bluuebunny/crossref_metadata_2025 huggingface dataset:
Peptide Based Inhibitors of Protein Binding to the Mitogen-Activated Protein Kinase Docking Groove
Authors: Alexa Anita , Ember Orsolya , Szabó Ildikó , Mo’ath Yousef , Póti Ádám L. , Reményi Attila , Bánóczi Zoltán
Published: July 2021

Mitogen-activated protein kinases (MAPK) are important regulatory units in cells and they take part in the regulation of many cellular functions such as cell division, differentiation or apoptosis. All MAPKs have a shallow docking groove that interacts with linear binding motifs of their substrate proteins and their regulatory proteins such as kinases, phosphatases, scaffolds. Inhibition of these protein–protein interactions may reduce or abolish the activity of the targeted kinase. Based on the wide range of their biological activity, this kind of inhibition can be useful in the treatment of many disorders like tumors, inflammation or undesired cell apoptosis. In this study a linear binding motif from the RHDF1 protein—a 15 amino acids long peptide—was selected for optimization to increase its cellular uptake but retaining its low micromolar binding affinity. First, we synthesized an octaarginine conjugate that showed efficient cellular uptake. Next, we set out to reduce the size of this construct. We were able to decrease the length of the original peptide, and to increase its cellular uptake with specific chemical modifications. These new constructs bound better to ERK2 and p38 kinases than the original peptide and they showed markedly increased cellular uptake. The new octaarginine conjugate and one of the minimized bicyclic derivatives could inhibit the phosphorylation of intracellular ERK or p38. However, the modulation of MAPK phosphorylation levels by these cell-penetrating peptides were complex, despite that in biochemical assays they all inhibited MAPK-substrate binding as well as phosphorylation. The optimized peptides depending on the applied concentration caused an expected decrease, but also some unexpected increase in MAPK phosphorylation patterns in the cell. This possibly reflects the complexity of MAPK docking groove mediated protein–protein interactions including bone fide MAPK clients such activator kinases, deactivating phosphatases or regulatory scaffolds. Thus, our findings with optimized cell-penetrating “inhibitory” peptides highlight the opportunities but also the pitfalls of docking peptide based MAPK activity regulation and call for a better quantitative understanding of MAPK mediated protein–protein interactions in cells.
Oxidative Damage to RNA is Altered by the Presence of Interacting Proteins or Modified Nucleosides
Authors: Estevez Mariana , Valesyan Satenik , Jora Manasses , Limbach Patrick A. , Addepalli Balasubrahmanyam
Published: July 2021

Oxidative stress triggered by the Fenton reaction (chemical) or UVR exposure (photo) can damage cellular biomolecules including RNA through oxidation of nucleotides. Besides such xenobiotic chemical modifications, RNA also contains several post-transcriptional nucleoside modifications that are installed by enzymes to modulate structure, RNA-protein interactions, and biochemical functions. We examined the extent of oxidative damage to naturally modified RNA which is required for cellular protein synthesis under two different contexts. The extent of oxidative damage is higher when RNA is not associated with proteins, but the degree of damage is lower when the RNA is presented in the form of a ribonucleoprotein complex, such as an intact ribosome. Our studies also indicate that absence of methylations in ribosomal RNA at specific positions could make it more susceptible to photooxidative stress. However, the extent of guanosine oxidation varied with the position at which the modification is deficient, indicating position-dependent structural effects. Further, an E. coli strain deficient in 5-methylaminomethyl-2-thiouridine (mnm5s2U) (found in lysine and glutamate tRNA anticodon) is more vulnerable to oxidative RNA damage compared to its wildtype strain suggesting an auxiliary function for the mnm5s2U modification. These studies indicate that oxidative damage to RNA is altered by the presence of enzymatic modified nucleosides or protein association inside the cell.
No Arachnoid Granulations—No Problems: Number, Size, and Distribution of Arachnoid Granulations From Birth to 80 Years of Age
Authors: Radoš Milan , Živko Matea , Periša Ante , Orešković Darko , Klarica Marijan
Published: July 2021

Introduction: The study aims to quantify changes in the number, size, and distribution of arachnoid granulations during the human lifespan to elucidate their role in cerebrospinal fluid physiology.

Material and Methods: 3T magnetic resonance imaging of the brain was performed in 120 subjects of different ages (neonate, 2 years, 10 years, 20 years, 40 years, 60 years, and 80 years) all with the normal findings of the cerebrospinal fluid system (CSF). At each age, 10 male and 10 female subjects were analyzed. Group scanned at neonatal age was re-scanned at the age of two, while all other groups were scanned once. Arachnoid granulations were analyzed on T2 coronal and axial sections. Each arachnoid granulation was described concerning size and position relative to the superior sagittal, transverse, and sigmoid sinuses and surrounding cranial bones.

