bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular Adenosine Triphosphate (eATP) and Its Metabolite, Extracellular Adenosine (eAdo), as Opposing “Yin–Yang” Regulators of Nlrp3 Inflammasome in the Trafficking of Hematopoietic Stem/Progenitor Cells
Authors: Ratajczak Mariusz Z. , Kucia Magda
Published: January 2021

Nlrp3 inflammasome plays a pleiotropic role in hematopoietic cells. On the one hand, physiological activation of this intracellular protein complex is crucial to maintaining normal hematopoiesis and the trafficking of hematopoietic stem progenitor cells (HSPCs). On the other hand, its hyperactivation may lead to cell death by pyroptosis, and prolonged activity is associated with sterile inflammation of the BM and, as a consequence, with the HSPCs aging and origination of myelodysplasia and leukemia. Thus, we need to understand better this protein complex’s actions to define the boundaries of its safety window and study the transition from being beneficial to being detrimental. As demonstrated, the Nlrp3 inflammasome is expressed and active both in HSPCs and in the non-hematopoietic cells that are constituents of the bone marrow (BM) microenvironment. Importantly, the Nlrp3 inflammasome responds to mediators of purinergic signaling, and while extracellular adenosine triphosphate (eATP) activates this protein complex, its metabolite extracellular adenosine (eAdo) has the opposite effect. In this review, we will discuss and focus on the physiological consequences of the balance between eATP and eAdo in regulating the trafficking of HSPCs in an Nlrp3 inflammasome-dependent manner, as seen during pharmacological mobilization from BM into peripheral blood (PB) and in the reverse mechanism of homing from PB to BM and engraftment. We propose that both mediators of purinergic signaling and the Nlrp3 inflammasome itself may become important therapeutic targets in optimizing the trafficking of HSPCs in clinical settings.
Tregs and Mixed Chimerism as Approaches for Tolerance Induction in Islet Transplantation
Authors: Pathak Shiva , Meyer Everett H.
Published: January 2021

Pancreatic islet transplantation is a promising method for the treatment of type 1 and type 3 diabetes whereby replacement of islets may be curative. However, long-term treatment with immunosuppressive drugs (ISDs) remains essential for islet graft survival. Current ISD regimens carry significant side-effects for transplant recipients, and are also toxic to the transplanted islets. Pre-clinical efforts to induce immune tolerance to islet allografts identify ways in which the recipient immune system may be reeducated to induce a sustained transplant tolerance and even overcome autoimmune islet destruction. The goal of these efforts is to induce tolerance to transplanted islets with minimal to no long-term immunosuppression. Two most promising cell-based therapeutic strategies for inducing immune tolerance include T regulatory cells (Tregs) and donor and recipient hematopoietic mixed chimerism. Here, we review preclinical studies which utilize Tregs for tolerance induction in islet transplantation. We also review myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT) strategies in preclinical and clinical studies to induce sustained mixed chimerism and allograft tolerance, in particular in islet transplantation. Since Tregs play a critical role in the establishment of mixed chimerism, it follows that the combination of Treg and HSCT may be synergistic. Since the success of the Edmonton protocol, the feasibility of clinical islet transplantation has been established and nascent clinical trials testing immune tolerance strategies using Tregs and/or hematopoietic mixed chimerism are underway or being formulated.
Herpes Simplex Virus and Pattern Recognition Receptors: An Arms Race
Authors: Zhao Jun , Qin Chao , Liu Yongzhen , Rao Youliang , Feng Pinghui
Published: January 2021

Herpes simplex viruses (HSVs) are experts in establishing persistent infection in immune-competent humans, in part by successfully evading immune activation through diverse strategies. Upon HSV infection, host deploys pattern recognition receptors (PRRs) to recognize various HSV-associated molecular patterns and mount antiviral innate immune responses. In this review, we describe recent advances in understanding the contributions of cytosolic PRRs to detect HSV and the direct manipulations on these receptors by HSV-encoded viral proteins as countermeasures. The continuous update and summarization of these mechanisms will deepen our understanding on HSV-host interactions in innate immunity for the development of novel antiviral therapies, vaccines and oncolytic viruses.
Therapeutic Lowering of C-Reactive Protein
Authors: Jimenez Rachel V. , Szalai Alexander J.
Published: January 2021

In the blood of healthy individuals C-reactive protein (CRP) is typically quite scarce, whereas its blood concentration can rise robustly and rapidly in response to tissue damage and inflammation associated with trauma and infectious and non-infectious diseases. Consequently, CRP plasma or serum levels are routinely monitored in inpatients to gauge the severity of their initial illness and injury and their subsequent response to therapy and return to health. Its clinical utility as a faithful barometer of inflammation notwithstanding, it is often wrongly concluded that the biological actions of CRP (whatever they may be) are manifested only when blood CRP is elevated. In fact over the last decades, studies done in humans and animals (e.g. human CRP transgenic and CRP knockout mice) have shown that CRP is an important mediator of biological activities even in the absence of significant blood elevation, i.e. even at baseline levels. In this review we briefly recap the history of CRP, including a description of its discovery, early clinical use, and biosynthesis at baseline and during the acute phase response. Next we overview evidence that we and others have generated using animal models of arthritis, neointimal hyperplasia, and acute kidney injury that baseline CRP exerts important biological effects. In closing we discuss the possibility that therapeutic lowering of baseline CRP might be a useful way to treat certain diseases, including cancer.
Infection Mechanism of SARS-COV-2 and Its Implication on the Nervous System
Authors: Reza-Zaldívar Edwin Estefan , Hernández-Sapiéns Mercedes Azucena , Minjarez Benito , Gómez-Pinedo Ulises , Márquez-Aguirre Ana Laura , Mateos-Díaz Juan Carlos , Matias-Guiu Jorge , Canales-Aguirre Alejandro Arturo
Published: January 2021

