bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-L1 Improves Motor Function and Alleviates Neuropathic Pain in Male Mice After Spinal Cord Injury by Inhibiting MAPK Pathway
Authors: Kong Fanqi , Sun Kaiqiang , Zhu Jian , Li Fudong , Lin Feng , Sun Xiaofei , Luo Xi , Ren Changzhen , Lu Lantao , Zhao ShuJie , Sun Jingchuan , Wang Yuan , Shi Jiangang
Published: April 2021

Background

Traumatic spinal cord injury (SCI) causes severe motor dysfunction and persistent central neuropathic pain (Nep), which has not yet been effectively cured. Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and contributes to the immune-suppressive in tumor microenvironment. However, the role of PD-L1 in regulating inflammatory response and Nep after SCI remains unclear. A growing amount of researches have begun to investigate the effect of PD-L1 on macrophages and microglia in recent years. Considering the pivotal role of macrophages/microglia in the inflammatory response after SCI, we proposed the hypothesis that PD-L1 improved the recovery of locomotor and sensory functions after SCI through regulating macrophages and microglia.

Methods

The mice SCI model was established to determine the changes in expression patterns of PD-L1. Meanwhile, we constructed PD-L1 knockout mice to observe differences in functional recovery and phenotypes of macrophages/microglia post-SCI.

Results

In present study, PD-L1 was significantly upregulated after SCI and highly expressed on macrophages/microglia at the injury epicenter. PD-L1 knockout (KO) mice showed worse locomotor recovery and more serious pathological pain compared with wild-type (WT) mice. Furthermore, deletion of PD-L1 significantly increased the polarization of M1-like macrophages/microglia. Mechanistic analysis revealed that PD-L1 may improve functional outcomes following SCI by inhibiting phosphorylation of p38 and ERK1/2.

Conclusions

Our observations implicate the involvement of PD-L1 in recovery of SCI and provide a new treatment strategy for the prevention and treatment of this traumatic condition.
Proteomic Analysis of the Parasitic Cnidarian Ceratonova shasta (Cnidaria: Myxozoa) Reveals Diverse Roles of Actin in Motility and Spore Formation
Authors: Brekhman Vera , Ofek-Lalzar Maya , Atkinson Stephen D. , Alama-Bermejo Gema , Maor-Landaw Keren , Malik Assaf , Bartholomew Jerri L. , Lotan Tamar
Published: April 2021

Myxozoans are widely distributed aquatic obligate endoparasites that were recently recognized as belonging within the phylum Cnidaria. They have complex life cycles with waterborne transmission stages: resistant, infectious spores that are unique to myxozoans. However, little is known about the processes that give rise to these transmission stages. To understand the molecular underpinnings of spore formation, we conducted proteomics on Ceratonova shasta, a highly pathogenic myxozoan that causes severe mortalities in wild and hatchery-reared salmonid fishes. We compared proteomic profiles between developmental stages from inside the fish host, and the mature myxospore, which is released into the water where it drifts passively, ready to infect the next host. We found that C. shasta contains 2,123 proteins; representing the first proteomic catalog of a myxozoan myxospore. Analysis of proteins differentially expressed between developing and mature spore stages uncovered processes that are active during spore formation. Our data highlight dynamic changes in the actin cytoskeleton, which provides myxozoan developmental stages with mobility through lamellipodia and filopodia, whereas in the mature myxospore the actin network supports F-actin stabilization that reinforces the transmission stage. These findings provide molecular insight into the myxozoan life cycle stages and, particularly, into the process of sporogenesis.
Snow Depth and Air Temperature Seasonality on Sea Ice Derived From Snow Buoy Measurements
Authors: Nicolaus Marcel , Hoppmann Mario , Arndt Stefanie , Hendricks Stefan , Katlein Christian , Nicolaus Anja , Rossmann Leonard , Schiller Martin , Schwegmann Sandra
Published: April 2021

Snow depth on sea ice is an essential state variable of the polar climate system and yet one of the least known and most difficult to characterize parameters of the Arctic and Antarctic sea ice systems. Here, we present a new type of autonomous platform to measure snow depth, air temperature, and barometric pressure on drifting Arctic and Antarctic sea ice. “Snow Buoys” are designed to withstand the harshest environmental conditions and to deliver high and consistent data quality with minimal impact on the surface. Our current dataset consists of 79 time series (47 Arctic, 32 Antarctic) since 2013, many of which cover entire seasonal cycles and with individual observation periods of up to 3 years. In addition to a detailed introduction of the platform itself, we describe the processing of the publicly available (near real time) data and discuss limitations. First scientific results reveal characteristic regional differences in the annual cycle of snow depth: in the Weddell Sea, annual net snow accumulation ranged from 0.2 to 0.9 m (mean 0.34 m) with some regions accumulating snow in all months. On Arctic sea ice, the seasonal cycle was more pronounced, showing accumulation from synoptic events mostly between August and April and maxima in autumn. Strongest ablation was observed in June and July, and consistently the entire snow cover melted during summer. Arctic air temperature measurements revealed several above-freezing temperature events in winter that likely impacted snow stratigraphy and thus preconditioned the subsequent spring snow cover. The ongoing Snow Buoy program will be the basis of many future studies and is expected to significantly advance our understanding of snow on sea ice, also providing invaluable in situ validation data for numerical simulations and remote sensing techniques.
Sensor System and Observer Algorithm Co-Design For Modern Internal Combustion Engine Air Management Based on H2 Optimization
Authors: Zhang Xu , Shaver Gregory M. , Lana Carlos A. , Gosala Dheeraj , Le Dat , Langenderfer David
Published: April 2021