Results: Our study shows that 85% of neonates and 2-year-old children do not have visible arachnoid granulations in the dural sinuses and cranial bones on magnetic resonance imaging. With age, the percentage of patients with arachnoid granulations in the superior sagittal sinus increases significantly, but there is no increase in the sigmoid and transverse sinuses. However, numerous individuals in different age groups do not have arachnoid granulations in dural sinuses. Arachnoid granulations in the cranial bones are found only around the superior sagittal sinus, for the first time at the age of 10, and over time their number increases significantly. From the age of 60 onwards, arachnoid granulations were more numerous in the cranial bones than in the dural sinuses.

Conclusion: The results show that the number, size, and distribution of arachnoid granulations in the superior sagittal sinus and surrounding cranial bones change significantly over a lifetime. However, numerous individuals with a completely normal CSF system do not have arachnoid granulations in the dural sinuses, which calls into question their role in CSF physiology. It can be assumed that arachnoid granulations do not play an essential role in CSF absorption as it is generally accepted. Therefore, the lack of arachnoid granulations does not appear to cause problems in intracranial fluid homeostasis.
The Drosophila Larval Locomotor Circuit Provides a Model to Understand Neural Circuit Development and Function
Authors: Hunter Iain , Coulson Bramwell , Zarin Aref Arzan , Baines Richard A.
Published: July 2021

It is difficult to answer important questions in neuroscience, such as: “how do neural circuits generate behaviour?,” because research is limited by the complexity and inaccessibility of the mammalian nervous system. Invertebrate model organisms offer simpler networks that are easier to manipulate. As a result, much of what we know about the development of neural circuits is derived from work in crustaceans, nematode worms and arguably most of all, the fruit fly, Drosophila melanogaster. This review aims to demonstrate the utility of the Drosophila larval locomotor network as a model circuit, to those who do not usually use the fly in their work. This utility is explored first by discussion of the relatively complete connectome associated with one identified interneuron of the locomotor circuit, A27h, and relating it to similar circuits in mammals. Next, it is developed by examining its application to study two important areas of neuroscience research: critical periods of development and interindividual variability in neural circuits. In summary, this article highlights the potential to use the larval locomotor network as a “generic” model circuit, to provide insight into mammalian circuit development and function.
Best Practices in the Clinical Management of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Consensus Statement of the CurePSP Centers of Care
Authors: Bluett Brent , Pantelyat Alexander Y. , Litvan Irene , Ali Farwa , Apetauerova Diana , Bega Danny , Bloom Lisa , Bower James , Boxer Adam L. , Dale Marian L. , Dhall Rohit , Duquette Antoine , Fernandez Hubert H. , Fleisher Jori E. , Grossman Murray , Howell Michael , Kerwin Diana R. , Leegwater-Kim Julie , Lepage Christiane , Ljubenkov Peter Alexander , Mancini Martina , McFarland Nikolaus R. , Moretti Paolo , Myrick Erica , Patel Pritika , Plummer Laura S. , Rodriguez-Porcel Federico , Rojas Julio , Sidiropoulos Christos , Sklerov Miriam , Sokol Leonard L. , Tuite Paul J. , VandeVrede Lawren , Wilhelm Jennifer , Wills Anne-Marie A. , Xie Tao , Golbe Lawrence I.
Published: July 2021

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.
Influence of Pregnancy in Multiple Sclerosis and Impact of Disease-Modifying Therapies
Authors: Simone Isabella Laura , Tortorella Carla , Ghirelli Alma
Published: July 2021

Purpose of this Review:This article is a systematic review on the influence pregnancy has on multiple sclerosis and the resulting impact of disease-modifying therapies.

Findings:Multiple sclerosis predominantly affects young women with a clinical onset most often during the child-bearing age. The impact of multiple sclerosis and disease-modifying therapies on fertility, pregnancy, fetal outcome, and breastfeeding is a pivotal topic when it comes to clinical practice. The introduction of disease-modifying therapies has changed not only the natural history of the disease but also the perspective of pregnancy in women with multiple sclerosis. Family planning requires careful consideration, especially because many disease-modifying drugs are contraindicated during pregnancy. In this article, we review current evidence collected from published literature and drug-specific pregnancy registers on the use of disease-modifying therapies. Additionally, we discuss safety profiles for each drug and correlate them to both risk for the exposed fetus and risk for the mothers interrupting treatments when seeking pregnancy.
Trail Making Test Performance Using a Touch-Sensitive Tablet: Behavioral Kinematics and Electroencephalography
Authors: Lin Zhongmin , Tam Fred , Churchill Nathan W. , Lin Fa-Hsuan , MacIntosh Bradley J. , Schweizer Tom A. , Graham Simon J.
Published: July 2021

The Trail Making Test (TMT) is widely used to probe brain function and is performed with pen and paper, involving Parts A (linking numbers) and B (alternating between linking numbers and letters). The relationship between TMT performance and the underlying brain activity remains to be characterized in detail. Accordingly, sixteen healthy young adults performed the TMT using a touch-sensitive tablet to capture enhanced performance metrics, such as the speed of linking movements, during simultaneous electroencephalography (EEG). Linking and non-linking periods were derived as estimates of the time spent executing and preparing movements, respectively. The seconds per link (SPL) was also used to quantify TMT performance. A strong effect of TMT Part A and B was observed on the SPL value as expected (Part B showing increased SPL value); whereas the EEG results indicated robust effects of linking and non-linking periods in multiple frequency bands, and effects consistent with the underlying cognitive demands of the test.
Determination of Diffusion Kinetics of Ketamine in Brain Tissue: Implications for in vitro Mechanistic Studies of Drug Actions
Authors: Geiger Zachary , VanVeller Brett , Lopez Zarin , Harrata Abdel K. , Battani Kathryn , Wegman-Points Lauren , Yuan Li-Lian
Published: July 2021