In late December 2019, multiple atypical pneumonia cases resulted in severe acute respiratory syndrome caused by a pathogen identified as a novel coronavirus SARS-CoV-2. The most common coronavirus disease 2019 (COVID-19) symptoms are pneumonia, fever, dry cough, and fatigue. However, some neurological complications following SARS-CoV-2 infection include confusion, cerebrovascular diseases, ataxia, hypogeusia, hyposmia, neuralgia, and seizures. Indeed, a growing literature demonstrates that neurotropism is a common feature of coronaviruses; therefore, the infection mechanisms already described in other coronaviruses may also be applicable for SARS-CoV-2. Understanding the underlying pathogenetic mechanisms in the nervous system infection and the neurological involvement is essential to assess possible long-term neurological alteration of COVID-19. Here, we provide an overview of associated literature regarding possible routes of COVID-19 neuroinvasion, such as the trans-synapse-connected route in the olfactory pathway and peripheral nerve terminals and its neurological implications in the central nervous system.
The Role of the Adipokine Leptin in Immune Cell Function in Health and Disease
Authors: Kiernan Kaitlin , MacIver Nancie J.
Published: January 2021

Leptin is a critical mediator of the immune response to changes in overall nutrition. Leptin is produced by adipocytes in proportion to adipose tissue mass and is therefore increased in obesity. Despite having a well-described role in regulating systemic metabolism and appetite, leptin displays pleiotropic actions, and it is now clear that leptin has a key role in influencing immune cell function. Indeed, many immune cells have been shown to respond to leptin directlyviathe leptin receptor, resulting in a largely pro-inflammatory phenotype. Understanding the role of adipose-tissue derived mediators in inflammation is critical to determining the pathophysiology of multiple obesity-associated diseases, such as type 2 diabetes, autoimmune disease, and infection. This review, therefore, focuses on the latest data regarding the role of leptin in modulating inflammation.
The Antiviral Effects of the Symbiont Bacteria Wolbachia in Insects
Authors: Pimentel André C. , Cesar Cássia S. , Martins Marcos , Cogni Rodrigo
Published: January 2021

Wolbachiais a maternally transmitted bacterium that lives inside arthropod cells. Historically, it was viewed primarily as a parasite that manipulates host reproduction, but more recently it was discovered thatWolbachiacan also protectDrosophilaspecies against infection by RNA viruses. Combined withWolbachia’s ability to invade insect populations due to reproductive manipulations, this provides a way to modify mosquito populations to prevent them transmitting viruses like dengue. In this review, we discuss the main advances in the field sinceWolbachia’santiviral effect was discovered 12 years ago, identifying current research gaps and potential future developments. We discuss that the antiviral effect works against a broad range of RNA viruses and depends on theWolbachialineage. We describe what is known about the mechanisms behind viral protection, and that recent studies suggest two possible mechanisms: activation of host immunity or competition with virus for cellular resources. We also discuss how association withWolbachiamay influence the evolution of virus defense on the insect host genome. Finally, we investigate whether the antiviral effect occurs in wild insect populations and its ecological relevance as a major antiviral component in insects.
Disease Severity, Fever, Age, and Sex Correlate With SARS-CoV-2 Neutralizing Antibody Responses
Authors: Schlickeiser Stephan , Schwarz Tatjana , Steiner Sophie , Wittke Kirsten , Al Besher Nabeel , Meyer Oliver , Kalus Ulrich , Pruß Axel , Kurth Florian , Zoller Thomas , Witzenrath Martin , Sander Leif Erik , Müller Marcel A. , Scheibenbogen Carmen , Volk Hans-Dieter , Drosten Christian , Corman Victor M. , Hanitsch Leif G.
Published: January 2021

Clinical trials on the use of COVID-19 convalescent plasma remain inconclusive. While data on safety is increasingly available, evidence for efficacy is still sparse. Subgroup analyses hint to a dose-response relationship between convalescent plasma neutralizing antibody levels and mortality. In particular, patients with primary and secondary antibody deficiency might benefit from this approach. However, testing of neutralizing antibodies is limited to specialized biosafety level 3 laboratories and is a time- and labor-intense procedure. In this single center study of 206 COVID-19 convalescent patients, clinical data, results of commercially available ELISA testing of SARS-CoV-2 spike-IgG and –IgA, and levels of neutralizing antibodies, determined by plaque reduction neutralization testing (PRNT), were analyzed. At a medium time point of 58 days after symptom onset, only 12.6% of potential plasma donors showed high levels of neutralizing antibodies (PRNT50 ≥ 1:320). Multivariable proportional odds logistic regression analysis revealed need for hospitalization due to COVID-19 (odds ratio 6.87; p-value 0.0004) and fever (odds ratio 3.00; p-value 0.0001) as leading factors affecting levels of SARS-CoV-2 neutralizing antibody titers in convalescent plasma donors. Using penalized estimation, a predictive proportional odds logistic regression model including the most important variables hospitalization, fever, age, sex, and anosmia or dysgeusia was developed. The predictive discrimination for PRNT50 ≥ 1:320 was reasonably good with AUC: 0.86 (with 95% CI: 0.79–0.92). Combining clinical and ELISA-based pre-screening, assessment of neutralizing antibodies could be spared in 75% of potential donors with a maximal loss of 10% of true positives (PRNT50 ≥ 1:320).
A Review and Meta-Analysis of Potential Impacts of Ocean Acidification on Marine Calcifiers From the Southern Ocean
Authors: Figuerola Blanca , Hancock Alyce M. , Bax Narissa , Cummings Vonda J. , Downey Rachel , Griffiths Huw J. , Smith Jodie , Stark Jonathan S.
Published: January 2021

