bluuebunny/crossref_metadata_2025 huggingface dataset:
SIRPα Suppresses Response to Therapeutic Antibodies by Nurse Like Cells From Chronic Lymphocytic Leukemia Patients
Authors: Chen Yu-Chen Enya , Burgess Melinda , Mapp Sally , Mollee Peter , Gill Devinder , Blumenthal Antje , Saunders Nicholas A.
Published: January 2021

Targeted antibody therapies improve outcomes for chronic lymphocytic leukemia (CLL) patients. However, resistance often develops. We have previously shown that resistance to therapeutic antibodies, by monocyte derived macrophages (referred to as nurse like cells, NLCs), from CLL patients is characterized by suppression of antibody dependent phagocytosis (ADP). The mechanism(s) contributing to the muted ADP responses remain unresolved. In this regard, an innate immune checkpoint was recently described that uses the CD47:SIRPα axis to suppress phagocytic responses by macrophages. In this study we examine whether the SIRPα axis regulates ADP responses to the anti-CD20 antibody, obinutuzumab, by NLCs. Using siRNA depletion strategies we show that SIRPα is a suppressor of ADP responses. Moreover, we show that this innate immune checkpoint contributes to the resistance phenotype in NLCs derived from CLL patients. Finally, we show that SIRPα suppression is mediated via the phosphatase, Shp1, which in turn suppresses SYK-dependent activation of ADP. Thus, we identify a druggable pathway that could be exploited to enhance sensitivity to existing therapeutic antibodies used in CLL. This is the first study to show that activation of the CD47:SIRPα innate immune checkpoint contributes to ADP resistance in NLCs from CLL patients.
STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation?
Authors: Smith Judith A.
Published: January 2021

The anti-viral pattern recognition receptor STING and its partnering cytosolic DNA sensor cGAS have been increasingly recognized to respond to self DNA in multiple pathologic settings including cancer and autoimmune disease. Endogenous DNA sources that trigger STING include damaged nuclear DNA in micronuclei and mitochondrial DNA (mtDNA). STING resides in the endoplasmic reticulum (ER), and particularly in the ER-mitochondria associated membranes. This unique location renders STING well poised to respond to intracellular organelle stress. Whereas the pathways linking mtDNA and STING have been addressed recently, the mechanisms governing ER stress and STING interaction remain more opaque. The ER and mitochondria share a close anatomic and functional relationship, with mutual production of, and inter-organelle communication via calcium and reactive oxygen species (ROS). This interdependent relationship has potential to both generate the essential ligands for STING activation and to regulate its activity. Herein, we review the interactions between STING and mitochondria, STING and ER, ER and mitochondria (vis-à-vis calcium and ROS), and the evidence for 3-way communication.
A Combination of Polybacterial MV140 and Candida albicans V132 as a Potential Novel Trained Immunity-Based Vaccine for Genitourinary Tract Infections
Authors: Martin-Cruz Leticia , Sevilla-Ortega Carmen , Benito-Villalvilla Cristina , Diez‐Rivero Carmen M. , Sanchez-Ramón Silvia , Subiza José Luis , Palomares Oscar
Published: January 2021

Recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems with high socio-economic impact worldwide. Antibiotic and antifungal prophylaxis remain the gold standard treatments for RUTIs and RVVCs, contributing to the massive rise of antimicrobial resistance, microbiota alterations and co-infections. Therefore, the development of novel vaccine strategies for these infections are sorely needed. The sublingual heat-inactivated polyvalent bacterial vaccine MV140 shows clinical efficacy for the prevention of RUTIs and promotes Th1/Th17 and IL-10 immune responses. V132 is a sublingual preparation of heat-inactivated Candida albicans developed against RVVCs. A vaccine formulation combining both MV140 and V132 might well represent a suitable approach for concomitant genitourinary tract infections (GUTIs), but detailed mechanistic preclinical studies are still needed. Herein, we showed that the combination of MV140 and V132 imprints human dendritic cells (DCs) with the capacity to polarize potent IFN-γ– and IL-17A–producing T cells and FOXP3+ regulatory T (Treg) cells. MV140/V132 activates mitogen-activated protein kinases (MAPK)-, nuclear factor-κB (NF-κB)- and mammalian target of rapamycin (mTOR)-mediated signaling pathways in human DCs. MV140/V132 also promotes metabolic and epigenetic reprogramming in human DCs, which are key molecular mechanisms involved in the induction of innate trained immunity. Splenocytes from mice sublingually immunized with MV140/V132 display enhanced proliferative responses of CD4+ T cells not only upon in vitro stimulation with the related antigens contained in the vaccine formulation but also upon stimulation with phytohaemagglutinin. Additionally, in vivo sublingual immunization with MV140/V132 induces the generation of IgG and IgA antibodies against all the components contained in the vaccine formulation. We uncover immunological mechanisms underlying the potential mode of action of a combination of MV140 and V132 as a novel promising trained immunity-based vaccine (TIbV) for GUTIs.
Activation of the Nlrp3 Inflammasome Contributes to Shiga Toxin-Induced Hemolytic Uremic Syndrome in a Mouse Model
Authors: Song Liqiong , Xiao Yuchun , Li Xianping , Huang Yuanming , Meng Guangxun , Ren Zhihong
Published: January 2021

Objective

To explore the role of the Nlrp3 inflammasome activation in the development of hemolytic uremic syndrome (HUS) induced by Stx2 and evaluate the efficacy of small molecule Nlrp3 inhibitors in preventing the HUS.