This paper outlines a novel sensor selection and observer design algorithm for linear time-invariant systems with both process and measurement noise based on H2 optimization to optimize the tradeoff between the observer error and the number of required sensors. The optimization problem is relaxed to a sequence of convex optimization problems that minimize the cost function consisting of the H2 norm of the observer error and the weighted l1 norm of the observer gain. An LMI formulation allows for efficient solution via semi-definite programing. The approach is applied here, for the first time, to a turbo-charged spark-ignited engine using exhaust gas circulation to determine the optimal sensor sets for real-time intake manifold burnt gas mass fraction estimation. Simulation with the candidate estimator embedded in a high fidelity engine GT-Power model demonstrates that the optimal sensor sets selected using this algorithm have the best H2 estimation performance. Sensor redundancy is also analyzed based on the algorithm results. This algorithm is applicable for any type of modern internal combustion engines to reduce system design time and experimental efforts typically required for selecting optimal sensor sets.
Phytotoxic Metabolites Produce by Fusarium oxysporum f. sp. cubense Race 2
Authors: Portal González N. , Soler A. , Ribadeneira C. , Solano J. , Portieles Roxana , Herrera Isla L. , Companioni B. , Borras-Hidalgo Orlando , Santos Bermudez Ramon
Published: April 2021

Banana is a major tropical fruit crop but banana production worldwide is seriously threatened due to Fusarium wilt. Fusarium oxysporum f. sp. cubense (Foc), the causal agent of Fusarium wilt of banana (also referred as Panama disease) is an asexual, soil inhabiting facultative parasite. Foc isolates can be classified into three races that are not defined genetically, but for their pathogenicity to different banana cultivars. Despite mycotoxins being some of the best studied virulence factors of phytopathogenic fungi and these have been useful for the prediction of Foc virulence on banana plants, toxins produced by Foc race 2 strains have not been previously identified. The aim of this contribution was to identify the phytotoxic metabolites closely related to banana wilt caused by a Foc race 2 strain. We used an in vitro bioassay on detached banana leaves to evaluate the specificity of the microbial culture filtrates before a partial purification and further identification of Foc race 2 phytotoxins. A 29-day-old host-specific culture filtrate was obtained but specificity of culture filtrate was unrecovered after partial purification. The non-specific phytotoxins were characterized as fusaric acid, beauvericin, and enniatin A. Whereas some, if not all, of these phytotoxins are important virulence factors, a proteinaceous fraction from the specific 29-day-old culture filtrate protected the leaves of the resistant banana cultivar from damage caused by such phytotoxic metabolites.
Lipoarabinomannan as a Point-of-Care Assay for Diagnosis of Tuberculosis: How Far Are We to Use It?
Authors: Flores Julio , Cancino Juan Carlos , Chavez-Galan Leslie
Published: April 2021

Tuberculosis (TB) is still a severe public health problem; the current diagnostic tests have limitations that delay treatment onset. Lipoarabinomannan (LAM) is a glycolipid that is a component of the cell wall of the bacillus Mycobacterium tuberculosis, the etiologic agent of TB. This glycolipid is excreted as a soluble form in urine. The World Health Organization has established that the design of new TB diagnostic methods is one of the priorities within the EndTB Strategy. LAM has been suggested as a biomarker to develop diagnostic tests based on its identification in urine, and it is one of the most prominent candidates to develop point-of-care diagnostic test because urine samples can be easily collected. Moreover, LAM can regulate the immune response in the host and can be found in the serum of TB patients, where it probably affects a wide variety of host cell populations, consequently influencing the quality of both innate and adaptive immune responses during TB infection. Here, we revised the evidence that supports that LAM could be used as a tool for the development of new point-of-care tests for TB diagnosis, and we discussed the mechanisms that could contribute to the low sensitivity of diagnostic testing.
Biological and Genetic Characterization of Pod Pepper Vein Yellows Virus-Associated RNA From Capsicum frutescens in Wenshan, China
Authors: Peng Jiejun , Bu Shan , Yin Yueyan , Hua Mengying , Zhao Kuangjie , Lu Yuwen , Zheng Hongying , Wan Qionglian , Zhang Songbai , Chen Hairu , Liu Yong , Chen Jianping , Mo Xiaohan , Yan Fei
Published: April 2021

Tombusvirus-like associated RNAs (tlaRNAs) are positive-sense single-stranded RNAs found in plants co-infected with some viruses of the genus Polerovirus. Pod pepper vein yellows virus (PoPeVYV) was recently reported as a new recombinant polerovirus causing interveinal yellowing, stunting, and leaf rolling in Capsicum frutescens plants at Wenshan city, Yunnan province, China. The complete genome sequence of its associated RNA has now been determined by next-generation sequencing and reverse transcription (RT) polymerase chain reaction (PCR). PoPeVYV-associated RNA (PoPeVYVaRNA) (GenBank Accession No. MW323470) has 2970 nucleotides and is closely related to other group II tlaRNAs, particularly tobacco bushy top disease-associated RNA (TBTDaRNA, GenBank Accession No. EF529625). In infection experiments on Nicotiana benthamiana and C. frutescens plants, synergism between PoPeVYVaRNA and PoPeVYV was demonstrated, leading to severe interveinal yellowing of leaves and stunting of plants. The results provide further information on the genetic and biological properties of the various agents associated with pepper vein yellows disease (PeVYD).
Suppression of Escherichia coli Growth Dynamics via RNAs Secreted by Competing Bacteria
Authors: Markelova Natalia , Glazunova Olga , Alikina Olga , Panyukov Valeriy , Shavkunov Konstantin , Ozoline Olga
Published: April 2021

