bluuebunny/crossref_metadata_2025 huggingface dataset:
Revealing Potential Spinal Cord Injury Biomarkers and Immune Cell Infiltration Characteristics in Mice
Authors: Cao Liang , Li Qing
Published: May 2022

Spinal cord injury (SCI) is a disabling condition with significant morbidity and mortality. Currently, no effective SCI treatment exists. This study aimed to identify potential biomarkers and characterize the properties of immune cell infiltration during this pathological event. To eliminate batch effects, we concurrently analyzed two mouse SCI datasets (GSE5296, GSE47681) from the GEO database. First, we identified differentially expressed genes (DEGs) using linear models for microarray data (LIMMA) and performed functional enrichment studies on those DEGs. Next, we employed bioinformatics and machine-learning methods to identify and define the characteristic genes of SCI. Finally, we validated them using immunofluorescence and qRT-PCR. Additionally, this study assessed the inflammatory status of SCI by identifying cell types using CIBERSORT. Furthermore, we investigated the link between key markers and infiltrating immune cells. In total, we identified 561 robust DEGs. We identified Rab20 and Klf6 as SCI-specific biomarkers and demonstrated their significance using qRT-PCR in the mouse model. According to the examination of immune cell infiltration, M0, M1, and M2 macrophages, along with naive CD8, dendritic cell-activated, and CD4 Follicular T cells may have a role in the progression of SCI. Therefore, Rab20 and Klf6 could be accessible targets for diagnosing and treating SCI. Moreover, as previously stated, immune cell infiltration may significantly impact the development and progression of SCI.
Premature Infants Have Normal Maturation of the T Cell Receptor Repertoire at Term
Authors: Morton Sarah U. , Schnur Maureen , Kerper Rylee , Young Vanessa , O’Connell Amy E.
Published: May 2022

Premature infants are known to have immature immune systems compared to term infants; however, the impacts of ex utero immune development are not well characterized. Our previous retrospective clinical review showed prolonged T cell lymphopenia in a subset of extremely premature infants, suggesting that they may have lasting abnormalities in their T cell compartments. We used T cell receptor (TCR) repertoire sequencing to analyze the composition of the T cell compartment in premature and term infants in our NICU. We collected twenty-eight samples from individual subjects and analyzed the number of clonotypes, repertoire diversity, CDR3 length, and V gene usage between groups based on gestational age at birth and postmenstrual age at the time of sample collection. Further, we examined the TCR repertoire in infants with severe bronchopulmonary dysplasia (BPD) and those with abnormal T cell receptor excision circle (TREC) assays. Former extremely premature infants who were corrected to term postmenstrual age had TCR repertoire diversity that was more similar to term born infants than extremely premature infants, supporting normal maturation of the repertoire. Infants with severe BPD did not appear to have increased abnormalities in repertoire diversity. Decreased TCR repertoire diversity was associated with repeatedly abnormal TREC screening, although the diversity was within the normal range for subjects without low TRECs. This study suggests that extremely premature infants demonstrate normal maturation of the T cell repertoire ex utero. Further work is needed to better characterize postnatal T cell development and function in this population.
NLRP1 Inflammasomes: A Potential Target for the Treatment of Several Types of Brain Injury
Authors: Mi Liang , Min Xiaobin , Chai Yan , Zhang Jianning , Chen Xin
Published: May 2022

NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) is a member of the NLR family. The NLRP1 inflammasome consists of the NLRP1 protein, the adaptor protein apoptosis-associated speck-like protein containing a CARD domain, and the effector molecule pro-caspase-1. When stimulated, the inflammasome initiates the cleavage of pro-caspase-1 and converts it into its active form, caspase-1; then, caspase-1 facilitates the cleavage of the proinflammatory cytokines interleukin-1β and interleukin-18 into their active and secreted forms. In addition, caspase-1 also mediates the cleavage of gasdermin D, which leads to pyroptosis, an inflammatory form of cell death. Pathological events that damage the brain and result in neuropathological conditions can generally be described as brain injury. Neuroinflammation, especially that driven by NLRP1, plays a considerable role in the pathophysiology of brain injury, such as early brain injury (EBI) of subarachnoid hemorrhage, ischemic brain injury during stroke, and traumatic brain injury (TBI). In this article, a thorough overview of NLRP1 is presented, including its structure, mechanism of activation, and role in neuroinflammation. We also present recent studies on NLRP1 as a target for the treatment of EBI, ischemic brain injury, TBI, and other types of brain injury, thus highlighting the perspective of NLRP1 as an effective mediator of catastrophic brain injury.
Interplay between Solid Tumors and Tumor Microenvironment
Authors: Kim Seung-Jin , Khadka Dipendra , Seo Jae Ho
Published: May 2022