Ketamine has been in use for over 50 years as a general anesthetic, acting primarily through blockade of N-methyl-D-aspartate receptors in the brain. Recent studies have demonstrated that ketamine also acts as a potent and rapid-acting antidepressant when administered at sub-anesthetic doses. However, the precise mechanism behind this effect remains unclear. We examined the diffusion properties of ketamine in brain tissue to determine their effects in in vitro studies related to the antidepressant action of ketamine. Brain slices from adult mice were exposed to artificial cerebrospinal fluid (aCSF) containing ∼17 μM ketamine HCl for varying amounts of time. The amount of ketamine within each slice was then measured by tandem high-performance liquid chromatography – mass spectrometry to characterize the diffusion of ketamine into brain tissue over time. We successfully modeled the diffusion of ketamine into brain tissue using a mono-exponential function with a time constant of τ = 6.59 min. This curve was then compared to a one-dimensional model of diffusion yielding a diffusion coefficient of approximately 0.12 cm2⋅s–1 for ketamine diffusing into brain tissue. The brain:aCSF partition coefficient for ketamine was determined to be approximately 2.76. Our results suggest that the diffusion properties of ketamine have a significant effect on drug concentrations achieved within brain tissue during in vitro experiments. This information is vital to determine the ketamine concentration necessary for in vitro slice preparation to accurately reflect in vivo doses responsible for its antidepressant actions.
LPC-DHA/EPA-Enriched Diets Increase Brain DHA and Modulate Behavior in Mice That Express Human APOE4
Authors: Scheinman Sarah B. , Sugasini Dhavamani , Zayed Monay , Yalagala Poorna C. R. , Marottoli Felecia M. , Subbaiah Papasani V. , Tai Leon M.
Published: July 2021

Compared with APOE3, APOE4 is associated with greater age-related cognitive decline and higher risk of neurodegenerative disorders. Therefore, development of supplements that target APOE genotype-modulated processes could provide a great benefit for the aging population. Evidence suggests a link between APOE genotype and docosahexaenoic acid (DHA); however, clinical studies with current DHA supplements have produced negative results in dementia. The lack of beneficial effects with current DHA supplements may be related to limited bioavailability, as the optimal form of DHA for brain uptake is lysophosphatidylcholine (LPC)-DHA. We previously developed a method to enrich the LPC-DHA content of krill oil through lipase treatment (LT-krill oil), which resulted in fivefold higher enrichment in brain DHA levels in wild-type mice compared with untreated krill oil. Here, we evaluated the effect of a control diet, diet containing krill oil, or a diet containing LT-krill oil in APOE3- and APOE4-targeted replacement mice (APOE-TR mice; treated from 4 to 12 months of age). We found that DHA levels in the plasma and hippocampus are lower in APOE4-TR mice and that LT-krill oil increased DHA levels in the plasma and hippocampus of both APOE3- and APOE4-TR mice. In APOE4-TR mice, LT-krill oil treatment resulted in higher levels of the synaptic vesicle protein SV2A and improved performance on the novel object recognition test. In conclusion, our data demonstrate that LPC-DHA/EPA-enriched krill oil can increase brain DHA and improve memory-relevant behavior in mice that express APOE4. Therefore, long-term use of LT-krill oil supplements may on some level protect against age-related neurodegeneration.
Structures of Pathological and Functional Amyloids and Prions, a Solid-State NMR Perspective
Authors: Daskalov Asen , El Mammeri Nadia , Lends Alons , Shenoy Jayakrishna , Lamon Gaelle , Fichou Yann , Saad Ahmad , Martinez Denis , Morvan Estelle , Berbon Melanie , Grélard Axelle , Kauffmann Brice , Ferber Mathias , Bardiaux Benjamin , Habenstein Birgit , Saupe Sven J. , Loquet Antoine
Published: July 2021