With the discovery of secreted RNAs, it has become apparent that the biological role of regulatory oligonucleotides likely goes beyond the borders of individual cells. However, the mechanisms of their action are still comprehended only in general terms and mainly for eukaryotic microRNAs, which can interfere with mRNAs even in distant recipient cells. It has recently become clear that bacterial cells lacking interference systems can also respond to eukaryotic microRNAs that have targets in their genomes. However, the question of whether bacteria can perceive information transmitted by oligonucleotides secreted by other prokaryotes remained open. Here we evaluated the fraction of short RNAs secreted by Escherichia coli during individual and mixed growth with Rhodospirillum rubrum or Prevotella copri, and found that in the presence of other bacteria E. coli tends to excrete oligonucleotides homologous to alien genomes. Based on this observation, we selected four RNAs secreted by either R. rubrum or P. copri, together with one E. coli-specific oligonucleotide. Both fragments of R. rubrum 23S-RNA suppressed the growth of E. coli. Of the two fragments secreted by P. copri, one abolished the stimulatory effect of E. coli RNA derived from the 3′-UTR of ProA mRNA, while the other inhibited bacterial growth only in the double-stranded state with complementary RNA. The ability of two RNAs secreted by cohabiting bacteria to enter E. coli cells was demonstrated using confocal microscopy. Since selected E. coli-specific RNA also affected the growth of this bacterium, we conclude that bacterial RNAs can participate in inter- and intraspecies signaling.
Chronic Migraine and Medication Overuse Headache Worsening After OnabotulinumtoxinA Withdrawn Due to the Severe Acute Respiratory Syndrome-Coronavirus-2 Pandemic
Authors: Baraldi Carlo , Ornello Raffaele , Favoni Valentina , Sacco Simona , Caponnetto Valeria , Pierangeli Giulia , Pani Luca , Cevoli Sabina , Guerzoni Simona
Published: April 2021

Introduction: OnabotulinumtoxinA (BT-A) is a preventive treatment for chronic migraine (CM), which needs to be administered regularly by a trained clinician every 3 months. The spread of the severe acute respiratory syndrome coronavirus-2 pandemic has forced many patients to momentarily stop the scheduled BT-A injections. The goal of this study was to explore whether those patients experienced a worsening of their CM and, if any, the clinical predictors of migraine worsening after BT-A withdrawal.

Methods: This was a retrospective, multicenter study. Patients' clinical data were obtained from their clinical documentation stored at each center. In particular, the following variables were collected: the mean number of headache days in the last month (NHD), the average number of painkillers taken in the last month (AC), the average number of days in which patients took, at least, one painkiller in the last month (NDM), the average intensity of migraine using the numeric rating scale (NRS) score in the last month, and the average score obtained at the six-item Headache Impact Test. The variables mentioned earlier were compared before and after BT-A withdrawal.

Results: After BT-A suspension, there was a significant increase in the NHD (P = 0.0313, Kruskal–Wallis rank test), AC (P = 0.0421, Kruskal–Wallis rank test), NDM (P = 0.0394, paired t-test), NRS score (P = 0.0069, Kruskal–Wallis rank test), and six-item Headache Impact Test score (P = 0.0372, Kruskal–Wallis rank test). Patients who were not assuming other preventive treatments other than BT-A displayed similar results. Patients who experienced a >30% worsening in NHD after BT-A was withdrawn displayed a longer CM history (P = 0.001, Kruskal–Wallis rank test), a longer MOH duration (P = 0.0017, Kruskal–Wallis rank test), a higher AC value at the baseline (P = 0.0149, Kruskal–Wallis rank test), a higher NDM (P = 0.0024, t-test), and a higher average value of the NRS score (P = 0.0073, Kruskal–Wallis rank test).

Conclusion: BT-A withdrawn during severe acute respiratory syndrome coronavirus-2 pandemic was associated with a general worsening in patients suffering from CM, hence the need to continue BT-A injection to avoid patients' worsening.
Sedentary Life and Reduced Mastication Impair Spatial Learning and Memory and Differentially Affect Dentate Gyrus Astrocyte Subtypes in the Aged Mice
Authors: Siqueira Mendes Fabíola de Carvalho Chaves de , Paixão Luisa Taynah Vasconcelos Barbosa , Diniz Daniel Guerreiro , Anthony Daniel Clive , Brites Dora , Diniz Cristovam Wanderley Picanço , Sosthenes Marcia Consentino Kronka
Published: April 2021

