bluuebunny/crossref_metadata_2025 huggingface dataset:
HSV-2-Specific Human Female Reproductive Tract Tissue Resident Memory T Cells Recognize Diverse HSV Antigens
Authors: Koelle David M. , Dong Lichun , Jing Lichen , Laing Kerry J. , Zhu Jia , Jin Lei , Selke Stacy , Wald Anna , Varon Dana , Huang Meei-Li , Johnston Christine , Corey Lawrence , Posavad Christine M.
Published: March 2022

Antigen-specific TRM persist and protect against skin or female reproductive tract (FRT) HSV infection. As the pathogenesis of HSV differs between humans and model organisms, we focus on humans with well-characterized recurrent genital HSV-2 infection. Human CD8+ TRM persisting at sites of healed human HSV-2 lesions have an activated phenotype but it is unclear if TRM can be cultivated in vitro. We recovered HSV-specific TRM from genital skin and ectocervix biopsies, obtained after recovery from recurrent genital HSV-2, using ex vivo activation by viral antigen. Up to several percent of local T cells were HSV-reactive ex vivo. CD4 and CD8 T cell lines were up to 50% HSV-2-specific after sorting-based enrichment. CD8 TRM displayed HLA-restricted reactivity to specific HSV-2 peptides with high functional avidities. Reactivity to defined peptides persisted locally over several month and was quite subject-specific. CD4 TRM derived from biopsies, and from an extended set of cervical cytobrush specimens, also recognized diverse HSV-2 antigens and peptides. Overall we found that HSV-2-specific TRM are abundant in the FRT between episodes of recurrent genital herpes and maintain competency for expansion. Mucosal sites are accessible for clinical monitoring during immune interventions such as therapeutic vaccination.
Inhibitory Immune Checkpoint Receptors and Ligands as Prognostic Biomarkers in COVID-19 Patients
Authors: Al-Mterin Mohammad A. , Alsalman Alhasan , Elkord Eyad
Published: March 2022

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2. During T-cell activation, the immune system uses different checkpoint pathways to maintain co-inhibitory and co-stimulatory signals. In COVID-19, expression of immune checkpoints (ICs) is one of the most important manifestations, in addition to lymphopenia and inflammatory cytokines, contributing to worse clinical outcomes. There is a controversy whether upregulation of ICs in COVID-19 patients might lead to T-cell exhaustion or activation. This review summarizes the available studies that investigated IC receptors and ligands in COVID-19 patients, as well as their effect on T-cell function. Several IC receptors and ligands, including CTLA-4, BTLA, TIM-3, VISTA, LAG-3, TIGIT, PD-1, CD160, 2B4, NKG2A, Galectin-9, Galectin-3, PD-L1, PD-L2, LSECtin, and CD112, were upregulated in COVID-19 patients. Based on the available studies, there is a possible relationship between disease severity and increased expression of IC receptors and ligands. Overall, the upregulation of some ICs could be used as a prognostic biomarker for disease severity.
Case Report: Multiple Causes of Cardiac Death After the First Infusion of Atezolizumab: Histopathological and Immunohistochemical Findings
Authors: Kushnareva Ekaterina , Stepanova Maria , Artemeva Elizaveta , Shuginova Tatyana , Kushnarev Vladimir , Simakova Maria , Moiseenko Fedor , Moiseeva Olga
Published: March 2022

Immune checkpoint inhibitors are promising agents for anticancer therapy. But despite their high efficacy in the treatment of solid tumors, there is still a problem with immune-related adverse events, especially cardiovascular complications with a very high mortality rate. Myocarditis or ischemic heart disease progression is not the only possible cause of cardiovascular death in patients treated with checkpoint inhibitors. We report a case of a patient with mucinous carcinoma of the lung, with a previous history of hypertension and moderate left ventricular dysfunction. The patient was prescribed atezolizumab, but the first atezolizumab infusion resulted in the patient cardiovascular death. Postmortem histopathological evaluation of myocardium revealed several possible reasons for hemodynamic instability: tumor embolism of the coronary arteries, micrometastases of mucinous carcinoma in the myocardium, and myocarditis diagnosed by both Dallas and immunohistochemistry criteria. In addition, testing for expression of PD-L1 detected the high levels of membranous and cytoplasmic PD-L1 protein even in the myocardium area free from tumor cells. The present clinical case demonstrates a problem of cardiovascular death in patients treated with checkpoint inhibitors and actualizes the need for future research of potential risk factors for cardiovascular complications.
SANTORY: SANTORini’s Seafloor Volcanic ObservatorY
Authors: Nomikou Paraskevi , Polymenakou Paraskevi N. , Rizzo Andrea Luca , Petersen Sven , Hannington Mark , Kilias Stephanos Pantelis , Papanikolaou Dimitris , Escartin Javier , Karantzalos Konstantinos , Mertzimekis Theodoros J. , Antoniou Varvara , Krokos Mel , Grammatikopoulos Lazaros , Italiano Francesco , Caruso Cinzia Giuseppina , Lazzaro Gianluca , Longo Manfredi , Sciré Scappuzzo Sergio , D’Alessandro Walter , Grassa Fausto , Bejelou Konstantina , Lampridou Danai , Katsigera Anna , Dura Anne
Published: March 2022