Infectious proteins or prions are a remarkable class of pathogens, where pathogenicity and infectious state correspond to conformational transition of a protein fold. The conformational change translates into the formation by the protein of insoluble amyloid aggregates, associated in humans with various neurodegenerative disorders and systemic protein-deposition diseases. The prion principle, however, is not limited to pathogenicity. While pathological amyloids (and prions) emerge from protein misfolding, a class of functional amyloids has been defined, consisting of amyloid-forming domains under natural selection and with diverse biological roles. Although of great importance, prion amyloid structures remain challenging for conventional structural biology techniques. Solid-state nuclear magnetic resonance (SSNMR) has been preferentially used to investigate these insoluble, morphologically heterogeneous aggregates with poor crystallinity. SSNMR methods have yielded a wealth of knowledge regarding the fundamentals of prion biology and have helped to solve the structures of several prion and prion-like fibrils. Here, we will review pathological and functional amyloid structures and will discuss some of the obtained structural models. We will finish the review with a perspective on integrative approaches combining solid-state NMR, electron paramagnetic resonance and cryo-electron microscopy, which can complement and extend our toolkit to structurally explore various facets of prion biology.
Assessment of Dietary Bioactive Phenolic Compounds and Agricultural Sustainability of an African Leafy Vegetable Corchorus olitorius L.
Authors: Guzzetti Lorenzo , Panzeri Davide , Ulaszewska Marynka , Sacco Grazia , Forcella Matilde , Fusi Paola , Tommasi Nicola , Fiorini Andrea , Campone Luca , Labra Massimo
Published: July 2021

Corchorus olitorius L. is an African leafy vegetable of high nutritional interest. To assess its agricultural suitability to sustainable cultivation conditions and its potential benefits for human nutrition, its phytochemical content in response to conservation agriculture practices [i.e., no-tillage (NT) and cover crop maintenance] and low water regime were evaluated and compared with response under conventional agriculture management. Hydric stress and NT did not affect the content of antioxidant metabolites, compared to conventional agricultural practices. In both conditions, leaves were found to be a great source of phenolic compounds. The effect of these phenolic fractions was assessed on two colon cell phenotypes to evaluate putative nutraceutical properties. Polyphenol-enriched extracts (PEEs) displayed selective cytotoxic activities against tumor Caco-2 cells but not on the healthy CCD841 line. PEEs were able to trigger oxidative stress and to inhibit the activity of glutathione-independent antioxidant enzymes on Caco-2 cells. C. olitorius showed to be a promising crop for improving both agricultural sustainability and health benefits due to the great amount of antioxidant compounds in leaves, whose occurrence is not altered by stressful farming conditions. Given its high adaptability, the cultivation of this crop is therefore recommendable also in the Mediterranean Basin.
Long-Term Safety and Efficacy of CT-Guided I125 Radioactive Seed Implantation as a Salvage Therapy for Recurrent Head and Neck Squamous Carcinoma: A Multicenter Retrospective Study
Authors: Jiang Yuliang , Zhen Peng , Dai Jinchao , Li Yixing , Liu Shifeng , Xu Junma , Wang Yufeng , Tian Suqing , Cui Yue , Ji Zhe , Guo Fuxin , Qiu Bin , Sun Haitao , Fan Jinghong , Wang Junjie
Published: July 2021

Purpose

To investigate the safety and efficacy of CT-guided I125 radioactive seed implantation (RSI) as a salvage therapy for recurrent head and neck squamous carcinoma (rHNSC) after external beam radiotherapy (EBRT) or surgery.

Materials and Methods

This is a multicenter retrospective study of 113 patients (83 males; median age 57 years) with rHNSC who underwent CT-guided I125 RSI between February 2003 and December 2017. Of the included patients, 107 patients previously received EBRT and 65 patients received surgery and all were ineligible or rejected for salvage surgery and/or repeat EBRT.

Results

During a median follow-up duration of 20 months (range, 3-152 months), 87 patients died. The 1-, 2-, 3-, and 5-year local control rate were 57.4%, 41.8%, 29.3%, and 15.2%, respectively. The median time to progression was 15 months [95% confidence interval (CI), 6.1-23.9 months]. The median overall survival (OS) was 20 months (95% CI, 12.4-27.6 months). The 1-, 2-, 3-, and 5-year OS rate were 63.6%, 44.6%, 29.9%, and 21.7%, respectively. Univariate and multivariate analyses revealed that KPS score and postoperative D90 were significantly associated with patients’ OS. The complications were mainly grade I/II skin and mucosal reactions: 18 cases (15.9%) of grade I/II and eight cases (7.0%) of grade III radiation dermatitis, and 14 cases (12.4%) of grade I/II and three cases (2.7%) grade III mucosal reactions. No grade IV or severer complications were found.

Conclusion

CT-guided I125 RSI may be safe as a salvage therapy for rHNSC after EBRT/surgery, yielding promising efficacy compared with historical data. KPS score and postoperative D90 may be significantly associated with OS.
Report of Eleven Patients of Subcutaneous Panniculitis-Like T-Cell Lymphoma: Clinicopathologic Features, 18F-FDG PET/CT Findings and Outcome
Authors: Jiang Maoqing , Zhao Long , Zheng Jianjun , Zhang Jingfeng , Chen Ping , Zhou Wenlan
Published: July 2021

Objectives

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a fairly rare subtype of primary cutaneous lymphoma. This study aims to investigate the clinicopathologic features, 18F-FDG PET/CT findings, and outcome of patients with SPTCL.

Methods

A retrospective single-center study enrolled 11 patients with SPTCL between August 2010 and March 2020. A total of 26 18F-FDG PET/CT scans were performed, and the initial and follow-up PET/CT imaging features, clinicopathologic and immunohistochemical characteristics, and outcome were analyzed.