Methods

Peritoneal macrophages (PMs) isolated from wild-type (WT) C57BL/6J mice and gene knockout mice (Nlrc4-/-,Aim2-/-, andNlrp3-/-) were treated with Stx2in vitroand their IL-1β releases were measured. WT mice andNlrp3-/-mice were also treated with Stx2in vivoby injection, and the biochemical indices (serum IL-1β, creatinine [CRE] and blood urea nitrogen [BUN]), renal injury, and animal survival were compared. To evaluate the effect of the Nlrp3 inhibitors in preventing HUS, WT mice were pretreated with different Nlrp3 inhibitors (MCC950, CY-09, Oridonin) before Stx2 treatment, and their biochemical indices and survival were compared with the WT mice without inhibitor pretreatment.

Results

When PMs were stimulated by Stx2in vitro, IL-1β release inNlrp3-/-PMs was significantly lower compared to the other PMs. TheNlrp3-/-mice treated by Stx2in vivo, showed lower levels of the biochemical indices, alleviated renal injuries, and increased survival rate. When the WT mice were pretreated with the Nlrp3 inhibitors, both the biochemical indices and survival were significantly improved compared to those without inhibitor pretreatment, with Oridonin being most potent.

Conclusion

Nlrp3 inflammasome activation plays a vital role in the HUS development when mice are challenged by Stx2, and Oridonin is effective in preventing HUS.
Exploring the Diversity of the Marine Environment for New Anti-cancer Compounds
Authors: Dayanidhi Divya L. , Thomas Beatrice C. , Osterberg Joshua S. , Vuong Mallissa , Vargas Giselle , Kwartler Sarah K. , Schmaltz Emma , Dunphy-Daly Meagan M. , Schultz Thomas F. , Rittschof Daniel , Eward William C. , Roy Christopher , Somarelli Jason A.
Published: January 2021

Marine ecosystems contain over 80% of the world’s biodiversity, and many of these organisms have evolved unique adaptations enabling survival in diverse and challenging environments. The biodiversity within the world’s oceans is a virtually untapped resource for the isolation and development of novel compounds, treatments, and solutions to combat human disease. In particular, while over half of our anti-cancer drugs are derived from natural sources, almost all of these are from terrestrial ecosystems. Yet, even from the limited analyses to date, a number of marine-derived anti-cancer compounds have been approved for clinical use, and several others are currently in clinical trials. Here, we review the current suite of marine-derived anti-cancer drugs, with a focus on how these compounds act upon the hallmarks of cancer. We highlight potential marine environments and species that could yield compounds with unique mechanisms. Continued exploration of marine environments, along with the characterization and screening of their inhabitants for unique bioactive chemicals, could prove fruitful in the hunt for novel anti-cancer therapies.
Bone and Joint Infection Involving Corynebacterium spp.: From Clinical Features to Pathophysiological Pathways
Authors: Chauvelot Pierre , Ferry Tristan , Tafani Virginie , Diot Alan , Tasse Jason , Conrad Anne , Chidiac Christian , Braun Evelyne , Lustig Sébastien , Laurent Frédéric , Valour Florent
Published: January 2021

Introduction: Corynebacteria represent often-neglected etiological agents of post-traumatic and/or post-operative bone and joint infection (BJI). We describe here clinical characteristics and bacteriological determinants of this condition.

Methods: A retrospective cohort study described characteristics, outcome and determinants of treatment failure of all patients with proven Corynebacterium spp. BJI (i.e., ≥2 culture-positive gold-standard samples). Available strains were further characterized regarding their antibiotic susceptibilies, abilities to form early (BioFilm Ring Test®) and mature (crystal violet staining method) biofilms and to invade osteoblasts (gentamicin protection assay).

Results: The 51 included BJI were mostly chronic (88.2%), orthopedic device-related (74.5%) and polymicrobial (78.4%). After a follow-up of 60.7 weeks (IQR, 30.1–115.1), 20 (39.2%) treatment failures were observed, including 4 Corynebacterium-documented relapses, mostly associated with non-optimal surgical management (OR 7.291; p = 0.039). Internalization rate within MG63 human osteoblasts was higher for strains isolated from delayed (>3 months) BJI (p < 0.001). Infection of murine osteoblasts deleted for the β1-integrin resulted in a drastic reduction in the internalization rate. No difference was observed regarding biofilm formation.

Conclusions: Surgical management plays a crucial role in outcome of BJI involving corynebacteria, as often chronic and device-associated infections. Sanctuarisation within osteoblasts, implicating the β1 cellular integrin, may represent a pivotal virulence factor associated with BJI chronicity.
Complement, a Therapeutic Target in Diabetic Kidney Disease
Authors: Budge Kelly , Dellepiane Sergio , Yu Samuel Mon-Wei , Cravedi Paolo
Published: January 2021

Currently available treatments of diabetic kidney disease (DKD) remain limited despite improved understanding of DKD pathophysiology. The complement system is a central part of innate immunity, but its dysregulated activation is detrimental and results in systemic diseases with overt inflammation. Growing evidence suggests complement activation in DKD. With existent drugs and clinical success of treating other kidney diseases, complement inhibition has emerged as a potential novel therapy to halt the progression of DKD. This article will review DKD, the complement system's role in diabetic and non-diabetic disease, and the potential benefits of complement targeting therapies especially for DKD patients.
A Longitudinal Study of the Human Oropharynx Microbiota Over Time Reveals a Common Core and Significant Variations With Self-Reported Disease
Authors: Bach Lydia Luise , Ram Asha , Ijaz Umer Z. , Evans Thomas J. , Lindström Jan
Published: January 2021