Submarine hydrothermal systems along active volcanic ridges and arcs are highly dynamic, responding to both oceanographic (e.g., currents, tides) and deep-seated geological forcing (e.g., magma eruption, seismicity, hydrothermalism, and crustal deformation, etc.). In particular, volcanic and hydrothermal activity may also pose profoundly negative societal impacts (tsunamis, the release of climate-relevant gases and toxic metal(loid)s). These risks are particularly significant in shallow (<1000m) coastal environments, as demonstrated by the January 2022 submarine paroxysmal eruption by the Hunga Tonga-Hunga Ha’apai Volcano that destroyed part of the island, and the October 2011 submarine eruption of El Hierro (Canary Islands) that caused vigorous upwelling, floating lava bombs, and natural seawater acidification. Volcanic hazards may be posed by the Kolumbo submarine volcano, which is part of the subduction-related Hellenic Volcanic Arc at the intersection between the Eurasian and African tectonic plates. There, the Kolumbo submarine volcano, 7 km NE of Santorini and part of Santorini’s volcanic complex, hosts an active hydrothermal vent field (HVF) on its crater floor (~500m b.s.l.), which degasses boiling CO2–dominated fluids at high temperatures (~265°C) with a clear mantle signature. Kolumbo’s HVF hosts actively forming seafloor massive sulfide deposits with high contents of potentially toxic, volatile metal(loid)s (As, Sb, Pb, Ag, Hg, and Tl). The proximity to highly populated/tourist areas at Santorini poses significant risks. However, we have limited knowledge of the potential impacts of this type of magmatic and hydrothermal activity, including those from magmatic gases and seismicity. To better evaluate such risks the activity of the submarine system must be continuously monitored with multidisciplinary and high resolution instrumentation as part of an in-situ observatory supported by discrete sampling and measurements. This paper is a design study that describes a new long-term seafloor observatory that will be installed within the Kolumbo volcano, including cutting-edge and innovative marine-technology that integrates hyperspectral imaging, temperature sensors, a radiation spectrometer, fluid/gas samplers, and pressure gauges. These instruments will be integrated into a hazard monitoring platform aimed at identifying the precursors of potentially disastrous explosive volcanic eruptions, earthquakes, landslides of the hydrothermally weakened volcanic edifice and the release of potentially toxic elements into the water column.
On the Role of Eddy Mixing in the Subtropical Ocean Circulation
Authors: Liu Tongya , Ou Hsien-Wang , Liu Xiaohui , Chen Dake
Published: March 2022

Most of the classic wind-driven circulation theories based on Sverdrup balance have neglected the profound influence of eddy mixing on the large-scale potential vorticity (PV) distribution, thus failing to explain some prominent features of the observed circulation. In this study, using a series of numerical experiments based on the MITgcm, we diagnose the PV balance to quantify the effect of eddy mixing on the subtropical gyre. Four horizontal grid-spacings of 1°, 1/3.2°, 1/10°, and 1/32° are selected to compare the structure of the upper-ocean circulation to examine the effect of different eddy influences. In the 1° grid case, the thermocline structure is as predicted by the Sverdrup dynamics, with its maximum depth located in the subtropical interior where the wind stress curl is strongest. With increasing resolution, however, this maximum depth is displaced towards the subtropical front, which more closely resembles the observed thermocline. From 1° to 1/32°, the enhanced eddy mixing tends to homogenize the macroscopic PV in the subtropical gyre and reduces the meridional PV range by about 75% of the non-eddy (1°) solution; and the region where Sverdrup balance holds is relegated to isolated patches, with its area reduced by about 60%. Furthermore, sensitivity experiments show that the observed thermocline structure is well reproduced in eddy-resolving runs, indicating that the PV mixing provides a reasonable explanation of the subtropical circulation. Our results suggest that the Sverdrup relationship should be treated carefully in the eddy-rich region, even in the subtropical interior.
Facile Low-Cost Synthesis of Highly Photocatalitycally Active Zinc Oxide Powders
Authors: Kedruk Y. Y. , Baigarinova G. A. , Gritsenko L. V. , Cicero G. , Abdullin Kh. A.
Published: March 2022

The industrial waste can cause significant harm to human health and to the environment. Organic dyes in particular are environmentally dangerous since they may cause the death of aquatic life or contaminate the feed chain. Thus, one of the current research fields consists of the development of an inexpensive and environmentally friendly method to purify wastewater from organic contaminants. Among the others, Zinc oxide (ZnO) is considered one of the most effective photocatalysts for the decomposition of organic pollutants in water. In this work, we developed a highly efficient low-temperature and environmentally safe synthesis method to obtain photocatalytically active nanostructured ZnO by chemical precipitation from a solution. The effect of the technological conditions of synthesis on the photocatalytic properties is considered in detail, the correlation with the morphology, structural, and optical properties of the synthesized ZnO samples is determined. It was found that the maximum photocatalytic activity with respect to the decomposition of the dye rhodamine-B (RhB) is achieved for samples synthesized at NaOH molar concentration from 0.4 to 0.7 M; in this case, the sizes of crystallites along the crystallographic direction 002 reach maximum values of ∼42 nm. On the contrary, the sizes of crystallites along the directions 100 and 101 decrease monotonically from 30 to 25 nm with an increase in the molar concentration of NaOH from 0.14 to 1 M.
Case Report: Chronic Active Epstein–Barr Virus Infection With Subcutaneous Nodules and Systemic Damage
Authors: Luo Huating , Yuan Zhe , Qin Bo
Published: March 2022