Results

The male-to-female ratio was 1.2. The mean age at diagnosis was 24.2 years (age range: 13–48 years). Histopathological examinations revealed atypical T-lymphocyte rimming of individual subcutaneous adipocytes, mostly with CD2+, CD3+, CD4−, CD5+, CD8+, CD56−, T-cell intracellular antigen-1+, Granzyme B+, and high Ki-67 index. Multiple large skin ulcerations with a maximum diameter of 10 cm were observed in one of the 11 patients (9.1%, 1/11), and hemophagocytic syndrome was found in another one. At initial PET/CT scans, the lesions in all 11 patients showed increased uptake of 18F-FDG with a wide range of maximum standard uptake value (SUVmax) from 2.0 to 14.9. The morphology of the lesions presented as multiple nodules and/or disseminated plaques mainly involving the trunk and/or limbs. Five patients had extracutaneous non-lymph node lesions with SUVmax of 5.6 ± 2.8 on 18F-FDG PET/CT. No significant correlation between SUVmax and Ki-67 index was observed (r = 0.19, P > 0.05). Follow-up 18F-FDG PET/CT scans in six patients showed complete remission of the disease in two, partial remission in three, and progressive disease in one. During the follow-up period, there was no death except for the patient with multiple ulcerations who died 4 months after diagnosis of SPTCL.

Conclusions

SPTCL may be a group of heterogeneous diseases with varying degrees of 18F-FDG uptake. 18F-FDG PET/CT demonstrates its usefulness in detecting disease extent, providing diagnostic work-up, staging, and evaluating treatment response of SPTCL. Multiple large skin ulcerations may be a factor of poor prognosis for patients with SPTCL.
Impact of Adjuvant Chemoradiotherapy on Survival of Resected Pancreatic Adenocarcinoma Cancer: A Surveillance, Epidemiology and End Results (SEER) Analysis
Authors: Shi Xiaomao , Peng Jin , Jiang Huangang , Gao Yu , Wang Wenbo , Zhou Fuxiang
Published: July 2021

Background

The benefits of postoperative adjuvant chemoradiotherapy (CRT) for pancreatic cancer remain controversial. The purpose of this study is to determine if adjuvant CRT can improve the overall survival of postoperative pancreatic cancer patients compared to adjuvant chemotherapy (CT).

Methods

Patients with resected pancreas adenocarcinoma were identified in the Surveillance, Epidemiology, and End Results (SEER) database (2004–2016). Multivariate Cox regression was used to determine the factors related to survival rate. Selection bias was reduced to a minimum through propensity matching analysis. Subgroup analyses by clinical characteristics were performed.

Results

This study identified 10,097 patients who received adjuvant CT (n = 5,454) or adjuvant CRT (n = 4,643). On multivariate analysis, age, sex, tumor size, site, grade, stage, T stage, and lymph node metastasis were independent risk factors for OS. The basic clinical characteristics were well balanced after propensity matching. After propensity matching, CRT can improve the survival rate compared with CT [median OS: 22 months vs 23 months (HR, 0.928; 95% CI, 0.881–0.977; P = 0.004)]. Subgroup analysis indicated that the survival benefit of adjuvant chemoradiotherapy was more significant in patients with female (HR, 0.860; 95% CI, 0.798–0.926; P = 0.005 for interaction) or T3 (HR, 0.905; 95% CI, 0.855–0.957; P = 0.04 for interaction) or lymph nodes positive (HR, 0.883; 95% CI, 0.832–0.938; P = 0.005 for interaction).

Conclusion

Adjuvant CRT was associated with improved survival compared with adjuvant CT in patients with resection of pancreatic ductal adenocarcinoma. The benefit was more significant in patients with female or T3 or lymph nodes positive.
USP9X Is Required to Maintain Cell Survival in Response to High-LET Radiation
Authors: Nickson Catherine M. , Fabbrizi Maria Rita , Carter Rachel J. , Hughes Jonathan R. , Kacperek Andrzej , Hill Mark A. , Parsons Jason L.
Published: July 2021

Ionizing radiation (IR) principally acts through induction of DNA damage that promotes cell death, although the biological effects of IR are more broad ranging. In fact, the impact of IR of higher-linear energy transfer (LET) on cell biology is generally not well understood. Critically, therefore, the cellular enzymes and mechanisms responsible for enhancing cell survival following high-LET IR are unclear. To this effect, we have recently performed siRNA screening to identify deubiquitylating enzymes that control cell survival specifically in response to high-LET α-particles and protons, in comparison to low-LET X-rays and protons. From this screening, we have now thoroughly validated that depletion of the ubiquitin-specific protease 9X (USP9X) in HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells using small interfering RNA (siRNA), leads to significantly decreased survival of cells after high-LET radiation. We consequently investigated the mechanism through which this occurs, and demonstrate that an absence of USP9X has no impact on DNA damage repair post-irradiation nor on apoptosis, autophagy, or senescence. We discovered that USP9X is required to stabilize key proteins (CEP55 and CEP131) involved in centrosome and cilia formation and plays an important role in controlling pericentrin-rich foci, particularly in response to high-LET protons. This was also confirmed directly by demonstrating that depletion of CEP55/CEP131 led to both enhanced radiosensitivity of cells to high-LET protons and amplification of pericentrin-rich foci. Our evidence supports the importance of USP9X in maintaining centrosome function and biogenesis and which is crucial particularly in the cellular response to high-LET radiation.
Factors Predicting Locoregional Recurrence After Neoadjuvant Chemotherapy and Nipple-Sparing/Skin-Sparing Mastectomy With Immediate Breast Reconstruction
Authors: Wu Zhen-Yu , Kim Hee Jeong , Lee Jong Won , Chung Il Yong , Kim Jisun , Lee Sae Byul , Son Byung-Ho , Eom Jin Sup , Jeong Jae Ho , Gong Gyungyub , Kim Hak Hee , Ahn Sei-Hyun , Ko BeomSeok
Published: July 2021