Our understanding of human microbial communities, in particular in regard to diseases is advancing, yet the basic understanding of the microbiome in healthy subjects over time remains limited. The oropharynx is a key target for colonization by several important human pathogens. To understand how the oropharyngeal microbiome might limit infections, and how intercurrent infections might be associated with its composition, we characterized the oropharyngeal microbiome of 18 healthy adults, sampled weekly over a 40-weeks using culture-independent molecular techniques. We detected nine phyla, 202 genera and 1438 assignments on OTU level, dominated by Firmicutes, Bacteroidetes, and Proteobacteria on phylum level. Individual microbiomes of participants were characterized by levels of high alpha diversity (mean = 204.55 OTUs, sd = 35.64), evenness (19.83, sd = 9.74) and high temporal stability (mean Pearson’s correlation between samples of 0.52, sd = 0.060), with greater differences in microbiome community composition between than within individuals. Significant changes in community composition were associated with disease states, suggesting that it is possible to detect specific changes in OTU abundance and community composition during illness. We defined the common core microbiota by varying occurrence and abundance thresholds showing that individual core microbiomes share a substantial number of OTUs across participants, chiefly Streptococci and Veillonella. Our results provide insights into the microbial communities that characterize the healthy human oropharynx, community structure and variability, and provide new approaches to define individual and shared cores. The wider implications of this result include the potential for modeling the general dynamics of oropharynx microbiota both in health and in response to antimicrobial treatments or probiotics.
Biogenic Silver Nanoparticles Can Control Toxoplasma gondii Infection in Both Human Trophoblast Cells and Villous Explants
Authors: Costa Idessania Nazareth , Ribeiro Mayara , Silva Franco Priscila , da Silva Rafaela José , de Araújo Thádia Evelyn , Milián Iliana Claudia Balga , Luz Luana Carvalho , Guirelli Pâmela Mendonça , Nakazato Gerson , Mineo José Roberto , Mineo Tiago W. P. , Barbosa Bellisa Freitas , Ferro Eloisa Amália Vieira
Published: January 2021

The combination of sulfadiazine and pyrimethamine plus folinic acid is the conventional treatment for congenital toxoplasmosis. However, this classical treatment presents teratogenic effects and bone marrow suppression. In this sense, new therapeutic strategies are necessary to reduce these effects and improve the control of infection. In this context, biogenic silver nanoparticles (AgNp-Bio) appear as a promising alternative since they have antimicrobial, antiviral, and antiparasitic activity. The purpose of this study to investigate the action of AgNp-Bio in BeWo cells, HTR-8/SVneo cells and villous explants and its effects against Toxoplasma gondii infection. Both cells and villous explants were treated with different concentrations of AgNp-Bio or combination of sulfadiazine + pyrimethamine (SDZ + PYZ) in order to verify the viability. After, cells and villi were infected and treated with AgNp-Bio or SDZ + PYZ in different concentrations to ascertain the parasite proliferation and cytokine production profile. AgNp-Bio treatment did not reduce the cell viability and villous explants. Significant reduction was observed in parasite replication in both cells and villous explants treated with silver nanoparticles and classical treatment. The AgNp-Bio treatment increased of IL-4 and IL-10 by BeWo cells, while HTR8/SVneo cells produced macrophage migration inhibitory factor (MIF) and IL-4. In the presence of T. gondii, the treatment induced high levels of MIF production by BeWo cells and IL-6 by HTR8SV/neo. In villous explants, the AgNp-Bio treatment downregulated production of IL-4, IL-6, and IL-8 after infection. In conclusion, AgNp-Bio can decrease T. gondii infection in trophoblast cells and villous explants. Therefore, this treatment demonstrated the ability to reduce the T. gondii proliferation with induction of inflammatory mediators in the cells and independent of mediators in chorionic villus which we consider the use of AgNp-Bio promising in the treatment of toxoplasmosis in BeWo and HTR8/SVneo cell models and in chorionic villi.
Environmental Enrichment as a Strategy to Confront Social Isolation Under the COVID-19 Pandemic
Authors: Davim André , Trindade da silva Laíse , Vieira Paulo
Published: January 2021

The moment of social isolation experienced by the world population due to the COVID-19 pandemic tends to trigger behavioral changes of different orders and on an exponential scale, regardless of social class, age, gender, or ethnicity. Environmental enrichment presents itself as an important strategy to face the social isolation imposed by the pandemic, in order to act as an important agent of induction of biological factors for cognitive and emotional development, favoring a better possibility of adaptation to isolation.
Transcranial Photobiomodulation to Improve Cognition in Gulf War Illness
Authors: Martin Paula I. , Chao Linda , Krengel Maxine H. , Ho Michael D. , Yee Megan , Lew Robert , Knight Jeffrey , Hamblin Michael R. , Naeser Margaret A.
Published: January 2021

Introduction: Approximately 25–30% of veterans deployed to Kuwait, 1990-91, report persistent multi-symptom Gulf War Illness (GWI) likely from neurotoxicant exposures. Photobiomodulation (PBM) in red/near-infrared (NIR) wavelengths is a safe, non-invasive modality shown to help repair hypoxic/stressed cells. Red/NIR wavelengths are absorbed by cytochrome C oxidase in mitochondria, releasing nitric oxide (increasing local vasodilation), and increasing adenosine tri-phosphate production. We investigated whether PBM applied transcranially could improve cognition, and health symptoms in GWI.