To explore the impact of reduced mastication and a sedentary lifestyle on spatial learning and memory in the aged mice, as well as on the morphology of astrocytes in the molecular layer of dentate gyrus (MolDG), different masticatory regimens were imposed. Control mice received a pellet-type hard diet, while the reduced masticatory activity group received a pellet diet followed by a powdered diet, and the masticatory rehabilitation group received a pellet diet, followed by powder diet and then a pellet again. To mimic sedentary or active lifestyles, mice were housed in an impoverished environment of standard cages or in an enriched environment. The Morris Water Maze (MWM) test showed that masticatory-deprived group, regardless of environment, was not able to learn and remember the hidden platform location, but masticatory rehabilitation combined with enriched environment recovered such disabilities. Microscopic three-dimensional reconstructions of 1,800 glial fibrillary acidic protein (GFAP)-immunolabeled astrocytes from the external third of the MolDG were generated using a stereological systematic and random sampling approach. Hierarchical cluster analysis allowed the characterization into two main groups of astrocytes with greater and lower morphological complexities, respectively, AST1 and AST2. When compared to compared to the hard diet group subjected to impoverished environment, deprived animals maintained in the same environment for 6 months showed remarkable shrinkage of astrocyte branches. However, the long-term environmental enrichment (18-month-old) applied to the deprived group reversed the shrinkage effect, with significant increase in the morphological complexity of AST1 and AST2, when in an impoverished or enriched environment. During housing under enriched environment, complexity of branches of AST1 and AST2 was reduced by the powder diet (pellet followed by powder regimes) in young but not in old mice, where it was reversed by pellet diet (pellet followed by powder and pellet regime again). The same was not true for mice housed under impoverished environment. Interestingly, we were unable to find any correlation between MWM data and astrocyte morphological changes. Our findings indicate that both young and aged mice subjected to environmental enrichment, and under normal or rehabilitated masticatory activity, preserve spatial learning and memory. Nonetheless, data suggest that an impoverished environment and reduced mastication synergize to aggravate age-related cognitive decline; however, the association with morphological diversity of AST1 and AST2 at the MolDG requires further investigation.
Stress and the Brain: An Emerging Role for Selenium
Authors: Torres Daniel J. , Alfulaij Naghum , Berry Marla J.
Published: April 2021

The stress response is an important tool in an organism’s ability to properly respond to adverse environmental conditions in order to survive. Intense acute or chronic elevation of glucocorticoids, a class of stress hormone, can have deleterious neurological effects, however, including memory impairments and emotional disturbances. In recent years, the protective role of the antioxidant micronutrient selenium against the negative impact of externally applied stress has begun to come to light. In this review, we will discuss the effects of stress on the brain, with a focus on glucocorticoid action in the hippocampus and cerebral cortex, and emerging evidence of an ability of selenium to normalize neurological function in the context of various stress and glucocorticoid exposure paradigms in rodent models.
Depletion of TrkB Receptors From Adult Serotonergic Neurons Increases Brain Serotonin Levels, Enhances Energy Metabolism and Impairs Learning and Memory
Authors: Sahu Madhusmita P. , Pazos-Boubeta Yago , Steinzeig Anna , Kaurinkoski Katja , Palmisano Michela , Borowecki Olgierd , Piepponen Timo Petteri , Castrén Eero
Published: April 2021

Neurotrophin brain-derived neurotrophic factor (BDNF) and neurotransmitter serotonin (5-HT) regulate each other and have been implicated in several neuronal mechanisms, including neuroplasticity. We have investigated the effects of BDNF on serotonergic neurons by deleting BDNF receptor TrkB from serotonergic neurons in the adult brain. The transgenic mice show increased 5-HT and Tph2 levels with abnormal behavioral phenotype. In spite of increased food intake, the transgenic mice are significantly leaner than their wildtype littermates, which may be due to increased metabolic activity. Consistent with increased 5-HT, the proliferation of hippocampal progenitors is significantly increased, however, long-term survival of newborn cells is unchanged. Our data indicates that BDNF-TrkB signaling regulates the functional phenotype of 5-HT neurons with long-term behavioral consequences.
A Metabolic Landscape for Maintaining Retina Integrity and Function
Authors: Viegas Filipe O. , Neuhauss Stephan C. F.
Published: April 2021

Neurons have high metabolic demands that are almost exclusively met by glucose supplied from the bloodstream. Glucose is utilized in complex metabolic interactions between neurons and glia cells, described by the astrocyte-neuron lactate shuttle (ANLS) hypothesis. The neural retina faces similar energy demands to the rest of the brain, with additional high anabolic needs to support continuous renewal of photoreceptor outer segments. This demand is met by a fascinating variation of the ANLS in which photoreceptors are the central part of a metabolic landscape, using glucose and supplying surrounding cells with metabolic intermediates. In this review we summarize recent evidence on how neurons, in particular photoreceptors, meet their energy and biosynthetic requirements by comprising a metabolic landscape of interdependent cells.
The Forward Model: A Unifying Theory for the Role of the Cerebellum in Motor Control and Sense of Agency
Authors: Welniarz Quentin , Worbe Yulia , Gallea Cecile
Published: April 2021

For more than two decades, there has been converging evidence for an essential role of the cerebellum in non-motor functions. The cerebellum is not only important in learning and sensorimotor processes, some growing evidences show its implication in conditional learning and reward, which allows building our expectations about behavioral outcomes. More recent work has demonstrated that the cerebellum is also required for the sense of agency, a cognitive process that allows recognizing an action as our own, suggesting that the cerebellum might serve as an interface between sensorimotor function and cognition. A unifying model that would explain the role of the cerebellum across these processes has not been fully established. Nonetheless, an important heritage was given by the field of motor control: the forward model theory. This theory stipulates that movements are controlled based on the constant interactions between our organism and its environment through feedforward and feedback loops. Feedforward loops predict what is going to happen, while feedback loops confront the prediction with what happened so that we can react accordingly. From an anatomical point of view, the cerebellum is at an ideal location at the interface between the motor and sensory systems, as it is connected to cerebral, striatal, and spinal entities via parallel loops, so that it can link sensory and motor systems with cognitive processes. Recent findings showing that the cerebellum participates in building the sense of agency as a predictive and comparator system will be reviewed together with past work on motor control within the context of the forward model theory.
Motility Profile of Captive-Bred Marmosets Revealed by a Long-Term In-Cage Monitoring System
Authors: Koizumi Masashi , Nogami Naotake , Owari Kensuke , Kawanobe Akiyo , Nakatani Terumi , Seki Kazuhiko
Published: April 2021

