey of big cats (Genus:Panthera) identifies novel microsatellites of utility in conservation genetic study
Authors: Hyun Jee Yun , Pandey Puneet , Kim Kyung Seok , Chon Alvin , Jeong Daecheol , Bhak Jong , Yoo Mi-Hyun , Song Hey-Kyung , Singh Randeep , Min Mi-Sook , Goyal Surendra Prakash , Bayarkhagva Damdingiin , Lee Hang
Published: July 2020

Big cats (Genus:Panthera) are among the most threatened mammal groups of the world, owing to illegal transnational trade. Conservation genetic studies and effective curbs on poaching are important for the conservation of these charismatic apex predators. A limited number of microsatellite markers exists forPantheraspecies and researchers often cross-amplify domestic cat microsatellites to study these species. We conducted data mining of sevenPantheragenome sequences to discover microsatellites for conservation genetic studies of four threatened big cat species. A total of 32 polymorphic microsatellite loci were identified in silico and tested with 99 big cat individuals and 7 Eurasian lynx. The developed markers were polymorphic in most of the tested species. We propose a set of 15 novel microsatellite markers for use in conservation genetics and wildlife forensic investigations of big cat species. Cumulatively, these markers have a high discriminatory power of one in a million for unrelated individuals and one in a thousand for siblings. Similar PCR conditions of these markers increase the prospects of achieving efficient multiplex PCR assays. This study is a pioneering attempt to synthesise genome wide microsatellite markers for big cats.
Production of benzylglucosinolate by engineering and optimizing the biosynthetic pathway inSaccharomyces cerevisiae
Authors: Wang Cuiwei , Crocoll Christoph , Nødvig Christina Spuur , Mortensen Uffe Hasbro , Clemmensen Sidsel Ettrup , Halkier Barbara Ann
Published: July 2020

Glucosinolates are amino acid-derived defense compounds characteristic of the Brassicales order. Benzylglucosinolate (BGLS) derived from phenylalanine is associated with health-promoting effects, which has primed a desire to produce BGLS in microorganisms for a stable and rich source. In this study, we engineered the BGLS production inSaccharomyces cerevisiaeby either stably integrating the biosynthetic genes into the genome or introducing them from plasmids. A comparison of the two approaches exhibited a significantly higher level of BGLS production (9.3-fold) by expression of the genes from genome than from plasmids. Towards optimization of BGLS production from genes stably integrated into the genome, we enhanced expression of the entry point enzymes CYP79A2 and CYP83B1 resulting in a 2-fold increase in BGLS production, but also a 4.8-fold increase in the biosynthesis of the last intermediate desulfo-benzylglucosinolate (dsBGLS). To alleviate the metabolic bottleneck in the last step converting dsBGLS to BGLS by 3’-phosphoadenosine-5’-phosphosulfate (PAPS)-dependent sulfotransferase, SOT16, we first obtained an increased BGLS production by 1.7-fold when overexpressingSOT16. Next, we introduced APS kinase APK1 ofArabidopsis thalianafor efficient PAPS regeneration, which improved the level of BGLS production by 1.7-fold. Our work shows an optimized production of BGLS inS. cerevisiaeand the effect of different approaches for engineering the biosynthetic pathway (plasmid expression and genome integration) on the production level of BGLS.