Materials and Methods: Forty-eight (40 M) participants completed this blinded, randomized, sham-controlled trial using Sham or Real, red/NIR light-emitting diodes (LED) applied transcranially. Fifteen, half-hour transcranial LED (tLED) treatments were twice a week (7.5 weeks, in-office). Goggles worn by participant and assistant maintained blinding for visible red. Pre-/Post- testing was at Entry, 1 week and 1 month post- 15th treatment. Primary outcome measures were neuropsychological (NP) tests; secondary outcomes, Psychosocial Questionnaires, including PTSD.

Results: Primary Analyses (all participants), showed improvement for Real vs. Sham, for Digit Span Forwards (p < 0.01); and a trend for Trails 4, Number/Letter Sequencing (p < 0.10). For secondary outcomes, Real group reported more improvement on the SF-36V Plus, Physical Component Score (p < 0.08). Secondary Analyses included only subjects scoring below norm (50%ile) at Entry, on specific NP test/s. Real and Sham improved at 1 week after 15th treatment; however, at 1 month, only those receiving Real improved further: Digit Span Total, Forwards and Backwards; Trails 4, Number/Letter Sequencing; California Verbal Learning Test-II, long delay free recall; Continuous Performance Test-II, False Alarm Rate; and Color-Word Interference, Stroop, Trial 3, Inhibition; Sham group worsened, toward Entry values. Only those with more post-traumatic stress disorder (PTSD) symptomatology at Entry, receiving Real, continued to have additional PTSD reduction at 1 month; Sham regressed.

Conclusion: This study was underpowered (n = 48), with large heterogeneity at Entry. This likely contributed to significance or trend to significance, for only two of the NP tests (Digit Span Forwards; Trails 4, Number/Letter Sequencing) and only one general health measure, the SF-36V Plus, Physical Component Score. More subjects receiving Real, self-reported increased concentration, relaxation and sleep. Controlled studies with newer, transcranial LED home treatment devices are warranted; this is expected to increase enrollment.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT01782378.
Autoimmune Encephalitis in Latin America: A Critical Review
Authors: Vasconcelos Gabriel de Albuquerque , Barreira Rodrigo Montenegro , Antoniollo Karmelita Emanuelle Nogueira Torres , Pinheiro Alina Maria Nuñez , Maia Cíntia Fernandes Rodrigues , Alves Danyela Martins Bezerra Soares , Nóbrega Paulo Ribeiro , Braga-Neto Pedro
Published: January 2021

Autoimmune encephalitis is an increasingly recognized cause of encephalitis. The majority of case series report patients residing in developed countries in the northern hemisphere. The epidemiologic features of autoimmune encephalitis in Latin America are still unclear. The aim of the study was to perform a review of the clinical presentation of autoimmune encephalitis in Latin America and compare to world literature. References were identified by an in-depth literature search and selected on the basis of relevance to the topic and authors' judgment. We selected clinical studies and case reports published from 2007 to July, 2020 including patients from Latin American countries. Of the 379 patients included, the majority were cases of anti-NMDA receptor encephalitis (93.14%), followed by anti-VGKC-complex encephalitis (N = 17; 4.48%), anti-GAD encephalitis (N = 9; 2.37%), anti-AMPA receptor encephalitis (N = 1; 0.26%), anti-GABA receptor encephalitis (N = 1; 0. 26%), anti-mGluR5 encephalitis (N = 1; 0. 26%), and anti-mGluR1 encephalitis (N = 1; 0. 26%). Reported cases of Anti-NMDA encephalitis in Latin-America had a very slight female predominance, lower prevalence of associated tumors and a lower incidence of extreme delta brush on electroencephalogram. Autoimmune encephalitis is possibly underdiagnosed in underdeveloped countries. Its outcome after treatment, however, appears to be similarly favorable in Latin American patients as has been reported in developed countries based on available case reports and case series. Regional specificities in the manifestation of autoimmune encephalitis could be related to epidemiologic factors, such as the presence of different triggers and different genetic and immunologic background, that need to be studied by future research.
Age-Related Clinical Presentation of MOG-IgG Seropositivity in Israel
Authors: Brill Livnat , Ganelin-Cohen Esther , Dabby Ron , Rabinowicz Shira , Zohar-Dayan Efrat , Rein Netaniel , Aloni Eyal , Karmon Yuval , Vaknin-Dembinsky Adi
Published: January 2021

Introduction:Myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders (MOGAD) have been recognized over the past 10 years as distinct inflammatory, demyelinating diseases of the central nervous system (CNS). Antibodies against MOG are found mostly in patients with optic neuritis (ON), acute disseminated encephalomyelitis (ADEM), and aquaporin-4 antibody (AQP4-abs)-seronegative neuromyelitis optica spectrum disorders (NMOSD). However, data on the disease course and disability outcomes of these patients are scarce.

Aim:To describe clinical and paraclinical features associated with MOG antibodies (abs) in a cohort of patients in Israel, and to assess baseline prognostic features of MOG-ab-associated diseases after a first acute demyelinating event.

Methods:MOG-abs were identified in serum using a cell-based assay, and clinical data were collected from the patients' medical records.

Results:Of 683 patients with demyelinating diseases tested for MOG-abs, 53 were positive (7.7%), with ON the most common presenting phenotype (68%). The age range of MOG-abs seropositive patients was 1–66 years, with increased prevalence in children (19% compared to 6.7% in adults) (p< 0.01). The highest prevalence of seropositivity was observed in children aged younger than 10 years (25.5%), followed by those aged 31–40 years (16.6%).