A quantitative evaluation of motility is crucial for studies employing experimental animals. Here, we describe the development of an in-cage motility monitoring method for new world monkeys using off-the-shelf components, and demonstrate its capability for long-term operation (e.g., a year). Based on this novel system, we characterized the motility of the common marmoset over different time scales (seconds, hours, days, and weeks). Monitoring of seven young animals belonging to two different age groups (sub-adult and young-adult) over a 231-day period revealed: (1) strictly diurnal activity (97.3% of movement during daytime), (2) short-cycle (∼20 s) transition in activity, and (3) bimodal diurnal activity including a “siesta” break. Additionally, while the mean duration of short-cycle activity, net daily activity, and diurnal activity changed over the course of development, 24-h periodicity remained constant. Finally, the method allowed for detection of progressive motility deterioration in a transgenic marmoset. Motility measurement offers a convenient way to characterize developmental and pathological changes in animals, as well as an economical and labor-free means for long-term evaluation in a wide range of basic and translational studies.
Ultrasound for Non-invasive Assessment and Monitoring of Quadriceps Muscle Thickness in Critically Ill Patients With Acute Kidney Injury
Authors: Sabatino Alice , Maggiore Umberto , Regolisti Giuseppe , Rossi Giovanni Maria , Di Mario Francesca , Gentile Micaela , Farina Maria Teresa , Fiaccadori Enrico
Published: April 2021

Background and aims: Critically ill patients with acute kidney injury (AKI) undergo major muscle wasting in the first few days of ICU stay. An important concern in this clinical setting is the lack of adequate tools for routine bedside evaluation of the skeletal muscle mass, both for the determination of nutritional status at admission, and for monitoring. In this regard, the present study aims to ascertain if ultrasound (US) is able to detect changes in quadriceps muscle thickness of critically ill patients with acute kidney injury (AKI) over short periods of time.

Methods: This is a prospective observational study with a follow-up at 5 days. All adult patients with AKI hospitalized at the Renal ICU of the Parma University Hospital over 12 months, with a hospital stay before ICU admission no longer than 72 h, and with a planned ICU stay of at least 5 days, were eligible for the study. An experienced investigator assessed quadriceps rectus femoris and vastus intermedius thickness (QRFT and QVIT) at baseline and after 5 days of ICU stay.

Results: We enrolled 30 patients with 74 ± 11 years of age and APACHE II score of 22 ± 5. Muscle thickness decreased by 15 ± 13% within the first 5 days of ICU stay (P < 0.001 for all sites as compared to ICU admission). Patients with more severe muscle loss had lower probability of being discharged home (OR: 0.04, 95%CI: 0.00–0.74; P = 0.031).

Conclusions: In critically ill patients with AKI, bedside muscle US identifies patients with accelerated muscle wasting.
Case Report: Pseudomeningeosis and Demyelinating Metastasis-Like Lesions From Checkpoint Inhibitor Therapy in Malignant Melanoma
Authors: Schmidt Teresa , Kebir Sied , Livingstone Elisabeth , Junker Andreas , Zülow Stefan , Lazaridis Lazaros , Oster Christoph , Chorti Eleftheria , Pierscianek Daniela , Pul Refik , Keyvani Kathy , Sure Ulrich , Stuschke Martin , Kleinschnitz Christoph , Scheffler Björn , Zimmer Lisa , Glas Martin
Published: April 2021

Immune checkpoint inhibitors (ICIs) have considerably expanded the effective treatment options for malignant melanoma. ICIs revert tumor-associated immunosuppression and potentiate T-cell mediated tumor clearance. Immune-related neurologic adverse events (irNAEs) manifest in the central (CNS) or peripheral nervous system (PNS) and most frequently present as encephalitis or myasthenia gravis respectively. We report on a 47-year old male patient with metastatic melanoma who developed signs of cerebellar disease five weeks after the start of ICI treatment (ipilimumab and nivolumab). Magnetic resonance imaging (MRI) of the brain and spine revealed multiple new contrast enhancements suggestive of parenchymal and leptomeningeal metastasis. Cerebral spinal fluid (CSF) evaluation showed a lymphomononuclear pleocytosis in the absence of tumor cells. Subsequent stereotactic brain biopsy confirmed demyelinating disease. High-dose corticosteroid treatment resulted in immediate improvement of the clinical symptoms. MRI scans and CSF re-evaluation were conducted six weeks later and showed a near-complete remission. The strong resemblance to neoplastic CNS dissemination and irNAEs is a particularly difficult diagnostic challenge. Treating physicians should be aware of irNAEs as those can be effectively treated with high-dose steroids.
TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia
Authors: Puzzolo Maria Cristina , Del Giudice Ilaria , Peragine Nadia , Mariglia Paola , De Propris Maria Stefania , Cappelli Luca Vincenzo , Trentin Livio , Reda Gianluigi , Cuneo Antonio , Molica Stefano , Piciocchi Alfonso , Arena Valentina , Mauro Francesca Romana , Guarini Anna , Foà Robin
Published: April 2021