Understanding the vulnerability of marine calcifiers to ocean acidification is a critical issue, especially in the Southern Ocean (SO), which is likely to be the one of the first, and most severely affected regions. Since the industrial revolution, ~30% of anthropogenic CO2 has been absorbed by the global oceans. Average surface seawater pH levels have already decreased by 0.1 and are projected to decline by ~0.3 by the year 2100. This process, known as ocean acidification (OA), is shallowing the saturation horizon, which is the depth below which calcium carbonate (CaCO3) dissolves, likely increasing the vulnerability of many resident marine calcifiers to dissolution. The negative impact of OA may be seen first in species depositing more soluble CaCO3 mineral phases such as aragonite and high-Mg calcite (HMC). Ocean warming could further exacerbate the effects of OA in these particular species. Here we combine a review and a quantitative meta-analysis to provide an overview of the current state of knowledge about skeletal mineralogy of major taxonomic groups of SO marine calcifiers and to make projections about how OA might affect a broad range of SO taxa. We consider a species' geographic range, skeletal mineralogy, biological traits, and potential strategies to overcome OA. The meta-analysis of studies investigating the effects of the OA on a range of biological responses such as shell state, development and growth rate illustrates that the response variation is largely dependent on mineralogical composition. Species-specific responses due to mineralogical composition indicate that taxa with calcitic, aragonitic, and HMC skeletons, could be at greater risk to expected future carbonate chemistry alterations, and low-Mg calcite (LMC) species could be mostly resilient to these changes. Environmental and biological control on the calcification process and/or Mg content in calcite, biological traits, and physiological processes are also expected to influence species-specific responses.
Effect of Plasmonic Nanostructures on the Optical Properties of CH3NH3PbI Perovskite Films
Authors: Afanasyev Dmitriy , Ibrayev Niyazbek , Nuraje Nurxat
Published: January 2021

This paper investigated the optical properties of both silver island films (SIF) and CH3NH3PbI3 perovskite films obtained on the surface of SIF. It was found that the surface morphology of SIF has a substantial effect on the optical density of perovskite films. Furthermore, a significant redshift in the absorption spectrum of the island films was observed when perovskite is deposited on them. The intensity and lifetime of the luminescence of perovskite films on the surface of the island films depend on the wavelength of the exciting light. The results indicate that SIFs not only can be potentially used to increase the intensity of light emitting diodes based on perovskites, but also prolong the lifetime of charge carriers in perovskites, and thus lead to potentially improve the photovoltaic properties of perovskite solar cells.
Performance Investigation of a Solar Thermal Collector Based on Nanostructured Energy Materials
Authors: Zain Muhammad , Amjad Muhammad , Farooq Muhammad , Anwar Zahid , Shoukat Rabia , Bandarra Filho Enio P. , Du Xiaoze
Published: January 2021

The convective and conductive heat transfer between the solar collector and working fluids make photothermal performance limited, and result in a higher rate of heat loss from the surface of the conventional absorber to the surroundings. Direct absorption solar collectors (DASC) are a favorable alternative for their improved photothermal performance. In this study, a simulation based on the performance of a nanostructured solar collector has been carried out using TRNSYS. The connective and conductive heat transfer from direct solar collectors were improved by using nanofluids and three different nanostructured materials, CuO, GO, and ZnO, in this study. The analysis determines the outlet temperature of the working fluids that passed through the direct solar collector. The TRNSYS model consists of a direct solar collector and weather model for Lahore city, the simulations were performed for the whole year for 1,440 h. The stability of these nanostructured materials in the water was investigated by using a UV‐Vis spectrophotometer. Various performance parameters of direct solar collectors were determined, such as variation in outlet collector temperature and heat transfer rates. The numerical model is validated with experimental results. A maximum outlet temperature of 63°C was observed for GO-based nanofluids. The simulation results show that for the whole year, nanofluids improved the performance of direct solar collectors. Significant improvements in the heat transfer rate of 23.52, 21.11, and 15.09% were observed for the nanofluids based on nanostructures of CuO, ZnO, and GO respectively, as compared to water. These nanostructured energy materials are beneficial in solar-driven applications like solar desalination, solar water, and space heating.
Case Report: Testicular Sarcoidosis: The Diagnostic Role of Contrast-Enhanced Ultrasound and Review of the Literature
Authors: De Cinque Antonio , Corcioni Beniamino , Rossi Martina Sofia , Franceschelli Alessandro , Colombo Fulvio , Golfieri Rita , Renzulli Matteo , Gaudiano Caterina
Published: January 2021