Chronic active Epstein–Barr virus (CAEBV) infection is a rare and progressive systemic lymphoproliferative disorder often beginning as an infectious mononucleosis (IM)-like illness. It manifests with fever, splenomegaly, hepatitis, lymphadenopathy, and occasionally cytopenias, pneumonitis, and vasculitis. We report a 23-year-old woman with fever and subcutaneous nodules first appearing on the limbs and then spreading to the body. Peripheral blood EBV antibodies were elevated and EBV-DNA loads significantly increased. A skin and lymph node biopsy identified T cell-based lymphocyte infiltration and EBV-encoded RNA positivity (EBER+). CAEBV was finally diagnosed. During the illness, her disease progressed to hemophagocytic syndrome (HPS). The patient then successfully received an allogeneic hematopoietic stem cell transplantation (HSCT) at 6 months. Current follow-up at 2 years indicated a stable condition and six negative EBV-DNA tests, and we reviewed the clinical manifestations, mechanism, diagnosis and differential diagnosis, treatment, and prognosis of CAEBV. Finally, subcutaneous nodules may occur when CAEBV invades the skin; therefore, clinicians must identify the cause of these nodules early. HSCT is effective but its timing must be appropriate.
Frailty and Emergency Surgery: Results of a Systematic Review and Meta-Analysis
Authors: Leiner Tamas , Nemeth David , Hegyi Peter , Ocskay Klementina , Virag Marcell , Kiss Szabolcs , Rottler Mate , Vajda Matyas , Varadi Alex , Molnar Zsolt
Published: March 2022

Background

Frailty, a “syndrome of loss of reserves,” is a decade old concept. Initially it was used mainly in geriatrics but lately its use has been extended into other specialties including surgery. Our main objective was to examine the association between frailty and mortality, between frailty and length of hospital stay (LOS) and frailty and readmission within 30 days in the emergency surgical population.

Methods

Studies reporting on frailty in the emergency surgical population were eligible. MEDLINE (via PubMed), EMBASE, Scopus, CENTRAL, and Web of Science were searched with terms related to acute surgery and frail*. We searched for eligible articles without any restrictions on the 2nd of November 2020. Odds ratios (OR) and weighted mean differences (WMD) were calculated with 95% confidence intervals (CI), using a random effect model. Risk of bias assessment was performed according to the recommendations of the Cochrane Collaboration. As the finally selected studies were either prospective or retrospective cohorts, the “Quality In Prognosis Studies” (QUIPS) tool was used.

Results

At the end of the selection process 21 eligible studies with total 562.070 participants from 8 countries were included in the qualitative and the quantitative synthesis. Patients living with frailty have higher chance of dying within 30 days after an emergency surgical admission (OR: 1.99; CI: 1.76–2.21; p < 0.001). We found a tendency of increased LOS with frailty in acute surgical patients (WMD: 4.75 days; CI: 1.79–7.71; p = 0.002). Patients living with frailty have increased chance of 30-day readmission after discharge (OR: 1.36; CI: 1.06–1.75; p = 0.015).

Conclusions

Although there is good evidence that living with frailty increases the chance of unfavorable outcomes, further research needs to be done to assess the benefits and costs of frailty screening for emergency surgical patients.

Systematic Review Registration

The review protocol was registered on the PROSPERO International Prospective Register of Systematic Reviews (CRD42021224689).
Effective Drugs Against Severe Fever With Thrombocytopenia Syndrome Virus in an in vitro Model
Authors: Bang Mi-Seon , Kim Choon-Mee , Kim Dong-Min , Yun Na Ra
Published: March 2022

Background

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV). This syndrome is endemic in China, South Korea, and Japan, with a fatality rate of approximately 20–30%. Although the World Health Organization has listed SFTS as a disease that requires urgent steps for the development of its treatment, no treatments are available.

Methods

We analyzed the antiviral activity of 41 drugs against the SFTSV to explore potential therapeutic candidates using real-time reverse transcription-polymerase chain reaction and plaque assay in vitro.

Results

Peramivir, nitazoxanide, and favipiravir were found to have inhibitory effects on the SFTSV at concentrations below the maximum plasma concentration (Cmax). The concentrations that inhibited the SFTSV by 50% were as follows: peramivir, half maximal effective concentration (EC50) 12.9 μg/mL; nitazoxanide, EC50 0.57 μg/mL; and favipiravir, EC50 4.14 μg/mL.

Conclusion

The effects of peramivir and nitazoxanide on the SFTSV were identified for the first time in this study. Future studies need to include animal models of SFTSV infection, clinical trials including dose-ranging trials, and evaluation of combination therapy with other potential antivirals.
Heparinase Digestion of 3-O-Sulfated Sequences: Selective Heparinase II Digestion for Separation and Identification of Binding Sequences Present in ATIII Affinity Fractions of Bovine Intestinal Heparins
Authors: Mourier Pierre
Published: March 2022