Ibrutinib may revert the T-helper (Th)2 polarization observed in chronic lymphocytic leukemia (CLL) by targeting the IL-2-inducible kinase, that shows a significant homology with the Bruton tyrosine kinase. In the front-line GIMEMA LLC1114 trial (ibrutinib+rituximab for 6 months, followed by ibrutinib maintenance), we investigated the modulation of T-cell cytokine production in 208 peripheral blood paired samples from 71 CLL patients: 71 samples prior to treatment (Day 0, D0) and at day +14 (D14; n=50), at month +8 (M8; 30), +12 (M12; 25), +18 (M18; 22) and +24 (M24; 10) of treatment. We documented a progressive decrease of CD3+CD4+IL-4+ T cells (Th2), that was significant at M8 and at M12 (p=0.019, p=0.002), a relative increase in the CD3+CD4+IFNγ+ T cells (Th1) and a decrease of CD3+CD4+IL-17+ (Th17) cells that was maintained up to M18 (M8 vs D0 p=0.003, M12 vs D0 p=0.003, M18 vs D0 p=0.004) of ibrutinib treatment. The Th2/Th1 ratio significantly decreased already after 14 days of treatment and was maintained thereafter (D14 vs D0 p=0.037, M8 vs D0 p=0.001, M12 vs D0 p=0.005, M18 vs D0 p=0.002). The Th2/Th1 modulation over time was significant only among patients with unmutated IGHV. The Th2/Th1 ratio below a cut-off of 0.088 at M8 was associated with the achievement of a complete response (CR) (p=0.016). Ibrutinib may shape the CLL T-cell profile, limiting Th2 activation and inducing a shift in the Th2/Th1 ratio. The association between the Th2/Th1 ratio decrease and the CR achievement suggests the in vivo generation of a potential host anti-tumor immune activation induced by ibrutinib.
SQSTM1/p62 Promotes Cell Growth and Triggers Autophagy in Papillary Thyroid Cancer by Regulating the AKT/AMPK/mTOR Signaling Pathway
Authors: Yu Fangqin , Ma Runsheng , Liu Chenguang , Zhang Lele , Feng Kaixiang , Wang Meiqi , Yin Detao
Published: April 2021

Background

Thyroid cancer is one of the most common endocrine malignancies worldwide, and papillary thyroid cancer (PTC) is the most common pathologic type of thyroid cancer. SQSTM1/p62 activity mediates different biological functions. This study aimed to investigate the effect of SQSTM1/p62, a multifunctional receptor, on biological function and autophagy characteristics in the human PTC cell line TPC-1.

Methods

A total of 105 primary PTC samples and matched adjacent normal thyroid tissue samples were obtained to evaluate the expression of p62 in clinical patients. A similar p62 expression pattern was found in PTC cell lines and normal human thyroid follicular epithelial cells. To evaluate the effect of SQSTM1/p62 on TPC-1 cells, we constructed the p62 knockout cell line p62-KO-TPC-1. Cell proliferation, cell cycle, and cell apoptosis were analyzed by colony formation tests, Cell Counting Kit-8 (CCK-8) assays and flow cytometry in vitro. TPC-1 and p62-KO-TPC-1 human PTC cell lines in the logarithmic growth phase were subcutaneously implanted into BALB/c nude mice to verify their proliferation effect in vivo. Furthermore, western blotting and immunohistochemistry (IHC) were used to detect the expression of AKT/AMPK/mTOR signaling pathway-related proteins.

Results

Overall, p62 expression was higher in tumor tissues than in normal tissues in 73 of 105 PTC patients (69.5%). The expression level of p62 in the PTC cell line was higher than that in the normal thyroid cell line. Our data indicated that in vitro, p62 deficiency could decrease the number of colonies, inhibit cell growth and the cell cycle, and induce apoptosis. Tumor xenograft experiments in BALB/c nude mice corroborated these findings. Moreover, the molecular mechanism was explored by western blotting, and we found that the AMPK/AKT/mTOR pathway was involved.

Conclusions

The results indicate that p62 might mediate cell autophagy and apoptosis in TPC-1 cells via the AMPK/AKT/mTOR pathway and could be used as a potential therapeutic approach for PTC.
Pattern of Recurrence in 428 Patients With Thoracic Esophageal Squamous Cell Carcinoma After Radical Surgery and Its Implication in Postoperative Radiotherapeutic Clinical Target Volume
Authors: Cui Tiantian , Zhang Hongjiao , Yu Tao , Chen Yiru , Liu Chengxin , Zhao Qian , Zhu Jian , Li Baosheng , Huang Wei
Published: April 2021

Purpose

This study aimed to analyze the recurrence patterns of thoracic esophageal squamous cell carcinoma (ESCC) after radical surgery, and to understand its implication in the clinical target volume (CTV) design of postoperative radiotherapy (PORT) in patients with ESCC.

Methods and materials

A total of 428 recurrent ESCC patients after radical surgery between 2014 and 2018 were included in this study. Recurrence patterns, especially anastomotic and regional lymph node recurrence (LNR), were analyzed. A T-shaped CTV were proposed for PORT and were evaluated whether it could cover most of regional LNR.

Results

These patients all experienced anastomotic and/or regional LNR. Among the 428 patients, 27 cases (6.3%) had anastomotic recurrence only, and184 cases (43.0%) had LNR only. Those sites with an LNR rate higher than 15% in upper thoracic ESCC were as follows: No.101, No.104R, No.104L, No.106recR, No.106recL, No.106pre, No.106tb, No.107, and No. 109. Those with middle thoracic ESCC were as follows: No.104R, No.104L, 106recR, No.106recL, No.106pre, No.106tb, and No.107. Lastly, individuals with lower thoracic ESCC were as follows: No.104L, 106recR, No.106recL, No. 106pre, No. 106tb, No.107, and abdominal No. 3. The proportion of LNR not included in the proposed T-shaped CTV was 12.5% (1/8), 4.7% (6/128), and 10.4% (5/48) in the upper, middle, and lower thoracic segments, respectively.