Sarcoidosis is a multisystemic disease histologically characterized by non-caseating epithelioid granulomas and multinucleated giant cells; the etiology is still uncertain, and likely related to a complex interplay between environmental and genetic factors. The genitourinary system is affected in fewer than 0.2% of all clinically diagnosed cases of sarcoidosis and in 5% of those identified in autopsy studies. In this report, we describe a case of a 42–year-old male with one hypoechoic lesion per testis on B-mode evaluation; contrast-enhanced ultrasound (CEUS) on both lesions was carried out. During the early phase, the masses showed a hypovascular appearance as compared to the surrounding testicular tissue, maintaining the hypo-enhancement in the late phase. Tissue biopsy for pathological evaluation confirmed testicular sarcoid involvement, showing non-caseating granulomas. Allowing visualization of testicular microvascularisation, CEUS may play an important role in excluding malignancy, avoiding unnecessary aggressive treatment for benign conditions, such as sarcoidosis. A review of the literature of reported cases since 2004 of sarcoidosis involving the testis is also included.
Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome
Authors: Holm Katharine Nichole , Herren Anthony W. , Taylor Sandra L. , Randol Jamie L. , Kim Kyoungmi , Espinal Glenda , Martínez-Cerdeño Verónica , Pessah Isaac N. , Hagerman Randi J. , Hagerman Paul J.
Published: January 2021

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation CGG-repeat expansions (55–200 repeats) in the 5′ non-coding portion of the fragile X mental retardation 1 (FMR1) gene. Core features of FXTAS include progressive tremor/ataxia, cognitive decline, variable brain volume loss, and white matter disease. The principal histopathological feature of FXTAS is the presence of central nervous system (CNS) and non-CNS intranuclear inclusions.

Objective: To further elucidate the molecular underpinnings of FXTAS through the proteomic characterization of human FXTAS cortexes.

Results: Proteomic analysis of FXTAS brain cortical tissue (n = 8) identified minor differences in protein abundance compared to control brains (n = 6). Significant differences in FXTAS relative to control brain predominantly involved decreased abundance of proteins, with the greatest decreases observed for tenascin-C (TNC), cluster of differentiation 38 (CD38), and phosphoserine aminotransferase 1 (PSAT1); proteins typically increased in other neurodegenerative diseases. Proteins with the greatest increased abundance include potentially novel neurodegeneration-related proteins and small ubiquitin-like modifier 1/2 (SUMO1/2). The FMRpolyG peptide, proposed in models of FXTAS pathogenesis but only identified in trace amounts in the earlier study of FXTAS inclusions, was not identified in any of the FXTAS or control brains in the current study.

Discussion: The observed proteomic shifts, while generally relatively modest, do show a bias toward decreased protein abundance with FXTAS. Such shifts in protein abundance also suggest altered RNA binding as well as loss of cell–cell adhesion/structural integrity. Unlike other neurodegenerative diseases, the proteome of end-stage FXTAS does not suggest a strong inflammation-mediated degenerative response.
The Relationship Between Retinal Nerve Fiber Layer Thickness and Clinical Symptoms of Alzheimer's Disease
Authors: Lian Teng-hong , Jin Zhao , Qu Yuan-zhen , Guo Peng , Guan Hui-ying , Zhang Wei-jiao , Ding Du-yu , Li Da-ning , Li Li-xia , Wang Xiao-min , Zhang Wei
Published: January 2021

Background/Aim: Retinal nerve fiber layer (RNFL) thickness (RT), which can reflect the status of the retinal optic nerve cells, may be affected in patients with Alzheimer's disease (AD). There are few studies on the correlation of RT of patients with AD (AD-RT) with clinical symptoms of various cognitive domains, neuropsychiatric symptoms, and activities of daily living (ADL). This study is to investigate the relationships between RT and the abovementioned clinical symptoms of AD.

Methods: A total of 96 patients with AD were included in this study. RT was measured in these patients using optical coherence tomography (OCT). Demographic variables, RT, and clinical symptoms were compared between the normal and the abnormal AD-RT groups. Clinical symptoms, including cognitive symptoms, neuropsychiatric symptoms, and ADL, were evaluated using a series of rating scales.

Results: The relationships between RT and cognitive symptoms scores were analyzed in patients with AD. Reduced RT was found in 54.4% of patients with AD. The average RT, RT of the superior 1/2 quadrant, and RT of the inferior 1/2 quadrant of both eyes were all significantly decreased in the abnormal AD-RT group (p < 0.001). Overall cognitive function and performance in multiple cognitive domains, including memory, language, attention, and executive function, were also significantly impaired in the abnormal AD-RT group (p < 0.05). For lower RT value, the global cognitive function and the performance in multiple cognitive domains were worse. ADL was significantly compromised in patients with AD having lower RT values (p < 0.05).