Binding to antithrombin-III (ATIII) determines the anticoagulant activity of heparin. The complexes formed between heparin and ATIII result from a specific pentasaccharide sequence containing a 3-O-sulfated glucosamine in medium position. Building block analysis of heparins, following heparinase digestion, is a critical method in quality control that provides a simple structural characterization of a complex product. Hence, in these applications, study of the digestion of 3-O-sulfated moieties merits special attention. With heparinase II, specific inhibition of cleavage of the non-reducing bond of 3-O-sulfated units is observed. This specificity was erroneously generalized to other heparinases when it was observed that in exhaustive digests of heparins with the heparinase mixture, resistant 3-O-sulfated tetrasaccharides were also obtained from the specific ATIII-binding pentasaccharides. In fact, the detection of unsaturated 3-O-sulfated disaccharides in digests of heparin by heparinases I+II+III, resulting from the cleavage of the 3-O sulfated unit by heparinase I in non-conventional sequences, shows that this inhibition has exceptions. Thus, in experiments where heparinase II is selectively applied, these sequences can only be digested into tetra- or hexasaccharides where the 3-O-sulfated glucosamine is shifted on the reducing end. Heparinase I+II+III and heparinase II digests with additional tagging by reductive amination with sulfanilic acid were used to study the structural neighborhood of 3-O-sulfated disaccharides in bovine mucosal heparin fractions with increasing affinity for ATIII. The 3-O-sulfated disaccharides detected in heparinase I+II+III digests turn into numerous specific 3-O-sulfated tetrasaccharides in heparinase II digests. Additionally, ATIII-binding pentasaccharides with an extra 3-O-sulfate at the reducing glucosamine are detected in fractions of highest affinity as heparinase II-resistant hexasaccharides with two consecutive 3-O-sulfated units.
Quantitative Assessment of Portal Hypertension by Two-Dimensional Shear Wave Elastography in Rat Models of Nonalcoholic Fatty Liver Disease: Comparison With Four Composite Scores
Authors: Dong Bingtian , Chen Yuping , Lyu Guorong , Chen Yongjian , Qin Ran
Published: March 2022

Background

Measurement of hepatic venous pressure gradients is the gold standard for assessing portal hypertension (PH) but is invasive with potential complications. We aimed to assess the performance in liver and spleen stiffness measurement (LSM and SSM, respectively) by two-dimensional shear wave elastography (2D-SWE) and composite scores including liver stiffness-spleen diameter to platelet ratio score (LSPS), platelet (PLT) count/spleen diameter ratio (PSR), aspartate aminotransferase (AST)/alanine aminotransferase ratio (AAR), and AST-to-PLT ratio index (APRI) for diagnosing PH in nonalcoholic fatty liver disease (NAFLD) rat models.

Methods

Animal models with PH in NAFLD were established in 65 rats, which then underwent 2D-SWE measurements. Morphological and biological parameters were collected for calculation of four composite scores. Correlations of noninvasive methods with portal venous pressure were evaluated by Spearman correlation analysis. The area under the receiver operating characteristic curve (AUC) was used to assess the performance of noninvasive methods in predicting PH.

Results

LSM and SSM were significantly associated with portal venous pressure (r = 0.636 and 0.602, respectively; all P < 0.001). The AUCs of LSM and SSM in the diagnosis of PH were 0.906 (95% confidence interval [CI]:0.841–0.97) and 0.87 (95% CI:0.776–0.964), respectively, and were significantly higher than those in composite scores. The AUCs for LSPS, PSR, AAR, and APRI were 0.793, 0.52, 0.668, and 0.533, respectively, for diagnosing PH. The AUCs of the combined models of LSM and SSM, LSM and PLT, SSM and PLT, and LSM, SSM and PLT were 0.923, 0.913, 0.872, and 0.923, respectively. The four combined models showed no statistical differences compared to LSM and SSM in evaluating PH (all P > 0.05).

Conclusions

LSM and SSM by 2D-SWE can be used as promising noninvasive parameters for diagnosing PH in NAFLD and have higher accuracy than composite scores. The combined models, compared to LSM and SSM, did not significantly improve the performance in diagnosing PH.
Application of Muscle Thickness and Quality Measured by Ultrasound in Frailty Assessment in China
Authors: Lv Shan , Ling Ling , Shi Hui , Chen Xing , Chen Shu , Zhu Siping , Lin Wei , Lv Rong , Ding Guoxian
Published: March 2022

To explore the correlation between Fried Frailty Phenotype (FFP) and the muscle thickness and quality of local muscle, and to provide a reasonable basis for the application of ultrasound measurement in the frailty assessment. A total of 150 people (age ≥ 65 years, 58 women, 92 men) were included from the First Hospital Affiliated to Nanjing Medical University. They were divided into Normal group (40 cases), Prefrailty group (69 cases) and Frailty group (41 cases). The thickness and the quality of local muscle were detected by ultrasound. Participants in the prefrailty group had a higher grayscale value of the vastus lateralis muscle, indicating the deterioration of muscle quality. At the frailty stage, the muscle thickness and quality of the vastus lateralis muscle and the anterior tibialis muscle decreased significantly compared with the normal and the prefrailty group. Pearson's correlation analysis also showed FFP was negatively correlated with muscle thickness and quality of the lower limbs. In multiple regression model, FFP was positively associated with gray value (Vastus lateralis muscle:β =0.457, p < 0.001; Anterior tibialis muscle: β = 0.220, p = 0.037) and inversely associated with muscle thickness (Vastus lateralis muscle:β = −0.973, p = 0.031; Anterior tibialis muscle: β = −4.551, p = 0.004) in the frailty stage. Together, FFP was closely related to muscle thickness and quality, especially vastus lateralis muscle. Moreover, Muscle quality has deteriorated in the prefrailty stage, which is earlier than muscle thickness.
The Dynamics of the Antimicrobial Resistance Mobilome of Salmonella enterica and Related Enteric Bacteria
Authors: Algarni Suad , Ricke Steven C. , Foley Steven L. , Han Jing
Published: March 2022