Conclusions:MOGAD are distinct autoimmune diseases that occurs at all stages of life with a significantly higher prevalence in children; the main clinical presenting phenotype in the entire cohort is ON and young children most often presented with ON or ADEM. Our data highlight the need for repeated evaluation of MOG-abs in patients with acquired CNS demyelinating disorders, especially in children under 10 and adults between 31 and 40 years of age.
Imaging Patterns of Recurrent Infarction in the Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease (MyRIAD) Study
Authors: Sangha Rajbeer S. , Prabhakaran Shyam , Feldmann Edward , Honda Tristan , Nizam Azhar , Cotsonis George A. , Campo-Bustillo Iszet , Romano Jose G. , Liebeskind David S.
Published: January 2021

Introduction: While much is known about recurrent clinical events in patients with intracranial atherosclerotic disease (ICAD), there is limited data on characteristics of recurrent infarcts.

Methods: The NIH-funded MyRIAD prospective, observational study was designed to identify mechanisms of ischemia and predictors of recurrence in ICAD. Recurrent infarction was assessed on MRI at 6–8 weeks. We reviewed the DWI/ADC and FLAIR sequences in patients with recurrent stroke and characterized the number of infarcts, infarct location, size, and patterns based on whether they were borderzone (BZ), perforator (SC/P), cortical or territorial (C/T), and mixed. Temporal characteristics were delineated by ADC/FLAIR correlation.

Results: Of the 89 patients with 6–8 weeks MRI, 22 (24.7%) had recurrent infarcts in the territory of the symptomatic artery. Recurrent infarcts were evident on DWI in 63.6% and single infarcts in 54.5%. The median recurrent infarct volume was 2.0 cm3 compared to median index infarct volumes of 2.5 cm3. A mixed infarct pattern was most common (40.9%), followed by borderzone (22.7%), cortical or territorial (27.3%), while only 9.1% were in a perforator artery distribution. Amongst those with a mixed pattern, 8/9 had a borderzone distribution infarct as part of their mixed infarct pattern.

Conclusion: These findings provide novel data on the characteristics of early recurrent infarcts in patients with symptomatic ICAD.
Dynamics in Endolymphatic Hydrops & Symptoms in Meniere's Disease After Endolymphatic Duct Blockage, Preliminary Results
Authors: He Jun , Peng Anquan , Hu Junjiao , Zhang Zhiwen , Chen Yichao , Wang Qin , Liu Wei , Chao Huang , Deng Kai , Jiang Wenqi
Published: January 2021

Objective: The purpose of the present study was to evaluate the dynamics of endolymphatic hydrops (EH) and symptoms in a group of patients who underwent endolymphatic duct blockage (EDB) for treatment of intractable Meniere's Disease (MD), and to explore a metric for verifying the effectiveness of EDB procedure.

Methods: A total of 22 patients with intractable MD patients who underwent EDB participated in the present study. EH was visualized using locally enhanced inner ear magnetic resonance imaging (MRI) prior to and following surgery. The vestibular hydrops ratio (VHR) in the second MRI examination was compared with the pre-surgery recordings.

Results: Following EDB, 6 patients exhibited complete or partial reversal of EH, complete control of vertigo spells and reported improvement in hearing; 13 patients showed no changes in EH or hearing, but 5 of these patients exhibited complete control of vertigo attacks, and the other 8 patients exhibited improved control of vertigo attacks. The final 3 patients showed an increase in EH, but symptomatic worsening in 2 patients, and symptomatic improvement in 1 patient. There was a significant difference in the average VHR prior to and following EDB. Postoperative VHR was positively correlated with the frequency of vertigo spells in the latest 6 months of follow-up and improvement of postoperative average hearing threshold.

Conclusion: The decreased EH accompanying the reduction in vertigo attacks and hearing preservation may provide a metric for verifying the effectiveness of EDB treatment in patients with MD.
A Functional MRI Paradigm for Efficient Mapping of Memory Encoding Across Sensory Conditions
Authors: Boenniger Meta M. , Diers Kersten , Herholz Sibylle C. , Shahid Mohammad , Stöcker Tony , Breteler Monique M. B. , Huijbers Willem
Published: January 2021

We introduce a new and time-efficient memory-encoding paradigm for functional magnetic resonance imaging (fMRI). This paradigm is optimized for mapping multiple contrasts using a mixed design, using auditory (environmental/vocal) and visual (scene/face) stimuli. We demonstrate that the paradigm evokes robust neuronal activity in typical sensory and memory networks. We were able to detect auditory and visual sensory-specific encoding activities in auditory and visual cortices. Also, we detected stimulus-selective activation in environmental-, voice-, scene-, and face-selective brain regions (parahippocampal place and fusiform face area). A subsequent recognition task allowed the detection of sensory-specific encoding success activity (ESA) in both auditory and visual cortices, as well as sensory-unspecific positive ESA in the hippocampus. Further, sensory-unspecific negative ESA was observed in the precuneus. Among others, the parallel mixed design enabled sustained and transient activity comparison in contrast to rest blocks. Sustained and transient activations showed great overlap in most sensory brain regions, whereas several regions, typically associated with the default-mode network, showed transient rather than sustained deactivation. We also show that the use of a parallel mixed model had relatively little influence on positive or negative ESA. Together, these results demonstrate a feasible, versatile, and brief memory-encoding task, which includes multiple sensory stimuli to guarantee a comprehensive measurement. This task is especially suitable for large-scale clinical or population studies, which aim to test task-evoked sensory-specific and sensory-unspecific memory-encoding performance as well as broad sensory activity across the life span within a very limited time frame.
Novel Targets of SARS-CoV-2 Spike Protein in Human Fetal Brain Development Suggest Early Pregnancy Vulnerability
Authors: Varma Parul , Lybrand Zane R. , Antopia Mariah C. , Hsieh Jenny
Published: January 2021