Background

Few data are available on the risk factors of locoregional recurrence (LRR) after neoadjuvant chemotherapy (NACT) and immediate breast reconstruction (IBR) in breast cancer. Herein, we evaluated the factors predicting LRR in a large series of patients who underwent either nipple- (NSM) or skin-sparing mastectomy (SSM) with IBR after NACT.

Methods

We retrospectively analyzed 609 breast cancer patients who underwent NACT and NSM/SSM with IBR between February 2010 and June 2017. Factors associated with an increased risk of LRR were analyzed by univariate (chi-square or Fisher’s exact test) and multivariate (Cox proportional hazard regression model) analyses.

Results

During a median follow-up of 63 months, LRR as the first event occurred in 73 patients, and the 5-year cumulative LRR rate was 10.8%. Multivariate analysis revealed post-NACT Ki67 ≥ 10% [hazard ratio (HR), 2.208; 95% confidence interval (CI), 1.295-3.765; P = 0.004], high tumor grade (HR, 1.738; 95% CI, 1.038-2.908; P = 0.035), and presence of lymphovascular invasion (LVI) (HR, 1.725; 95% CI, 1.039-2.864; P = 0.035) as independently associated with increased LRR risk. The 10-year LRR rate was 8.5% for patients with none of the three associated risk factors, 11.6% with one factor, 25.1% with two factors, and 33.7% with all three factors (P < 0.001).

Conclusions

Post-NACT Ki67 ≥ 10%, high tumor grade, and presence of LVI are independently associated with an increased risk of developing LRR after NACT and NSM/SSM with IBR. Future prospective trials are warranted to decrease the risk of LRR in patients with associated risk factors.
Clinicopathological Characteristics and Prognosis in Endometrial Cancer With Bone Metastasis: A SEER-Based Study of 584 Women
Authors: Hu Hejia , Wang Zhan , Zhang Miaofeng , Niu Feng , Yu Qunfei , Ren Ying , Ye Zhaoming
Published: July 2021

Purpose

Bone metastasis from endometrial cancer (EC) is rare and poorly described. The purpose of the present study was to investigate the correlation between the clinically accessible factors and survival time among EC patients with bone metastasis.

Patients and Methods

We retrospectively identified and reviewed EC patients with bone metastasis from 2010 to 2016, based on the Surveillance, Epidemiology and End Results (SEER) database. Univariable and multivariable Cox regressions were applied to evaluate the effects of clinical variables on survival. Kaplan–Meier plots were used to visually demonstrate the correlation between independent risk factors and survival.

Results

Clinical data of 584 EC patients with bone metastasis from the SEER database were analyzed. EC patients with bone metastasis experienced extremely poor survival, with 1-year overall survival (OS) and cancer-specific survival (CSS) rates 33.8 and 35.8%, respectively. Variables associated with OS and CSS in the univariable analysis included race, tumor grade, tumor subtype, tumor size, lung, liver and brain metastases, surgery, radiotherapy, and chemotherapy. In the multivariable analysis, tumor grade, tumor subtype, liver and brain metastases, local surgery, and systemic chemotherapy remained independent risk factors for OS and CSS. However, local radiotherapy was an independent predictor of OS, not CSS.

Conclusions

We identified several factors affect the survival of EC patients with bone metastasis, which is useful for clinicians to assess patients’ outcomes. Our study supports surgery and radiotherapy of primary EC, and systemic chemotherapy for prolonging survival among EC patients with bone metastasis, which lays a solid foundation for defining optimal treatment strategy in this specific cohort.
Clinical Characteristics and Genetic Etiology of Children With Developmental Language Disorder
Authors: Plug Marielle B. , van Wijngaarden Vivian , de Wilde Hester , van Binsbergen Ellen , Stegeman Inge , van den Boogaard Marie-José H. , Smit Adriana L.
Published: July 2021

Objective:Developmental language delay (DLD) is one of the most common disabilities in childhood and can negatively affect a child's communication skills and academic and/or psychosocial development. To date, an increasing number of causative genes have been identified by diagnostic techniques like next generation sequencing. An early genetic diagnosis is important to properly prepare and counsel children and parents for possible future difficulties. Despite this, genetic assessment is usually not part of a standardized diagnostic set in children with developmental language delay. In this study, we aim to assess the diagnostic outcomes of children primarily assessed for speech and language delay who were subsequently referred for genetic etiological assessment.