The foodborne pathogen Salmonella enterica is considered a global public health risk. Salmonella enterica isolates can develop resistance to several antimicrobial drugs due to the rapid spread of antimicrobial resistance (AMR) genes, thus increasing the impact on hospitalization and treatment costs, as well as the healthcare system. Mobile genetic elements (MGEs) play key roles in the dissemination of AMR genes in S. enterica isolates. Multiple phenotypic and molecular techniques have been utilized to better understand the biology and epidemiology of plasmids including DNA sequence analyses, whole genome sequencing (WGS), incompatibility typing, and conjugation studies of plasmids from S. enterica and related species. Focusing on the dynamics of AMR genes is critical for identification and verification of emerging multidrug resistance. The aim of this review is to highlight the updated knowledge of AMR genes in the mobilome of Salmonella and related enteric bacteria. The mobilome is a term defined as all MGEs, including plasmids, transposons, insertion sequences (ISs), gene cassettes, integrons, and resistance islands, that contribute to the potential spread of genes in an organism, including S. enterica isolates and related species, which are the focus of this review.
The Integrated Study on the Chemical Profiling to Explore the Constituents and Mechanism of Traditional Chinese Medicine Preparation Huatuo Jiuxin Pills Based on UPLC-Q-TOF/MSE and Network Pharmacology
Authors: Zhu Yulong , Zhu Yaqin , Tao Shuyue , Liang Wanhui , Zhang Jing , Zhang Yunjing , Xuan Zihua , Xu Jingjing , Peng Can , Wu Huan , Wu Deling
Published: March 2022

Huatuo Jiuxin Pills (HJP), a traditional Chinese medicine (TCM) preparation, has been widely used to treat Cardiovascular Diseases (CVDs) for more than 20 years. However, there were still gaps in the study of chemical components and potential pharmacological effects in the HJP. In this study, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MSE) combined with network pharmacology was used to comprehensively explore the chemical components in HJP and explore its potential active compounds and the mechanism for the treatment of CVDs. A total of 117 compounds, mainly including saponins, cholic acids, and bufadienolides, were rapidly identified and characterized. Simultaneously, the fragmentation mode and characteristic ion analysis of different types of representative compounds were carried out. Network pharmacology results showed that the more important active ingredients mainly include 5β‐hydroxybufotalin, 19 oxo‐cinobufagin, bufarenogin, etc. While, the main targets were PIK3CA, MAPK1, VEGFA and so on. Importantly, HJP has therapeutic effects on CVDs by acting on endocrine resistance, PI3K-Akt signaling pathway, HIF-1 signaling pathway, etc. In addition, molecular docking results showed that the core active ingredients with higher degrees in HJP have a strong affinity with the core targets of CVDs. The current work fills the gap in the chemical substance basis of HJP, and also facilitates a better understanding of the effective components, therapeutic targets, and signaling pathways of HJP in the treatment of CVDs.
Effects of the FNDC5/Irisin on Elderly Dementia and Cognitive Impairment
Authors: Peng Jin , Wu Jinhui
Published: March 2022

Population aging is an inevitable problem nowadays, and the elderly are going through a lot of geriatric symptoms, especially cognitive impairment. Irisin, an exercise-stimulating cleaved product from transmembrane fibronectin type III domain-containing protein 5 (FNDC5), has been linked with favorable effects on many metabolic diseases. Recently, mounting studies also highlighted the neuroprotective effects of irisin on dementia. The current evidence remains uncertain, and few clinical trials have been undertaken to limit its clinical practice. Therefore, we provided an overview of current scientific knowledge focusing on the preventive mechanisms of irisin on senile cognitive decline and dementia, in terms of the possible connections between irisin and neurogenesis, neuroinflammation, oxidative stress, and dementia-related diseases. This study summarized the recent advances and ongoing studies, aiming to provide a better scope into the effectiveness of irisin on dementia progression, as well as a mediator of muscle brain cross talk to provide theoretical support for exercise therapy for patients with dementia. Whether irisin is a diagnostic or prognostic factor for dementia needs more researches.
A Neuroanatomy of Positive Affect Display – Subcortical Fiber Pathways Relevant for Initiation and Modulation of Smiling and Laughing
Authors: Coenen Volker A. , Sajonz Bastian E. A. , Hurwitz Trevor A. , Böck Marlies , Hosp Jonas A. , Reinacher Peter C. , Urbach Horst , Blazhenets Ganna , Meyer Philipp T. , Reisert Marco
Published: March 2022

Background

We here report two cases of stimulation induced pathological laughter (PL) under thalamic deep brain stimulation (DBS) for essential tremor and interpret the effects based on a modified neuroanatomy of positive affect display (PAD).

Objective/Hypothesis

The hitherto existing neuroanatomy of PAD can be augmented with recently described parts of the motor medial forebrain bundle (motorMFB). We speculate that a co-stimulation of parts of this fiber structure might lead to a non-volitional modulation of PAD resulting in PL.

Methods

We describe the clinical and individual imaging workup and combine the interpretation with normative diffusion tensor imaging (DTI)-tractography descriptions of motor connections of the ventral tegmental area (VTA) (n = 200 subjects, HCP cohort), [[18F] fluorodeoxyglucose (18FDG)] positron emission tomography (PET), and volume of activated tissue simulations. We integrate these results with literature concerning PAD and the neuroanatomy of smiling and laughing.

Results

DBS electrodes bilaterally co-localized with the MB-pathway (“limiter pathway”). The FDG PET activation pattern allowed to explain pathological PAD. A conceptual revised neuroanatomy of PAD is described.