Pregnant women are at greater risk of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), because of their altered immunity and strained cardiovascular system. Emerging studies of placenta, embryos, and cerebral organoids suggest that fetal organs including brain could also be vulnerable to coronavirus disease 2019 (COVID-19). Additionally, a case study from Paris has reported transient neurological complications in neonates born to pregnant mothers. However, it remains poorly understood whether the fetal brain expresses cellular components that interact with Spike protein (S) of coronaviruses, which facilitates fusion of virus and host cell membrane and is the primary protein in viral entry. To address this question, we analyzed the expression of known (ACE2, TMPRSS2, and FURIN) and novel (ZDHHC5, GOLGA7, and ATP1A1) S protein interactors in publicly available fetal brain bulk and single cell RNA sequencing datasets. Bulk RNA sequencing analysis across multiple regions of fetal brain spanning 8 weeks post conception (wpc)−37wpc indicates that two of the known S protein interactors are expressed at low levels with median normalized gene expression values ranging from 0.08 to 0.06 (ACE2) and 0.01–0.02 (TMPRSS2). However, the third known S protein interactor FURIN is highly expressed (11.1–44.09) in fetal brain. Interestingly, all three novel S protein interactors are abundantly expressed throughout fetal brain development with median normalized gene expression values ranging from 20.38–21.60 (ZDHHC5), 92.47–68.35 (GOLGA7), and 65.45–194.5 (ATP1A1). Moreover, the peaks of expression of novel interactors is around 12–26wpc. Using publicly available single cell RNA sequencing datasets, we further show that novel S protein interactors show higher co-expression with neurons than with neural progenitors and astrocytes. These results suggest that even though two of the known S protein interactors are present at low levels in fetal brain, novel S protein interactors are abundantly present and could play a direct or indirect role in SARS-CoV-2 fetal brain pathogenesis, especially during the 2nd and 3rd trimesters of pregnancy.
Edge-Aware Pyramidal Deformable Network for Unsupervised Registration of Brain MR Images
Authors: Cao Yiqin , Zhu Zhenyu , Rao Yi , Qin Chenchen , Lin Di , Dou Qi , Ni Dong , Wang Yi
Published: January 2021

Deformable image registration is of essential important for clinical diagnosis, treatment planning, and surgical navigation. However, most existing registration solutions require separate rigid alignment before deformable registration, and may not well handle the large deformation circumstances. We propose a novel edge-aware pyramidal deformable network (referred as EPReg) for unsupervised volumetric registration. Specifically, we propose to fully exploit the useful complementary information from the multi-level feature pyramids to predict multi-scale displacement fields. Such coarse-to-fine estimation facilitates the progressive refinement of the predicted registration field, which enables our network to handle large deformations between volumetric data. In addition, we integrate edge information with the original images as dual-inputs, which enhances the texture structures of image content, to impel the proposed network pay extra attention to the edge-aware information for structure alignment. The efficacy of our EPReg was extensively evaluated on three public brain MRI datasets including Mindboggle101, LPBA40, and IXI30. Experiments demonstrate our EPReg consistently outperformed several cutting-edge methods with respect to the metrics of Dice index (DSC), Hausdorff distance (HD), and average symmetric surface distance (ASSD). The proposed EPReg is a general solution for the problem of deformable volumetric registration.
Yokukansankachimpihange Is Useful to Treat Behavioral/Psychological Symptoms of Dementia
Authors: Katsumoto Eiichi , Ishida Toru , Kinoshita Kenji , Shimizu Miho , Tsutsumi Toshihito , Nagai Yoko , Nishimura Masakazu , Yokouchi Toshio , Yoshida Yasushi
Published: January 2021

Yokukansankachimpihange is a Japanese herbal medicine reported to benefit anxiety and sleep disorders, and it has recently been introduced to treat behavioral and psychological symptoms of dementia. There are no multicenter studies of its effectiveness regarding dementia in Japan, and this study's main objective was to clarify the effects of Yokukansankachimpihange on behavioral and psychological symptoms of dementia in a sample of patients from multiple healthcare centers. Nine facilities affiliated with Osaka Association of Psychiatric Clinics participated in November 2013 through April 2015 and provided 32 Alzheimer's disease patients to whom Yokukansankachimpihange was orally administered for 8 weeks. During the study, the patients continued their regular medication regimens. Behavioral and psychological symptoms of dementia (Behavioral Pathology in Alzheimer's Disease Rating Scale [Behave-AD]), core symptoms [Mini-Mental State Examination (MMSE)], activities of daily living [Nishimura Activity of Daily Living Scale (N-ADL)], and gastrointestinal symptoms (nausea/vomiting, loss of appetite, gastric discomfort, constipation, and diarrhea) were measured at baseline, after 4 weeks of treatment and after 8 weeks of treatment. Yokukansankachimpihange was orally administered at a dosage of 7.5 g twice daily before or between meals for 8 weeks. The Behave-AD mean score significantly improved after 8 weeks of treatment. There were no significant changes in MMSE, N-ADL, or gastrointestinal symptoms; however, decreased gastrointestinal scores were observed after 8 weeks. There were no side effects related to Yokukansankachinpihange. Pharmaceutical treatments are important for treating behavioral and psychological symptoms of dementia, and this study confirmed Yokukansankachimpihange's efficacy for treating Alzheimer's disease. Because the aggressiveness and sleep disorder components of the Behave-AD construct were the symptoms most improved and those symptoms are known to significantly burden dementia patients' caregivers, Yokukansankachimpihange's efficacy might indirectly relieve these caregivers' burden of care.
Acute Effects of Cinnamon Spice on Post-prandial Glucose and Insulin in Normal Weight and Overweight/Obese Subjects: A Pilot Study
Authors: Wang Jing , Wang Sijia , Yang Jieping , Henning Susanne M. , Ezzat-Zadeh Zahra , Woo Shih-Lung , Qin Tianyu , Pan Yajing , Tseng Chi-Hong , Heber David , Li Zhaoping
Published: January 2021