Conclusions: Lower RT value appear to be correlated with cognitive impairment, and RT may be an indicator of cognitive decline in patients with AD. Further studies are required to confirm our findings.
The Relationship Between Socioeconomic Status and Scalp Event-Related Potentials: A Systematic Review
Authors: Perera-W.A. Hiran , Salehuddin Khazriyati , Khairudin Rozainee , Schaefer Alexandre
Published: January 2021

Several decades of behavioral research have established that variations in socioeconomic status (SES) are related to differences in cognitive performance. Neuroimaging and psychophysiological techniques have recently emerged as a method of choice to better understand the neurobiological processes underlying this phenomenon. Here we present a systematic review of a particular sub-domain of this field. Specifically, we used the PICOS approach to review studies investigating potential relationships between SES and scalp event-related brain potentials (ERP). This review found evidence that SES is related to amplitude variations in a diverse range of ERPs: P1, N1, N2, Error-Related Negativities (ERN), N400, auditory evoked potentials, negative difference waves (Nd), P3 and slow waves (SW). These ERPs include early, mid-latency and late potentials that reflect a broad range of cognitive processes (e.g., automatic attentional processes, overt attention, language, executive function, etc.). In this review, all SES effects on ERPs appeared to reflect an impairment or a less efficient form of task-related neural activity for low-SES compared to high-SES individuals. Overall, these results confirm that a wide variety of distinct neural processes with different functional meanings are sensitive to SES differences. The findings of this review also suggest that the relationship between SES and some ERP components may depend on the developmental stage of study participants. Results are further discussed in terms of the current limitations of this field and future avenues of research.
“The Boundless Realm Where All Form Lies”. Representing Imagination at the Crossway Between Literary and Neurocognitive Studies
Authors: Gambino Renata , Pulvirenti Grazia
Published: January 2021

According to ancient texts on poetics, the concept of representation is deeply bound to that of “mimesis;” this last was intended in two main ways: as “imitation” and as “world construction.” In Aristotle's Poetics, mimesis is theorized as the main form of “world simulation,” giving rise to the complex universe of fiction. The concept of simulation plays a pivotal role in the neurocognitive theories on the embodied mind: within this frame, embodied simulation is intended as a functional prelinguistic activation of the human sensorimotor mechanism. This happens not only with regard to intercorporeality and intersubjectivity in the real world but also in relation to the process of imagination giving rise to literary imagery and to the reader's reception of the fictional world, since human beings share a common sensorimotor apparatus. Imagination is a central concept in the recent neurocognitive studies since it plays a core role in human life and in artistic production and reception. Imagination has been considered as a complex emergent cognitive faculty deeply intertwined with perception, memory, and consciousness, shaping human life and transforming the limited horizon of our perceptual affective understanding, being, and acting. Although there is an immense bulk of literature on this topic, imagination is still an elusive concept: its definition and understanding change according to different heuristic frames—mainly the philosophical, aesthetic, poetic, and cognitive ones—giving rise to debates about its modalities and effects, particularly in relation to the construction of aesthetic and symbolic constraints. In this paper, we claim that scientific research may take advantage from the literary representation of the imaginative faculties, which occurs in specific tests characterized by dynamic images and motion. In such meta-representation of the imagination, we witness the phenomenological emergence of endogenous dynamic processes involving a cluster of cognitive faculties, activated by triggering the reader's embodied simulation. One of the main German poets, Johann Wolfgang von Goethe, in the second part of his masterwork Faust II, intuitively represents the very process of the imagination and its responding to embodied simulation with regard both to the author's creative act and to its reception by the reader. At the crossway between literary and neurocognitive, this study aims to highlight the advantage offered to future transdisciplinary inquiries by the literary representation showing features and dynamics of the still mysterious phenomenon of the imagination.
Neuropathological Characterization of a Dravet Syndrome Knock-In Mouse Model Useful for Investigating Cannabinoid Treatments
Authors: Satta Valentina , Alonso Cristina , Díez Paula , Martín-Suárez Soraya , Rubio Marta , Encinas Juan M. , Fernández-Ruiz Javier , Sagredo Onintza
Published: January 2021

Dravet syndrome (DS) is an epileptic syndrome caused by mutations in the Scn1a gene encoding the α1 subunit of the sodium channel Nav1.1, which is associated with febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved to reduce seizures in DS, but it may also be active against these comorbidities. The aim of this study was to validate a new mouse model of DS having lower mortality than previous models, which may serve to further evaluate therapies for the long-term comorbidities. This new model consists of heterozygous conditional knock-in mice carrying a missense mutation (A1783V) in Scn1a gene expressed exclusively in neurons of the CNS (Syn-Cre/Scn1aWT/A1783V). These mice have been used here to determine the extent and persistence of the behavioral deterioration in different postnatal days (PND), as well as to investigate the alterations that the disease produces in the endocannabinoid system and the contribution of inflammatory events and impaired neurogenesis in the pathology. Syn-Cre/Scn1aWT/A1783V mice showed a strong reduction in hindlimb grasp reflex at PND10, whereas at PND25, they presented spontaneous convulsions and a greater susceptibility to pentylenetetrazole-induced seizures, marked hyperactivity, deficient spatial working memory, lower levels of anxiety, and altered social interaction behavior. These differences disappeared at PND40 and PND60, except the changes in social interaction and anxiety. The analysis of CNS structures associated with these behavioral alterations revealed an elevated glial reactivity in the prefrontal cortex and the dentate gyrus. This was associated in the dentate gyrus with a greater cell proliferation detected with Ki67 immunostaining, whereas double-labeling analyses identified that proliferating cells were GFAP-positive suggesting failed neurogenesis but astrocyte proliferation. The analysis of the endocannabinoid system of Syn-Cre/Scn1aWT/A1783V mice confirmed reductions in CB1 receptors and MAGL and FAAH enzymes, mainly in the cerebellum but also in other areas, whereas CB2 receptors became upregulated in the hippocampus. In conclusion, Syn-Cre/Scn1aWT/A1783V mice showed seizuring susceptibility and several comorbidities (hyperactivity, memory impairment, less anxiety, and altered social behavior), which exhibited a pattern of age expression similar to DS patients. Syn-Cre/Scn1aWT/A1783V mice also exhibited greater glial reactivity and a reactive response in the neurogenic niche, and regional changes in the status of the endocannabinoid signaling, events that could contribute in behavioral impairment.
Searching for a Putative Mechanism of RIZ2 Tumor-Promoting Function in Cancer Models
Authors: Rienzo Monica , Sorrentino Anna , Di Zazzo Erika , Di Donato Marzia , Carafa Vincenzo , Marino Maria Michela , De Rosa Caterina , Gazzerro Patrizia , Castoria Gabriella , Altucci Lucia , Casamassimi Amelia , Abbondanza Ciro
Published: January 2021