Conclusion

Eliciting pathological PAD through chronic thalamic DBS is a new finding and has previously not been reported. PAD is evolution driven, hard wired to the brain and realized over previously described branches of the motorMFB. A major relay region is the VTA/mammillary body complex. PAD physiologically undergoes conscious modulation mainly via the MB branch of the motorMFB (limiter). This limiter in our cases is bilaterally disturbed through DBS. The here described anatomy adds to a previously described framework of neuroanatomy of laughter and humor.
A Distributed Multi-Agent Formation Control Method Based on Deep Q Learning
Authors: Xie Nianhao , Hu Yunpeng , Chen Lei
Published: March 2022

Distributed control method plays an important role in the formation of a multi-agent system (MAS), which is the prerequisite for an MAS to complete its missions. However, the lack of considering the collision risk between agents makes many distributed formation control methods lose practicability. In this article, a distributed formation control method that takes collision avoidance into account is proposed. At first, the MAS formation control problem can be divided into pair-wise unit formation problems where each agent moves to the expected position and only needs to avoid one obstacle. Then, a deep Q network (DQN) is applied to model the agent's unit controller for this pair-wise unit formation. The DQN controller is trained by using reshaped reward function and prioritized experience replay. The agents in MAS formation share the same unit DQN controller but get different commands due to various observations. Finally, through the min-max fusion of value functions of the DQN controller, the agent can always respond to the most dangerous avoidance. In this way, we get an easy-to-train multi-agent collision avoidance formation control method. In the end, unit formation simulation and multi-agent formation simulation results are presented to verify our method.
Efficacy of Disease Modifying Therapies in Progressive MS and How Immune Senescence May Explain Their Failure
Authors: Manouchehri Navid , Salinas Victor H. , Rabi Yeganeh Negar , Pitt David , Hussain Rehana Z. , Stuve Olaf
Published: March 2022

The advent of disease modifying therapies (DMT) in the past two decades has been the cornerstone of successful clinical management of multiple sclerosis (MS). Despite the great strides made in reducing the relapse frequency and occurrence of new signal changes on neuroimaging in patients with relapsing remitting MS (RRMS) by approved DMT, it has been challenging to demonstrate their effectiveness in non-active secondary progressive MS (SPMS) and primary progressive MS (PPMS) disease phenotypes. The dichotomy of DMT effectiveness between RRMS and progressive MS informs on distinct pathogeneses of the different MS phenotypes. Conversely, factors that render patients with progressive MS resistant to therapy are not understood. Thus far, age has emerged as the main correlate of the transition from RRMS to SPMS. Whether it is aging and age-related factors or the underlying immune senescence that qualitatively alter immune responses as the disease transitions to SPMS, that diminish DMT effectiveness, or both, is currently not known. Here, we will discuss the role of immune senescence on different arms of the immune system, and how it may explain relative DMT resistance.
Association Between Riboflavin Intake and Telomere Length: A Cross-Sectional Study From National Health and Nutrition Examination Survey 1999–2002
Authors: Chen Weihua , Shi Shanshan , Jiang Yizhou , Chen Liling , Liao Ying , Chen Kaihong , Huang Kun
Published: March 2022

Background

Dietary habits and dietary intake affect telomere length, a reliable marker of biological aging and a predictor of chronic disease. Riboflavin (RF) is known as a water-soluble antioxidant vitamin, but its role in telomere length maintenance has yet to be elucidated.

Objective

The purpose of this study was to examine the relationship between dietary RF intake and telomere length in a nationally representative sample of adults.

Methods

Using the NHANES (1999–2002), telomere data of 4,298 participants aged ≥45 years were analyzed in a cross-sectional manner. Leukocyte telomere length was measured using the quantitative real-time polymerase chain reaction (qPCR). Dietary RF intake was assessed by a trained interviewer using 24-h dietary recall method. Generalized linear regressions were performed to evaluate the association between dietary RF intake and telomere length. Subgroup analyses were performed to further explore this relationship in sex and body mass index (BMI) subgroups.

Results

Among the 3,788 participants included, the average telomere length was longer in females (P = 0.014), while they had a lower average RF intake compared to males (P < 0.001). There was a weak positive correlation between RF intake and telomere length both when unadjusted (β = 0.011; P = 0.037) and adjusted for age, sex, and ethnicity (β = 0.013; P = 0.033). Subgroup analyses showed a positive association between RF intake and the telomere length in female after adjusting for confounding factors (β = 0.029; P = 0.046). In the female subgroup, there were significant positive relationships between telomere length and RF intake in the obese group (β = 0.086, P = 0.022).

Conclusion

Increased dietary RF intake was significantly associated with longer telomere length in middle-aged and older American females, especially in low RF intake obese female.
A Novel Defined Pyroptosis-Related Gene Signature for Predicting Prognosis and Treatment of Glioma
Authors: Yang Zhihao , Chen Zhigang , Wang Yu , Wang Zhiwei , Zhang Deran , Yue Xiaoyu , Zheng Yinfei , Li Lianxin , Bian Erbao , Zhao Bing
Published: March 2022