Clinical studies and meta-analyses have supported the notion that consuming cinnamon spice long term can have beneficial effects in individuals with normal glucose homeostasis and varying degrees of glucose intolerance including type 2 diabetes. The objective of this study was to evaluate the acute effect of cinnamon on the post-prandial responses to a typical American breakfast in normal and overweight/obese participants (ClinicalTrials.gov registration No. NCT04686552). The consumption of a single dose of 6 g of cinnamon added to oatmeal prepared with milk resulted in a significant reduction of one of our primary outcomes post-prandial insulin response (niAUC0−180min) in overweight/obese participants compared to control consuming breakfast without cinnamon. We also performed exploratory analysis of secondary outcomes. In normal weight participants, we observed a decrease of post-prandial glucagon response (niAUC0−180min and glucagon levels at 60–120 min) and C-peptide response (30 min) comparing breakfast with to without cinnamon. Cinnamon consumption did not change post-prandial glycemic response in normal weight participants, but increased 60 min post-prandial glucose in overweight/obese participants compared to control. In summary, cinnamon consumption differentially affected post-prandial hormonal responses in normal and overweight/obese participants.
The Burden of Malnutrition and Fatal COVID-19: A Global Burden of Disease Analysis
Authors: Mertens Elly , Peñalvo José L.
Published: January 2021

Background: Although reasonable to assume, it is not yet clear whether malnourished countries are at higher risk for severe or fatal coronavirus disease 2019 (COVID-19). This study aims to identify the countries where prevalent malnutrition may be a driving factor for fatal disease after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Methods: Using estimates from the Global Burden of Disease 2019, country-level burden of malnutrition was quantified using four indicators: death rates for child growth failure (underweight, stunting, and/or wasting) and years lived with disability (YLD) attributed to iron and vitamin A deficiencies and high body mass index (BMI). Global mortality descriptors of the ongoing COVID-19 pandemic were extracted from the European Centre for Disease Prevention and Control, and case fatality ratios (CFRs) were calculated introducing a lag time of 10 weeks after the first death of a confirmed case. Bivariate analyses for 172 countries were carried out for malnutrition indicators and fatal COVID-19. Correlations between burden indicators were characterized by Spearman's rank correlation coefficients (ρ) and visually by scatterplots. Restricted cubic splines and underlying negative binomial regressions adjusted for countries' age-structure, prevalent chronic comorbidities related to COVID-19, population density, and income group were used to explore non-linear relationships.

Results: Stratified by the World Bank income group, a moderate positive association between YLD rates for iron deficiency and CFRs for COVID-19 was observed for low-income countries (ρ = 0.60, p = 0.027), whereas no clear indications for the association with child growth failure, vitamin A deficiency, or high BMI were found (ρ < 0.30). Countries ranking high on at least three malnutrition indicators and presenting also an elevated CFR for COVID-19 are sub-Saharan African countries, namely, Angola, Burkina Faso, Chad, Liberia, Mali, Niger, Sudan, and Tanzania, as well as Yemen and Guyana.

Conclusions: Population-level malnutrition appears to be related to increased rates of fatal COVID-19 in areas with an elevated burden of undernutrition, such as countries in the Sahel strip. COVID-19 response plans in malnourished countries, vulnerable to fatal COVID-19, should incorporate food security, nutrition, and social protection as a priority component in order to reduce COVID-19 fatality.
Long-Term Outcomes and Prognostic Analysis of Computed Tomography-Guided Radioactive 125I Seed Implantation for Locally Recurrent Rectal Cancer After External Beam Radiotherapy or Surgery
Authors: Wang Hao , Wang Lu , Jiang Yuliang , Ji Zhe , Guo Fuxin , Jiang Ping , Li Xuemin , Chen Yi , Sun Haitao , Fan Jinghong , Du Gang , Wang Junjie
Published: January 2021

Background

Management of locally recurrent rectal cancer (LRRC) after surgery or external beam radiotherapy (EBRT) remains a clinical challenge, given the limited treatment options and unsatisfactory outcomes. This study aimed to assess long-term outcomes of computed tomography (CT)-guided radioactive 125I seed implantation in patients with LRRC and associated prognostic factors.

Methods

A total of 101 patients with LRRC treated with CT-guided 125I seed implantation from October 2003 to April 2019 were retrospectively studied. Treatment procedures involved preoperative planning design, 125I seed implantation, and postoperative dose evaluation. We evaluated the therapeutic efficacy, adverse effects, local control (LC) time, and overall survival (OS) time.