Positive Regulatory Domain (PRDM) gene family members commonly express two main molecular variants, the PR-plus isoform usually acting as tumor suppressor and the PR-minus one functioning as oncogene. Accordingly, PRDM2/RIZ encodes for RIZ1 (PR-plus) and RIZ2 (PR-minus). In human cancers, genetic or epigenetic modifications induce RIZ1 silencing with an expression level imbalance in favor of RIZ2 that could be relevant for tumorigenesis. Additionally, in estrogen target cells and tissues, estradiol increases RIZ2 expression level with concurrent increase of cell proliferation and survival. Several attempts to study RIZ2 function in HeLa or MCF-7 cells by its over-expression were unsuccessful. Thus, we over-expressed RIZ2 in HEK-293 cells, which are both RIZ1 and RIZ2 positive but unresponsive to estrogens. The forced RIZ2 expression increased cell viability and growth, prompted the G2-to-M phase transition and organoids formation. Accordingly, microarray analysis revealed that RIZ2 regulates several genes involved in mitosis. Consistently, RIZ silencing in both estrogen-responsive MCF-7 and -unresponsive MDA-MB-231 cells induced a reduction of cell proliferation and an increase of apoptosis rate. Our findings add novel insights on the putative RIZ2 tumor-promoting functions, although additional attempts are warranted to depict the underlying molecular mechanism.
Outcomes of Stereotactic Body Radiotherapy for Metastatic Colorectal Cancer With Oligometastases, Oligoprogression, or Local Control of Dominant Tumors
Authors: Ji Xiaoqin , Zhao Yulu , Zhu Xixu , Shen Zetian , Li Aomei , Chen Cheng , Chu Xiaoyuan
Published: January 2021

Aim

To evaluate the clinical outcomes of metastatic colorectal cancer (mCRC) patients with oligometastases, oligoprogression, or local control of dominant tumors after stereotactic body radiotherapy (SBRT) and establish a nomogram model to predict the prognosis for these patients.

Methods and Materials

A cohort of 94 patients with 162 mCRC metastases was treated with SBRT at a single institution. Treatment indications were oligometastases, oligoprogression, and local control of dominant tumors. End points of this study were the outcome in terms of progression-free survival (PFS), overall survival (OS), local progression (LP), and cumulative incidence of starting or changing systemic therapy (SCST). In addition, univariate and multivariable analyses to assess variable associations were performed. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve.

Results

Median PFS were 12.6 months, 6.8 months, and 3.7 months for oligometastases, oligoprogression, and local control of dominant tumors, respectively. 0-1 performance status, < 10 ug/L pre-SBRT CEA, and ≤ 2 metastases were significant predictors of higher PFS on multivariate analysis. Median OS were 40.0 months, 26.1 months, and 6.5 months for oligometastases, oligoprogression, and local control of dominant tumors, respectively. In the multivariate analysis of the cohort, the independent factors for survival were indication, performance status, pre-SBRT CEA, and PTV, all of which were selected into the nomogram. The calibration curve for probability of survival showed the good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.848.

Conclusions

SBRT for metastases derived from colorectal cancer offered favorable survival and symptom palliation without significant complications. The proposed nomogram could provide individual prediction of OS for patients with mCRC after SBRT.
The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer
Authors: Leeksma Alexander C. , Derks Ingrid A. M. , Kasem M. Haidar , Kilic Emine , de Klein Annelies , Jager Martine J. , van de Loosdrecht Arjan A. , Jansen Joop H. , Navrkalova Veronika , Faber Laura M. , Zaborsky Nadja , Egle Alexander , Zenz Thorsten , Pospisilova Sarka , Abdel-Wahab Omar , Kater Arnon P. , Eldering Eric
Published: January 2021