Conclusions

LNR was the most common type of local-regional recurrence in patients after radical surgery. Supraclavicular, superior and middle mediastinal lymph nodes had the highest recurrence rate, the rate of LNR which was outside T-shaped PORT CTV we proposed was less than 15%.
Salvage Radiotherapy for Macroscopic Local Recurrence Following Radical Prostatectomy
Authors: Zaine Hind , Vandendorpe Benjamin , Bataille Benoit , Lacornerie Thomas , Wallet Jennifer , Mirabel Xavier , Lartigau Eric , Pasquier David
Published: April 2021

Introduction

Salvage radiotherapy is the only curative treatment for biochemical progression after radical prostatectomy. Macroscopic recurrence may be found in the prostatic bed. The purpose of our study is to evaluate the effectiveness of salvage radiotherapy of the prostate bed with a boost to the area of the macroscopic recurrence.

Material and Methods

From January 2005 to January 2020, 89 patients with macroscopic recurrence in the prostatectomy bed were treated with salvage radiotherapy +/- hormone therapy. The average PSA level prior to radiotherapy was 1.1 ng/mL (SD: 1.6). At the time of biochemical progression, 96% of the patients had a MRI that revealed the macroscopic recurrence, and 58% had an additional choline PET scan. 67.4% of the patients got a boost to the macroscopic nodule, while 32.5% of the patients only underwent radiotherapy of the prostate bed without a boost. The median total dose of radiotherapy was 70 Gy (Min.: 60 – Max.: 74). The most commonly-used regimen was radiotherapy of the prostatectomy bed with a concomitant boost. 48% of the patients were concomitantly treated with hormone therapy.

Results

After a median follow-up of 53.7 months, 77 patients were alive and 12 had died, of which 4 following metastatic progression. The 5-year and 8-year survival rates (CI95%) are, respectively, 90.2% (78.9-95.6%) and 69.8% (46.4-84.4%). The 5-year biochemical progression-free survival rate (CI95%) is 50.8% (36.7-63.3). Metastatic recurrence occurred in 11.2% of the patients. We did not find any statistically significant impact from the various known prognostic factors for biochemical progression-free survival. No toxicity with a grade of > or = to 3 was found.

Conclusions

Our series is one of the largest published to date. Salvage radiotherapy has its place in the management of patients with biochemical progression with local recurrence in the prostate bed, with an acceptable toxicity profile. The interest of the boost is to be evaluated in prospective trials.
Analyzing the Underlying Structure of Online Teaching During the COVID-19 Pandemic Period: An Empirical Investigation of Issues of Students
Authors: Shaukat Muhammad Zeeshan , Niazi Abdul Aziz Khan , Qazi Tehmina Fiaz , Basit Abdul
Published: April 2021

The aim of the study is to reveal the underlying structure of issues of university students taking online classes during the COVID-19 pandemic period. The overall design of the study includes a review of contemporary literature and field survey for data collection and analysis. Discourse of literature coupled with expert opinion has been employed for identification of issues. Interpretive Structural Modeling (ISM) is used for the determination of intra-issue relationships and analyzing the underlying structure. Cross impact matrix multiplication applied to classification (MICMAC analysis) is used as a technique for classifying issues on the basis of driving–dependence power. Results of the literature show that there are 21 major issues faced by the students taking online classes. ISM shows that lack of institutional guidelines, lack of regulators’ guidelines, stress of pandemic situation, and abrupt (not planned) start of online classes are the most critical issues. MICMAC analysis reveals that there is no autonomous issue, 4 (i.e., connectivity issue, shy to use technology, lack of institutional guidelines, and stress of pandemic situation) are independent, 6 other issues are dependent, and the remaining 11 are linking. This is a valuable study having practical implications for regulators, students, parents, and society to understand the current problem. It is an original attempt that contributes toward literature in the form of a structural model and a diagram of classification of issues.
Meaning-Based Coping and Spirituality During the COVID-19 Pandemic: Mediating Effects on Subjective Well-Being
Authors: Arslan Gökmen , Yıldırım Murat
Published: April 2021

The coronavirus pandemic has significantly affected the Turkish population. During the pandemic, people with high coronavirus stress are at risk of experiencing poor subjective well-being. There is no research investigating the role of meaning-based coping and spirituality in explaining the link between coronavirus stress and subjective well-being. This study examined the mediating roles of meaning-based coping and spiritual well-being in the link between coronavirus stress and subjective well-being in young adults during the COVID-19 pandemic. The sample included 427 young adults (71% female), ranging in age between 18 and 48 years (M= 21.06;SD= 2.62). Turkish young adults completed an online survey, including measures of coronavirus stress, subjective well-being, meaning-based coping, and spiritual well-being. The results indicate that greater meaning-based coping and spiritual well-being mediated decreases in the adverse impacts of coronavirus stress on subjective well-being. These results suggest that the importance of a combination of meaning-based coping and spirituality processes mitigate the adverse effects of stress on well-being during the coronavirus pandemic. Interventions focusing on meaning-based coping and spirituality in those experiencing high coronavirus stress are urgently needed to improve the mental health and well-being of young adults.
Workplace Violence Against Chinese Frontline Clinicians During the COVID-19 Pandemic and Its Associations With Demographic and Clinical Characteristics and Quality of Life: A Structural Equation Modeling Investigation
Authors: Yang Yuan , Li Yue , An Ying , Zhao Yan-Jie , Zhang Ling , Cheung Teris , Hall Brian J. , Ungvari Gabor S. , An Feng-Rong , Xiang Yu-Tao
Published: April 2021

Background: Workplace violence is a major concern for clinicians worldwide. There has been little data on the epidemiology of workplace violence against frontline clinicians during the COVID-19 pandemic. This study examined the pattern of workplace violence and its association with quality of life (QOL) against frontline clinicians during the outbreak of COVID-19 pandemic in China.