Methods:Medical records of children referred to the department of Otorhinolaryngology of the Wilhelmina Children's Hospital for diagnostic work-up for a suspected speech and language delay between June 2011 and December 2018 who were additionally referred to a geneticist were evaluated. Study parameters concerning medical history, behavioral problems, language development, intelligence, and hearing were recorded. Outcomes of genetic analysis were evaluated.

Results:A total of 127 patients were diagnosed with a developmental language delay. Genetic analysis was conducted in 119 out of 127 patients with a language delay and eligible for this study. The median time between initial speech and language assessment and the first genetic consultation was 10 months (IQR 5.0–23.0). In 34 out of 127 patients a causative genetic diagnosis was found to explain their DLD.

Conclusion:In approximately a quarter of the patients (26.8%) diagnosed with developmental language delay, a causative genetic diagnosis was confirmed. This demonstrates the opportunity to identify an underlying genetic etiology in children with developmental language delay. However, in order to optimize the diagnostic process and clinical care for these children, two important research gaps need to be addressed. First, research should focus on assessing the clinical impact and effect on treatment outcomes of a genetic diagnosis. Secondly, it is important to recognize for which children genetic testing is most beneficial.
Network Pharmacological Analysis and Experimental Validation of the Mechanisms of Action of Si-Ni-San Against Liver Fibrosis
Authors: Wang Siliang , Tang Cheng , Zhao Heng , Shen Peiliang , Lin Chao , Zhu Yun , Han Dan
Published: July 2021

Background: Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear.

Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays.

Results: SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further in vivo experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-α and Act D in vitro. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained in vitro by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation.

Conclusion: SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition.
Development and Validation of Prediction Equation of “Athens Authentic Marathon” Men’s Race Speed
Authors: Nikolaidis Pantelis T. , Rosemann Thomas , Knechtle Beat
Published: July 2021

Aim

Despite the increasing popularity of outdoor endurance running races of different distances, little information exists about the role of training and physiological characteristics of recreational runners. The aim of the present study was (a) to examine the role of training and physiological characteristics on the performance of recreational marathon runners and (b) to develop a prediction equation of men’s race time in the “Athens Authentic Marathon.”

Methods

Recreational male marathon runners (n= 130, age 44.1 ± 8.6 years)—who finished the “Athens Authentic Marathon” 2017—performed a series of anthropometry and physical fitness tests including body mass index (BMI), body fat percentage (BF), maximal oxygen uptake (VO2max), anaerobic power, squat, and countermovement jump. The variation of these characteristics was examined by quintiles (i.e., five groups consisting of 26 participants in each) of the race speed. An experimental group (EXP,n= 65) was used to develop a prediction equation of the race time, which was verified in a control group (CON,n= 65).

Results

In the overall sample, a one-way ANOVA showed a main effect of quintiles on race speed on weekly training days and distance, age, body weight, BMI, BF, and VO2max (p≤ 0.003, η2≥ 0.121), where the faster groups outscored the slower groups. Running speed during the race correlated moderately with age (r= −0.36,p< 0.001) and largely with the number of weekly training days (r= 0.52,p< 0.001) and weekly running distance (r= 0.58,p< 0.001), but not with the number of previously finished marathons (r= 0.08,p= 0.369). With regard to physiological characteristics, running speed correlated largely with body mass (r= −0.52,p< 0.001), BMI (r= −0.60,p< 0.001), BF (r= −0.65,p< 0.001), VO2max (r= 0.67,p< 0.001), moderately with isometric muscle strength (r= 0.42,p< 0.001), and small with anaerobic muscle power (r= 0.20,p= 0.021). In EXP, race speed could be predicted (R2= 0.61, standard error of the estimate = 1.19) using the formula “8.804 + 0.111 × VO2max + 0.029 × weekly training distance in km −0.218 × BMI.” Applying this equation in CON, no bias was observed (difference between observed and predicted value 0.12 ± 1.09 km/h, 95% confidence intervals −0.15, 0.40,p= 0.122).

Conclusion

These findings highlighted the role of aerobic capacity, training, and body mass status for the performance of recreational male runners in a marathon race. The findings would be of great practical importance for coaches and trainers to predict the average marathon race time in a specific group of runners.
Automated Localization of Focal Ventricular Tachycardia From Simulated Implanted Device Electrograms: A Combined Physics–AI Approach
Authors: Monaci Sofia , Gillette Karli , Puyol-Antón Esther , Rajani Ronak , Plank Gernot , King Andrew , Bishop Martin
Published: July 2021

Background: Focal ventricular tachycardia (VT) is a life-threating arrhythmia, responsible for high morbidity rates and sudden cardiac death (SCD). Radiofrequency ablation is the only curative therapy against incessant VT; however, its success is dependent on accurate localization of its source, which is highly invasive and time-consuming.