Over the past few decades, basic studies aimed at curing patients with cancer have been constantly evolving. A myriad of mechanistic studies on physiological changes and related factors in tumor growth and metastasis have been reported. Recently, several studies have been considerate to how tumors adapt to unfavorable environments, such as glucose deprivation, oxidative stress, hypoxic conditions, and immune responses. Tumors attempt to adapt to unfavorable environments with genetic or non-genetic changes, the alteration of metabolic signals, or the reconfiguration of their environment through migration to other organs. One of the distinct features in solid tumors is heterogeneity because their environments vary due to the characteristics of colony growth. For this reason, researchers are paying attention to the communication between growing tumors and neighboring environments, including stromal cells, immune cells, fibroblasts, and secreted molecules, such as proteins and RNAs. During cancer survival and progression, tumor cells undergo phenotype and molecular changes collectively referred to as cellular plasticity, which result from microenvironment signals, genetics and epigenetic alterations thereby contributing to tumor heterogeneity and therapy response. In this review, we herein discuss the adaptation process of tumors to adverse environments via communication with neighboring cells for overcoming unfavorable growth conditions. Understanding the physiology of these tumors and their communication with the tumor environment can help to develop promising tumor treatment strategies.
Tumor-Derived Exosomes Regulate Apoptosis of CD45+EpCAM+ Cells in Lung Cancer
Authors: Lu Shixiang , Sun Zhen , Liu Lili , Li Peng , Li Bin , Li Wenjing , Wu Zhaojun , Zhao Mingming , Liu Wenna , Wang Yongjie , Wang Bin
Published: May 2022

Lung cancer has the highest mortality rate among human cancers, and the majority of deaths result from metastatic spread. The tumor microenvironment plays an important role in suppressing the immune surveillance and elimination of tumor cells. A few studies have reported the presence of CD45+EpCAM+ double-positive cells in cancer, but the underlying mechanism remains unclear with respect to how these cells originate and their function in cancer biology. In this study, we analyzed 25 lung tumor samples. We confirmed the presence of CD45+EpCAM+ cells in lung cancer, and these cells exhibited higher apoptosis than CD45+EpCAM− cells. Using co-culture of lung cancer cell-derived exosomes with healthy donor peripheral blood mononuclear cells, we recapitulated CD45+EpCAM+ cell formation and increased apoptosis that occurs in patients with primary lung cancer. Further analysis suggested that microRNAs in lung cancer cell-derived exosomes may alter the gene expression profile of CD45+EpCAM+ cells, resulting in elevated TP53 expression and increased apoptosis. To our knowledge, this is the first report of cancer cell-derived exosomes that can inhibit the immune system by promoting immune cell apoptosis.
Analysis of the Transmission of SARS-CoV-2 Delta VOC in Yantai, China, August 2021
Authors: Sun Yulou , Zhang Yuwei , Liu Zimo , Li Xia , Liu Juan , Tian Xinghan , Gao Qiao , Niu Peihua , Zhai Hongli , Sun Zhenlu , Tian Yunlong , Wang Ji
Published: May 2022

Objective

Starting 31 July 2021, a SARS-CoV-2 outbreak occurred in Yantai, Shandong Province. The investigation showed that this outbreak was closely related to the epidemic at Nanjing Lukou Airport. In view of the fact that there were many people involved in this outbreak and these people had a complex activity area, the transmission route cannot be analyzed by simple epidemiological investigation. Here we combined the SARS-COV-2 whole-genome sequencing with epidemiology to determine the epidemic transmission route of Yantai.

Methods

Thirteen samples of SARS-CoV-2 outbreak cases from 31 July to 4 August 2021 were collected and identified by fluorescence quantitative PCR, then whole-genome deep sequencing based on NGS was performed, and the data were analyzed and processed by biological software.

Results

All sequences were over 29,000 bases in length and all belonged to B.1.617.2, which was the Delta strain. All sequences shared two amino acid deletions and 9 amino acid mutations in Spike protein compared with reference sequence NC_045512.2 (Wuhan virus strain). Compared with the sequence of Lukou Airport Delta strain, the homology was 99.99%. In order to confirm the transmission relationship between patients, we performed a phylogenetic tree analysis. The results showed that patient 1, patient 2, and patient 9 belong to an independent branch, and other patients have a close relationship. Combined with the epidemiological investigation, we speculated that the epidemic of Yantai was transmitted by two routes at the same time. Based on this information, our prevention and control work was carried out in two ways and effectively prevented the further spread of this epidemic.
Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer
Authors: Iranzo Patricia , Callejo Ana , Assaf Juan David , Molina Gaspar , Lopez Daniel Esteban , Garcia-Illescas David , Pardo Nuria , Navarro Alejandro , Martinez-Marti Alex , Cedres Susana , Carbonell Caterina , Frigola Joan , Amat Ramon , Felip Enriqueta
Published: May 2022