Results

All the patients had previously undergone surgery or EBRT. The median age of patients was 59 (range, 31–81) years old. The median follow-up time was 20.5 (range, 0.89–125.8) months. The median LC and OS time were 10 (95% confidence interval (CI): 8.5–11.5) and 20.8 (95% CI: 18.7–22.9) months, respectively. The 1-, 2-, and 5-year LC rates were 44.2%, 20.7%, and 18.4%, respectively. The 1-, 2-, and 5-year OS rates were 73%, 31.4%, and 5%, respectively. Univariate analysis of LC suggested that when short-time tumor response achieved partial response (PR) or complete response (CR), or D90>129 Gy, or GTV ≤ 50 cm3, the LC significantly prolonged (P=0.044, 0.041, and <0.001, respectively). The multivariate analysis of LC indicated that the short-time tumor response was an independent factor influencing LC time (P<0.001). Besides, 8.9% (9/101) of the patients had adverse effects (≥grade 3): radiation-induced skin reaction (4/101), radiation-induced urinary reaction (1/101), fistula (2/101), and intestinal obstruction (2/101). The cumulative irradiation dose and the activity of a single seed were significantly correlated with adverse effects ≥grade 3 (P=0.047 and 0.035, respectively).

Conclusion

CT-guided 125I seed implantation is a safe and effective salvage treatment for LRRC patients who previously underwent EBRT or surgery. D90 and GTV significantly influenced prognosis of such patients.
RETRACTED: Establishment of Criteria for Molecular Differential Diagnosis of MPLC and IPM
Authors: Wang Xiaohui , Gong Yuan , Yao Jianfei , Chen Yan , Li Yuemin , Zeng Zhen , Lu Yinying , Song Lele
Published: January 2021

Backgrounds

Differential diagnosis of multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) is one difficulty in lung cancer diagnosis, and crucial for establishment of treatment strategies and prognosis prediction. This study aims to establish the criteria for molecular differential diagnosis of synchronous MPLC and IPM by the next-generation sequencing (NGS) method.

Methods

Training cohort included 30 synchronous MPLC (67 samples) patients and 5 synchronous IPM (13 samples) patients with adenocarcinoma. Criteria of MPLC/IPM differential diagnosis were established by results from a NGS-based 605-gene panel test. Subsequently, 16 patients (36 samples) were recruited as the validation cohort to verify the criteria.

Results

IPM lesions showed a high degree of mutation overlap with an average concordance rate of 60.2% (range: 15.8%–91.7%). IPM lesions had at least three common alterations, including both high-frequency driver gene alterations and low-frequency gene alterations. In contrast, the average concordance rate of MPLC was 11.0% (range: 0.0%–100.0%), among which 66.7% (20/30) of patients had no common alterations (concordance rate: 0%). In the remaining 10 patients, 9 had only one overlapping alteration while 1 had two overlapping alterations, in which 6 patients had EGFR L858R overlapping mutation. Alterations were classified into trunk, shared, and branch subtypes. Branch alterations accounted for 94.4% of mutations in MPLC, while accounted for only 45.0% in IMP. In contrast, the ratio of trunk (38.3%) and shared (16.7%) alterations in IPM was significantly higher. The criteria for differentiating MPLC from IPM using 605-gene panel was established: 1) MPLC can be interpreted if no overlapping alterations is found; 2) MPLC is recommended if one overlapping high-frequency drive gene alteration and/or one overlapping low-frequency gene alteration are/is found; 3) IPM can be interpreted if more than three common alterations are found. Subsequently, 16 patients were recruited as the validation cohort in the single-blind manner to verify the criteria, and 14 MPLC and 2 IPM were identified, which was 100% consistent with the results from independent imaging and pathological diagnosis.

Conclusions

NGS detection can distinguish synchronous MPLC from IPM and is a useful tool to assist differential diagnosis.
Regulation of Gene Expression Associated With the N6-Methyladenosine (m6A) Enzyme System and Its Significance in Cancer
Authors: Tian Shuoran , Lai Junzhong , Yu Tingting , Li Qiumei , Chen Qi
Published: January 2021

N6-methyladenosine (m6A), an important RNA modification, is a reversible behavior catalyzed by methyltransferase complexes (m6A “writers”), demethylated transferases (m6A “erasers”), and binding proteins (m6A “readers”). It plays a vital regulatory role in biological functions, involving in a variety of physiological and pathological processes. The level of m6A will affect the RNA metabolism including the degradation of mRNA, and processing or translation of the modified RNA. Its abnormal changes will lead to disrupting the regulation of gene expression and promoting the occurrence of aberrant cell behavior. The abnormal expression of m6A enzyme system can be a crucial impact disturbing the abundance of m6A, thus affecting the expression of oncogenes or tumor suppressor genes in various types of cancer. In this review, we elucidate the special role of m6A “writers”, “erasers”, and “readers” in normal physiology, and how their altered expression affects the cell metabolism and promotes the occurrence of tumors. We also discuss the potential to target these enzymes for cancer diagnosis, prognosis, and the development of new therapies.
An Easily Overlooked Contamination of Syringes in Newborn Screening by Tandem Mass Spectrometry
Authors: Wang Yanyun , Sun Yun , Jiang Tao
Published: January 2021

Background: Tandem mass spectrometry becomes a common and important test in newborn screening, but potential contamination of the equipment has largely been ignored.

Methods: The source of contamination through Biosan quality control samples was examined prospectively, and further confirmed by retrospective analysis of patient samples.

Results: We found that the source of contamination came from a syringe in the Biosan quality control samples. Furthermore, we found that a large number of indicators in the patient sample were interfered by syringe contamination in our center, and also in two other newborn screening centers, but the affected indicators were different in different screening centers.

Conclusion: Syringe contamination will affect the detection of patient samples by tandem mass spectrometry and should be monitored carefully and immediately.