Objective: The goal of our study is, as a proof of concept, to demonstrate the possibility of utilizing electrogram (EGM) recordings from cardiac implantable electronic devices (CIEDs). To achieve this, we utilize fast and accurate whole torso electrophysiological (EP) simulations in conjunction with convolutional neural networks (CNNs) to automate the localization of focal VTs using simulated EGMs.

Materials and Methods: A highly detailed 3D torso model was used to simulate ∼4000 focal VTs, evenly distributed across the left ventricle (LV), utilizing a rapid reaction-eikonal environment. Solutions were subsequently combined with lead field computations on the torso to derive accurate electrocardiograms (ECGs) and EGM traces, which were used as inputs to CNNs to localize focal sources. We compared the localization performance of a previously developed CNN architecture (Cartesian probability-based) with our novel CNN algorithm utilizing universal ventricular coordinates (UVCs).

Results: Implanted device EGMs successfully localized VT sources with localization error (8.74 mm) comparable to ECG-based localization (6.69 mm). Our novel UVC CNN architecture outperformed the existing Cartesian probability-based algorithm (errors = 4.06 mm and 8.07 mm for ECGs and EGMs, respectively). Overall, localization was relatively insensitive to noise and changes in body compositions; however, displacements in ECG electrodes and CIED leads caused performance to decrease (errors 16–25 mm).

Conclusion: EGM recordings from implanted devices may be used to successfully, and robustly, localize focal VT sources, and aid ablation planning.
Growth Performance Can Be Increased Under High Nitrate and High Salt Stress Through Enhanced Nitrate Reductase Activity in Arabidopsis Anthocyanin Over-Producing Mutant Plants
Authors: Lee Ye Ji , Lee Won Je , Le Quang Tri , Hong Suk-Whan , Lee Hojoung
Published: July 2021

Nitrogen is one of the most important macro-nutrients for plant growth and crop productivity. The amount of synthetic nitrogen fertilizers supplied to crops has dramatically increased, leading to a notable rise in crop yields. However, excessive nitrogen use has an enormous negative impact on ecosystems and human health through the emission of intense greenhouse gases, such as nitric oxide derived from the nitrate (NO3–) assimilation cascade. Additionally, owing to the development of extensive irrigation in agriculture, crops are known to suffer from high salt stress. The effect of excessive nitrogen fertilizer application has been studied in some crops, but the effect of high nitrate level and salt stress on plant stress tolerance has not been studied in detail. Therefore, in this study we aimed to study the effects of high concentrations of NO3– on salt stress tolerance in Arabidopsis. In addition, since anthocyanin functions as a reactive oxygen species (ROS) scavenger under abiotic stress conditions, we investigated whether enhanced anthocyanin content helps Arabidopsis to withstand higher salt stress levels under high NO3– concentrations by using pap1-D/fls1ko double mutant plants, which accumulate excessive amount of anthocyanin. We found that Col-0 plants are more sensitive to salt stress under high NO3– concentrations. Although both the pap1-D/fls1ko and fls1ko plants accumulated higher anthocyanin levels and radical scavenging activities than Col-0 plants under both normal and salt stress conditions, the fls1ko plants exhibited much better growth than the pap1-D/fls1ko plants. It appears that the enhanced NR activities and transcript levels of NIA1 and NIA2 in pap1-D/fls1ko and fls1ko plants led to an increase in the synthesis of proteins and proline, which increases osmolytes against salt stress. Our results demonstrate that optimal levels of anthocyanin accumulation can enhance growth performance of plants under high NO3– and salt stress conditions.
Phenotyping Local Eggplant Varieties: Commitment to Biodiversity and Nutritional Quality Preservation
Authors: Martínez-Ispizua Eva , Calatayud Ángeles , Marsal José Ignacio , Mateos-Fernández Rubén , Díez María José , Soler Salvador , Valcárcel José Vicente , Martínez-Cuenca Mary-Rus
Published: July 2021

Given the little variability among commercialised eggplants mainly in developed countries, exploring, and structuring of traditional varieties germplasm collections have become a key element for extending ecotypes and promoting biodiversity preservation and consumption. Thirty-one eggplant landraces from Spain were characterised with 22 quantitative and 14 qualitative conventional morphological descriptors. Landraces were grouped based on their fruit skin colour (black-purple, striped, white, and reddish). Landraces B7, B20, and B24 were left out for their distinctive fruit characteristics. Wide variation for plant, leaf, flower, and fruit phenology traits was observed across the local landraces, and fruit descriptors were considered the most important ones. In a second experiment, landraces, B14, B16, and B17 were selected to determine fruit quality. By contemplating the benefits provided by antioxidants and sugars for human health, pulp antioxidant capacity, total phenolic, ascorbic acid, carotenoid, flavonoid, and total sugar content were determined. Significant differences were observed across these three landraces, and B14 was highlighted for its antioxidant properties, while B17 stood out for its high sugar content. B16 did not stand out for any traits. The results indicate the wide variability in eggplants for their phenotypic and nutritional characteristics, which emphasises the importance of traditional varieties as the main source of agricultural biodiversity.