Pyroptosis, a form of programmed cell death, that plays a significant role in the occurrence and progression of tumors, has been frequently investigated recently. However, the prognostic significance and therapeutic value of pyroptosis in glioma remain undetermined. In this research, we revealed the relationship of pyroptosis-related genes to glioma by analyzing whole transcriptome data from The Cancer Genome Atlas (TCGA) dataset serving as the training set and the Chinese Glioma Genome Atlas (CGGA) dataset serving as the validation set. We identified two subgroups of glioma patients with disparate prognostic and clinical features by performing consensus clustering analysis on nineteen pyroptosis-related genes that were differentially expressed between glioma and normal brain tissues. We further derived a risk signature, using eleven pyroptosis-related genes, that was demonstrated to be an independent prognostic factor for glioma. Furthermore, we used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) to implement functional analysis of our gene set, and the results were closely related to immune and inflammatory responses in accordance with the characteristics of pyroptosis. Moreover, Gene Set Enrichment Analysis (GSEA) results showed that that the high-risk group exhibited enriched characteristics of malignant tumors in accordance with its poor prognosis. Next, we analyzed different immune cell infiltration between the two risk groups using ssGSEA. Finally, CASP1 was identified as a core gene, so we subsequently selected an inhibitor targeting CASP1 and simulated molecular docking. In addition, the inhibitory effect of belnacasan on glioma was verified at the cellular level. In conclusion, pyroptosis-related genes are of great significance for performing prognostic stratification and developing treatment strategies for glioma.
New Insights Into a Classification-Based Microvascular Invasion Prediction Model in Hepatocellular Carcinoma: A Multicenter Study
Authors: Xu Wei , Wang Yonggang , Yang Zhanwei , Li Jingdong , Li Ruineng , Liu Fei
Published: March 2022

Background and Aims

Most microvascular invasion (MVI)-predicting models have not considered MVI classification, and thus do not reflect true MVI effects on prognosis of patients with hepatocellular carcinoma (HCC). We aimed to develop a novel MVI-predicting model focused on MVI classification, hoping to provide useful information for clinical treatment strategy decision-making.

Methods

A retrospective study was conducted with data from two Chinese medical centers for 800 consecutive patients with HCC (derivation cohort) and 250 matched patients (external validation cohort). MVI-associated variables were identified by ordinal logistic regression. Predictive models were constructed based on multivariate analysis results and validated internally and externally. The models’ discriminative ability and calibration ability were examined.

Results

Four factors associated independently with MVI: tumor diameter, tumor number, serum lactate dehydrogenase (LDH) ≥ 176.58 U/L, and γ-glutamyl transpeptidase (γ-GGT). Area under the curve (AUC)s for our M2, M1, and M0 nomograms were 0.864, 0.648, and 0.782. Internal validation of all three models was confirmed with AUC analyses in D-sets (development datasets) and V-sets (validation datasets) and C-indices for each cohort. GiViTI calibration belt plots and Hosmer-Lemeshow (HL) chi-squared calibration values demonstrated good consistency between observed frequencies and predicted probabilities for the M2 and M0 nomograms. Although the M1 nomogram was well calibrated, its discrimination was poor.

Conclusion

We developed and validated MVI prediction models in patients with HCC that differentiate MVI classification and may provide useful guidance for treatment planning.
Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5
Authors: Liang Shiwei , Zhu Chuxu , Suo Caixia , Wei Haoran , Yu Yingxuan , Gu Xuemei , Chen Liang , Yuan Mengqiu , Shen Shengqi , Li Shiting , Sun Linchong , Gao Ping
Published: March 2022

Staphylococcal nuclease domain-containing protein 1 (SND1) is an evolutionarily conserved multifunctional protein that functions mainly in the nucleus and cytoplasm. However, whether SND1 regulates cellular activity through mitochondrial-related functions remains unclear. Herein, we demonstrate that SND1 is localized to mitochondria to promote phosphoglycerate mutase 5 (PGAM5)-mediated mitophagy. We find that SND1 is present in mitochondria based on mass spectrometry data and verified this phenomenon in different liver cancer cell types by performing organelle subcellular isolation. Specifically, The N-terminal amino acids 1-63 of SND1 serve as a mitochondrial targeting sequence (MTS), and the translocase of outer membrane 70 (TOM 70) promotes the import of SND1 into mitochondria. By immunoprecipitation-mass spectrometry (IP-MS), we find that SND1 interacts with PGAM5 in mitochondria and is crucial for the binding of PGAM5 to dynamin-related protein 1 (DRP1). Importantly, we demonstrate that PGAM5 and SND1-MTS are required for SND1-mediated mitophagy under FCCP and glucose deprivation treatment as well as for SND1-mediated cell proliferation and tumor growth both in vitro and in vivo. Aberrant expression of SND1 and PGAM5 predicts poor outcomes in hepatocellular carcinoma (HCC) patients. Taken together, these findings establish a previously unappreciated role of SND1 and the association of mitochondrion-localized SND1 with PGAM5 in mitophagy and tumor progression.
Rapidly Progressive Classic Adamantinoma of the Spine: Case Report and Literature Review
Authors: Lou Yan , Li Ying , Xu Lei , Jing Xiaoping , Chen Su , Yang Minglei , Jiang Hongyu , Zhao Chenglong , Wei Haifeng , Xiao Jianru
Published: March 2022

Adamantinoma is a locally aggressive or malignant tumor, accounting for <0.5% of all primary bone tumors. The tumor usually progresses slowly, with a relatively promising prognosis. Primary or metastatic spinal adamantinoma of bone are rarer. Only four cases have been documented till date. We present two cases of aggressive spinal adamantinoma whose microphotography and radiographic appearance were unusual, with extensive involvement of multiple segments and rapid progression. Case 1 was a 36-year-old woman, presenting with back pain, progressive numbness and motor weakness, who was diagnosed with metastatic adamantinoma in the T2, T7, L2, and L4. She underwent spondylectomy three times to resect these lesions, respectively. Case 2 was a 68-year-old male with complaints of severe left back pain. MRI revealed destructive changes in T1-T4. He underwent posterior decompression (T1-T3), partial vertebrectomy (T2), fixation and fusion (C5-C7, T4-T6). The pathology of two patients was metastatic spinal adamantinoma, whose primary lesions were from tibia and femoral adamantinoma, respectively. Rapid squamous progression was observed in specimens of T2 and T7 lesions of Case 1 in two months. Twenty-five months after surgery, Case 1 developed paralysis, but she refused to receive further examination and treatment. Two months after surgery, Case 2 presented with an upper back pain again. The MRI revealed an increase in osseous destruction and paravertebral mass size. He was administered radiotherapy, with his upper back pain partially relieved. The biological behavior of classic adamantinoma is highly unpredictable, often exhibiting more aggressive behavior upon recurrence or metastasis. The pathological diagnosis of adamantinoma should be confirmed by preoperative biopsy. En bloc resection with a wide margin is the preferred treatment for primary spinal adamantinoma. Radiation therapy can partially relieve the pain.
BRAF-Mutated Non-Small Cell Lung Cancer: Current Treatment Status and Future Perspective
Authors: Yan Ningning , Guo Sanxing , Zhang Huixian , Zhang Ziheng , Shen Shujing , Li Xingya
Published: March 2022