Recurrent mutations in splicing factor 3B subunit 1 (SF3B1) have been identified in several malignancies and are associated with an increased expression of 3’ cryptic transcripts as a result of alternative branchpoint recognition. A large fraction of cryptic transcripts associated with SF3B1 mutations is expected to be sensitive for RNA degradation via nonsense-mediated mRNA decay (NMD). Several studies indicated alterations in various signaling pathways in SF3B1-mutated cells, including an impaired DNA damage response (DDR) in chronic lymphocytic leukemia (CLL). In this study, we investigated isogenic cell lines and treatment naïve primary CLL samples without any TP53 and/or ATM defect, and found no significant effects of SF3B1 mutations on the ATM/p53 response, phosphorylation of H2AX and sensitivity to fludarabine. Cryptic transcripts associated with SF3B1 mutation status were observed at relatively low levels compared to the canonical transcripts and were validated as target for mRNA degradation via NMD. Expression of cryptic transcripts increased after NMD inhibition. In conclusion, our results confirm involvement of NMD in the biological effects of SF3B1 mutations. Further studies may elucidate whether SF3B1-mutant patients could benefit from NMD modulatory agents.
Quantitative Magnetic Resonance Imaging for Biological Image-Guided Adaptive Radiotherapy
Authors: van Houdt Petra J. , Yang Yingli , van der Heide Uulke A.
Published: January 2021

MRI-guided radiotherapy systems have the potential to bring two important concepts in modern radiotherapy together: adaptive radiotherapy and biological targeting. Based on frequent anatomical and functional imaging, monitoring the changes that occur in volume, shape as well as biological characteristics, a treatment plan can be updated regularly to accommodate the observed treatment response. For this purpose, quantitative imaging biomarkers need to be identified that show changes early during treatment and predict treatment outcome. This review provides an overview of the current evidence on quantitative MRI measurements during radiotherapy and their potential as an imaging biomarker on MRI-guided radiotherapy systems.
Targeting MYCN in Molecularly Defined Malignant Brain Tumors
Authors: Borgenvik Anna , Čančer Matko , Hutter Sonja , Swartling Fredrik J.
Published: January 2021

Misregulation of MYC genes, causing MYC overexpression or protein stabilization, is frequently found in malignant brain tumors highlighting their important roles as oncogenes. Brain tumors in children are the most lethal of all pediatric malignancies and the most common malignant primary adult brain tumor, glioblastoma, is still practically incurable. MYCN is one of three MYC family members and is crucial for normal brain development. It is associated with poor prognosis in many malignant pediatric brain tumor types and is focally amplified in specific adult brain tumors. Targeting MYCN has proved to be challenging due to its undruggable nature as a transcription factor and for its importance in regulating developmental programs also in healthy cells. In this review, we will discuss efforts made to circumvent the difficulty of targeting MYCN specifically by using direct or indirect measures to treat MYCN-driven brain tumors. We will further consider the mechanism of action of these measures and suggest which molecularly defined brain tumor patients that might benefit from MYCN-directed precision therapies.
Elucidating the Consequences of Heparan Sulfate Binding by Heparanase 2
Authors: Gross-Cohen Miriam , Feld Sari , Arvatz Gil , Ilan Neta , Vlodavsky Israel
Published: January 2021

Unlike the intense research effort devoted to exploring the significance of heparanase in human diseases, very little attention was given to its close homolog, heparanase 2 (Hpa2). The emerging role of Hpa2 in a rare autosomal recessive congenital disease called urofacial syndrome (UFS), clearly indicates that Hpa2 is not a pseudogene but rather a gene coding for an important protein. Hpa2 lacks the heparan sulfate (HS)-degrading activity typical of heparanase, yet exhibits high affinity to HS, affinity that is 10-fold higher than that of heparanase. The consequences of this high-affinity interaction of Hpa2 with plasma membrane HSPG has not been explored yet. Here, we used highly purified Hpa2 protein to examine this aspect. We provide evidence that cells adhere to and spread on dishes coated with Hpa2. We also show that cell migration is attenuated markedly by exogenous addition of Hpa2 to primary and transformed cells, a function that agrees with the anti-cancer properties of Hpa2. Interestingly, we found that exogenous addition of Hpa2 also disrupts the morphology of cell colonies, resulting in cell scattering. This implies that under certain conditions and experimental settings, Hpa2 may exhibit pro-tumorigenic properties. We further developed a panel of anti-Hpa2 monoclonal antibodies (mAb) and show that these properties of Hpa2 are prevented by some of the newly-developed mAb, thus providing new molecular tools to better appreciate the significance of Hpa2 in health and disease.
Acylated Ghrelin is Protective Against 6-OHDA-induced Neurotoxicity by Regulating Autophagic Flux
Authors: He Xin , Yuan Wei , Liu Fei , Feng Juan , Guo Yanxia
Published: January 2021