Methods: A cross-sectional online study was conducted in China between March 15 and March 20, 2020. Frontline clinicians' experience with workplace violence was measured with six standardized questions derived from the Workplace Violence Scale, while anxiety, depressive, and insomnia symptoms, and QOL were measured using the General Anxiety Disorder Questionnaire, the Patient Health Questionnaire, the Insomnia Severity Index, and the World Health Organization Quality of Life Questionnaire, respectively. Univariate analyses, multivariable logistic regression analyses, and structural equation modeling (SEM) were conducted.

Results: A total of 15,531 clinicians completed the assessment; 2,878 (18.5, 95% CI = 17.92–19.14%) reported workplace violence during the outbreak of the COVID-19 pandemic (verbal violence: 16.1%; physical violence: 6.9%). According to multivariable models, key correlates of workplace violence were male gender, longer work experience, higher education level, smoking, working in the psychiatry or emergency department, working in tertiary hospitals, being involved in direct care of infected patients, having infected family/ friends/ colleagues, and frequently using social communication programs. Clinicians working in inpatient departments were less likely to report workplace violence compared to those working in outpatient departments. SEM analysis revealed that both violence and emotional disturbances (anxiety, depression, and insomnia) directly affected QOL (standardized direct effect = −0.031, and −0.566, respectively, P < 0.05), while emotional disturbances partly mediated the association between work violence and QOL (standardized indirect effect = −0.184, P < 0.05).

Conclusion: Frontline clinicians were vulnerable to workplace violence during the COVID-19 pandemic. Due to the negative impact of workplace violence on quality of care and clinicians' QOL, health authorities and policymakers should take effective measures to reduce workplace violence against clinicians.
Deep Neural Network to Differentiate Brain Activity Between Patients With First-Episode Schizophrenia and Healthy Individuals: A Multi-Channel Near Infrared Spectroscopy Study
Authors: Chou Po-Han , Yao Yun-Han , Zheng Rui-Xuan , Liou Yi-Long , Liu Tsung-Te , Lane Hsien-Yuan , Yang Albert C. , Wang Shao-Cheng
Published: April 2021

Backgrounds:Reduced brain cortical activity over the frontotemporal regions measured by near infrared spectroscopy (NIRS) has been reported in patients with first-episode schizophrenia (FES). This study aimed to differentiate between patients with FES and healthy controls (HCs) on basis of the frontotemporal activity measured by NIRS with a support vector machine (SVM) and deep neural network (DNN) classifier. In addition, we compared the accuracy of performance of SVM and DNN.

Methods:In total, 33 FES patients and 34 HCs were recruited. Their brain cortical activities were measured using NIRS while performing letter and category versions of verbal fluency tests (VFTs). The integral and centroid values of brain cortical activity in the bilateral frontotemporal regions during the VFTs were selected as features in SVM and DNN classifier.

Results:Compared to HCs, FES patients displayed reduced brain cortical activity over the bilateral frontotemporal regions during both types of VFTs. Regarding the classifier performance, SVM reached an accuracy of 68.6%, sensitivity of 70.1%, and specificity of 64.6%, while DNN reached an accuracy of 79.7%, sensitivity of 88.8%, and specificity of 74.9% in the classification of FES patients and HCs.

Conclusions:Compared to findings of previous structural neuroimaging studies, we found that using DNN to measure the NIRS signals during the VFTs to differentiate between FES patients and HCs could achieve a higher accuracy, indicating that NIRS can be used as a potential marker to classify FES patients from HCs. Future additional independent datasets are needed to confirm the validity of our model.
Non-aureus Staphylococci and Bovine Udder Health: Current Understanding and Knowledge Gaps
Authors: De Buck Jeroen , Ha Vivian , Naushad Sohail , Nobrega Diego B. , Luby Christopher , Middleton John R. , De Vliegher Sarne , Barkema Herman W.
Published: April 2021

Despite considerable efforts to control bovine mastitis and explain its causes, it remains the most costly and common disease of dairy cattle worldwide. The role and impact of non-aureusstaphylococci (NAS) in udder health are not entirely understood. These Gram-positive bacteria have become the most frequently isolated group of bacteria in milk samples of dairy cows and are associated with (mild) clinical and subclinical mastitis. Different species and strains of NAS differ in their epidemiology, pathogenicity, virulence, ecology and host adaptation, and antimicrobial resistance profiles. They have distinct relationships with the microbiome composition of the udder and may also have protective effects against other mastitis pathogens. Some appear to persist on the skin and in the teat canal and udder, while others seem to be transient residents of the udder from the environment. Analyzing genotypic and phenotypic differences in individual species may also hold clues to why some appear more successful than others in colonizing the udder. Understanding species-level interactions within the microbiome and its interactions with host genetics will clarify the role of NAS in bovine mastitis and udder health.