V-Raf murine sarcoma viral oncogene homolog B (BRAF) kinase, which was encoded by BRAF gene, plays critical roles in cell signaling, growth, and survival. Mutations in BRAF gene will lead to cancer development and progression. In non-small cell lung cancer (NSCLC), BRAF mutations commonly occur in never-smokers, women, and aggressive histological types and accounts for 1%–2% of adenocarcinoma. Traditional chemotherapy presents limited efficacy in BRAF-mutated NSCLC patients. However, the advent of targeted therapy and immune checkpoint inhibitors (ICIs) have greatly altered the treatment pattern of NSCLC. However, ICI monotherapy presents limited activity in BRAF-mutated patients. Hence, the current standard treatment of choice for advanced NSCLC with BRAF mutations are BRAF-targeted therapy. However, intrinsic or extrinsic mechanisms of resistance to BRAF-directed tyrosine kinase inhibitors (TKIs) can emerge in patients. Hence, there are still some problems facing us regarding BRAF-mutated NSCLC. In this review, we summarized the BRAF mutation types, the diagnostic challenges that BRAF mutations present, the strategies to treatment for BRAF-mutated NSCLC, and resistance mechanisms of BRAF-targeted therapy.
The Differential Expression of CD47 may be Related to the Pathogenesis From Myelodysplastic Syndromes to Acute Myeloid Leukemia
Authors: Yan Xiao , Lai Binbin , Zhou Xuyan , Yang Shujun , Ge Qunfang , Zhou Miao , Shi Cong , Xu Zhijuan , Ouyang Guifang
Published: March 2022

Myelodysplastic syndrome (MDS) can lead to the development of peripheral blood cytopenia and abnormal cell morphology. MDS has the potential to evolve into AML and can lead to reduced survival. CD47, a member of the immunoglobulin family, is one molecule that is overexpressed in a variety of cancer cells and is associated with clinical features and poor prognosis in a variety of malignancies. In this study, we analyzed the expression and function of CD47 in MDS and AML, and further analyzed its role in other tumors. Our analysis revealed significantly low CD47 expression in MDS and significantly high expression in AML. Further analysis of the function or pathway of CD47 from different perspectives identified a relationship to the immune response, cell growth, and other related functions or pathways. The relationship between CD47 and other tumors was analyzed from four aspects: DNA methyltransferase, TMB, MSI, and tumor cell stemness. Changes in gene expression levels have a known association with aberrant DNA methylation, and this methylation is the main mechanism of tumor suppressor gene silencing and clonal variation during the evolution of MDS to AML. Taken together, our findings support the hypothesis that the differential expression of CD47 might be related to the transformation of MDS to AML.
A Patient With Stage III Locally Advanced Pancreatic Adenocarcinoma Treated With Intra-Arterial Infusion FOLFIRINOX: Impressive Tumoral Response and Death due to Legionella pneumophila Infection: A Unique Case Report
Authors: Ranieri Girolamo , Sablone Sara , Fazio Vito , De Ceglia Dario , Porcelli Mariangela , Molinari Pasquale , Fucci Livia , Laface Carmelo , Gadaleta Cosmo Damiano
Published: March 2022

Patients affected by pancreatic ductal adenocarcinoma (PDAC) have very poor prognosis, whereby at a follow-up of 5 years, the mortality rate is very similar to the incidence rate. Globally, around 10% of patients are amenable to radical surgery at the time of diagnosis, which represents the only chance of cure or long-term survival for these patients. Almost 40% of patients with PDAC show locally advanced pancreatic cancer (LAPC). LAPC is not a metastatic disease, although it is not amenable to radical surgery. For these patients, systemic induction chemotherapy with intravenous FOLFIRINOX (5-fluorouracil, folic acid, irinotecan, oxaliplatin) regimen is administered, with the aim of conversion to surgery, although the conversion rate remains low, at approximately 10% to 15%. Pancreatic arterial chemotherapy has been explored to overcome the intrinsic tumor pancreatic resistance to systemic chemotherapy, where an intra-arterial port-a-cath is placed by means of interventional oncology techniques under angiographic guidance in the operating theater. Here, we treated a patient with an intra-arterially modified FOLFIRINOX regimen. Three courses were administered, and the patient experienced no adverse events. At the end of the third course, the patient rapidly developed lung failure due to nosocomial Legionella pneumophila infection, despite the impressive pathological tumor response shown in the autopsy report. This is a first and unique report that demonstrates that pancreatic intra-arterial FOLFIRINOX can be safe and efficacious. We believe that this preliminary result will be confirmed in the next patients to be enrolled and that it provides a glimmer of hope for patients with this lethal disease.