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, and our previous study revealed that autophagic flux dysfunction contributes to the neuron death in 6-OHDA-induced PD models. Acylated ghrelin is a neuropeptide that has a variety of actions in the central nervous system. In the current study, we aimed to investigate whether ghrelin is neuroprotective in 6-OHDA-induced rat model and SH-SY5Y cell model and whether it is related to autophagic flux regulation. We observed that ghrelin could effectively reduce apomorphine-induced contralateral rotation in 6-OHDA-induced PD rats, preserve the expression of tyrosine hydroxylase (TH) and increase the cell viability. It could upregulate the expression of autophagy related proteins like Atg7 and LC3-II and downregulate p62, and downregulate apoptosis related proteins like bax and cleaved caspase 3. SH-SY5Y cells transfected with adenovirus Ad-mCherry-GFP-LC3B further revealed that ghrelin could relieve the autophagic flux dysfunction induced by 6-OHDA. Lysotracker staining showed that ghrelin could reverse the decrease in lysosomes induced by 6-OHDA and immunofluorescence staining revealed a reverse of TFEB level in SH-SY5Y cells. Blocking autophagy activation with 3-methyladenine (3-MA) in rats treated with ghrelin and 6-OHDA showed no notable change in apoptosis-related markers, while blocking autophagosome fusion with lysosomes with chloroquine could notably reverse the downregulation of bax/bcl-2 ratio and cleaved caspase three expression by ghrelin. Additionally, knockdown ATG7, the upstream regulator of autophagy, with siRNA could further decrease the number of apoptotic cells in SH-SY5Y cells exposed to 6-OHDA and treated with ghrelin, while knockdown TFEB, a key transcription factor for lysosome biosynthesis and function, with siRNA could completely abolish the anti-apoptosis effect of ghrelin. These data suggest that ghrelin is neuroprotective in 6-OHDA-induced PD models via improving autophagic flux dysfunction and restoration of TFEB level.
Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias
Authors: van der Westhuizen Emma T. , Choy K. H. Christopher , Valant Celine , McKenzie-Nickson Simon , Bradley Sophie J. , Tobin Andrew B. , Sexton Patrick M. , Christopoulos Arthur
Published: January 2021

The M1and M4muscarinic acetylcholine receptors (mAChRs) are highly pursued drug targets for neurological diseases, in particular for Alzheimer’s disease and schizophrenia. Due to high sequence homology, selective targeting of any of the M1-M5mAChRs through the endogenous ligand binding site has been notoriously difficult to achieve. With the discovery of highly subtype selective mAChR positive allosteric modulators in the new millennium, selectivity through targeting an allosteric binding site has opened new avenues for drug discovery programs. However, some hurdles remain to be overcome for these promising new drug candidates to progress into the clinic. One challenge is the potential for on-target side effects, such as for the M1mAChR where over-activation of the receptor by orthosteric or allosteric ligands can be detrimental. Therefore, in addition to receptor subtype selectivity, a drug candidate may need to exhibit a biased signaling profile to avoid such on-target adverse effects. Indeed, recent studies in mice suggest that allosteric modulators for the M1mAChR that bias signaling toward specific pathways may be therapeutically important. This review brings together details on the signaling pathways activated by the M1and M4mAChRs, evidence of biased agonism at these receptors, and highlights pathways that may be important for developing new subtype selective allosteric ligands to achieve therapeutic benefit.
Effect of Chinese Herbal Medicine Therapy on Overall and Cancer Related Mortality in Patients With Advanced Nasopharyngeal Carcinoma in Taiwan
Authors: Wang Chen-Yu , Wang Tang-Chuan , Liang Wen-Miin , Hung Chien-Hui , Chiou Jian-Shiun , Chen Chao-Jung , Tsai Fuu-Jen , Huang Sheng-Teng , Chang Ta-Yuan , Lin Ting-Hsu , Liao Chiu-Chu , Huang Shao-Mei , Li Te-Mao , Lin Ying-Ju
Published: January 2021

Nasopharyngeal carcinoma (NPC) is a head and neck cancer involving epithelial squamous-cell carcinoma of the nasopharynx that mainly occurs in individuals from East and Southeast Asia. We investigated whether Chinese herbal medicine (CHM) as a complementary therapy offers benefits to these patients. We retrospectively evaluated the Taiwan Cancer Registry (Long Form) database for patients with advanced NPC, using or not using CHM, between 2007–2013. Cox proportional-hazard model and Kaplan‒Meier survival analyses were applied for patient survival. CHM-users showed a lower overall and cancer-related mortality risk than non-users. For advanced NPC patients, the overall mortality risk was 0.799-fold for CHM-users, after controlling for age, gender, and Charlson comorbidity index (CCI) score (Cancer stages 3 + 4: adjusted hazard ratio [aHR]: 0.799, 95% confidence interval [CI]: 0.676–0.943, p = 0.008). CHM-users also showed a lower cancer-related mortality risk than non-users (aHR: 0.71, 95% CI: 0.53–0.96, p = 0.0273). Association rule analysis showed that CHM pairs were Ban-Zhi-Lian (BZL; Scutellaria barbata D.Don) and For single herbs, Bai-Hua-She-She-Cao (Herba Hedyotis Diffusae; Scleromitrion diffusum (Willd.) R.J.Wang (syn. Hedyotis diffusa Willd.) and Mai-Men-Dong (MMD; Ophiopogon japonicus (Thunb.) Ker Gawl.), and Gan-Lu-Yin (GLY) and BHSSC. Network analysis revealed that BHSSC was the core CHM, and BZL, GLY, and Xin-Yi-Qing-Fei-Tang (XYQFT) were important CHMs in cluster 1. In cluster 2, ShengDH, MMD, Xuan-Shen (XS; Scrophularia ningpoensis Hensl.), and Gua-Lou-Gen (GLG; Trichosanthes kirilowii Maxim.) were important CHMs. Thus, as a complementary therapy, CHM, and particularly the 8 CHMs identified, are important for the treatment of advanced NPC patients.