In recent years, immunotherapy-based regimens have been included into the treatment's algorithm of several cancer types. Programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) interact with their ligands found on the surface of antigen presenting cells (APC) or tumor cells (PD-L1/2 and CD80/86). Through these interactions, stimulatory or inhibitory signals are established. Immune checkpoint inhibitors (ICIs), block these interactions, and when administered not only as monotherapy but also as part of combination regimens, have shown to improve survival results in multiple advanced cancers leading to an increasing number of patients treated with ICI and, as a consequence, a rise in the number of patients developing immune-related adverse events (irAEs). Presence of irAEs has been associated with greater benefit from treatment, especially when blocking PD-L1. Recent data suggests that treatment benefit persists after discontinuation of ICIs due to a treatment related adverse event, regardless of the grade. Patients experiencing grade 3-4 irAEs are at risk of toxicity recurrence after reintroducing immunotherapy and therefore, the decision to resume the treatment is challenging. In these cases, a multidisciplinary approach is always needed and several factors should be considered. Management of severe toxicities may require systemic corticosteroids which can impact on T-cell function. Due to their immunosuppressive properties, it is necessary to deeper determine how corticosteroids influence responses. In terms of overall survival (OS), the use of steroids as therapy for irAEs seems not to reduce OS and several studies have reported durable responses in patients experiencing autoimmune toxicities treated with corticosteroids.
Tolerance of Senecavirus A to Mutations in Its Kissing-Loop or Pseudoknot Structure Computationally Predicted in 3′ Untranslated Region
Authors: Liu Fuxiao , Zhao Di , Wang Ning , Li Ziwei , Dong Yaqin , Liu Shuang , Zhang Feng , Cui Jin , Meng Hailan , Ni Bo , Wei Rong , Shan Hu
Published: May 2022

Senecavirus A (SVA) is an emerging virus that belongs to the genus Senecavirus in the family Picornaviridae. Its genome is a positive-sense and single-stranded RNA, containing two untranslated regions (UTRs). The 68-nt-long 3′ UTR is computationally predicted to possess two higher-order RNA structures: a kissing-loop interaction and an H-type-like pseudoknot, both of which, however, cannot coexist in the 3′ UTR. In this study, we constructed 17 full-length SVA cDNA clones (cD-1 to -17): the cD-1 to -7 contained different point mutations in a kissing-loop-forming motif (KLFM); the cD-8 to -17 harbored one single or multiple point mutations in a pseudoknot-forming motif (PFM). These 17 mutated cDNA clones were independently transfected into BSR-T7/5 cells for rescuing recombinant SVAs (rSVAs), named rSVA-1 to −17, corresponding to cD-1 to −17. The results showed that the rSVA-1, -2, -3, -4, -5, -6, -7, -9, -13, and -15 were successfully rescued from their individual cDNA clones. Moreover, all mutated motifs were genetically stable during 10 viral passages in vitro. This study unveiled viral abilities of tolerating mutations in the computationally predicted KLFM or PFMs. It can be concluded that the putative kissing-loop structure, even if present in the 3′ UTR, is unnecessary for SVA replication. Alternatively, if the pseudoknot formation potentially occurs in the 3′ UTR, its deformation would have a lethal effect on SVA propagation.
Tamoxifen Increased Parasite Burden and Induced a Series of Histopathological and Immunohistochemical Changes During Chronic Toxoplasmosis in Experimentally Infected Mice
Authors: Barakat Ashraf Mohamed , El Fadaly Hassan Ali Mohamed , Selem Rabab Fawzy , Madboli Abd El-Nasser A. , Abd El-Razik Khaled A. , Hassan Ehssan Ahmed , Alghamdi Ali H. , Elmahallawy Ehab Kotb
Published: May 2022

The global distribution of breast cancer and the opportunistic nature of the parasite have resulted in many patients with breast cancer becoming infected with toxoplasmosis. However, very limited information is available about the potential effects of tamoxifen on chronic toxoplasmosis and its contribution to the reactivation of the latent infection. The present study investigated the potential effects of tamoxifen on chronic toxoplasmosis in animal models (Swiss albino mice). Following induction of chronic toxoplasmosis and treatment with the drug for 14 and 28 days, the anti-parasitic effects of tamoxifen were evaluated by parasitological assessment and counting of Toxoplasma cysts. In addition, the effects of the drug on the parasite load were evaluated and quantitated using TaqMan real-time quantitative PCR followed by investigation of the major histopathological changes and immunohistochemical findings. Interestingly, tamoxifen increased the parasite burden on animals treated with the drug during 14 and 28 days as compared with the control group. The quantification of the DNA concentrations of Toxoplasma P29 gene after the treatment with the drug revealed a higher parasite load in both treated groups vs. control groups. Furthermore, treatment with tamoxifen induced a series of histopathological and immunohistochemical changes in the kidney, liver, brain, and uterus, revealing the exacerbating effect of tamoxifen against chronic toxoplasmosis. These changes were represented by the presence of multiple T. gondii tissue cysts in the lumen of proximal convoluted tubules associated with complete necrosis in their lining epithelium of the kidney section. Meanwhile, liver tissue revealed multiple T. gondii tissue cysts in hepatic parenchyma which altered the structure of hepatocytes. Moreover, clusters of intracellular tachyzoites were observed in the lining epithelium of endometrium associated with severe endometrial necrosis and appeared as diffuse nuclear pyknosis combined with sever mononuclear cellular infiltration. Brain tissues experienced the presence of hemorrhages in pia mater and multiple T. gondii tissue cysts in brain tissue. The severity of the lesions was maximized by increasing the duration of treatment. Collectively, the study concluded novel findings in relation to the potential role of tamoxifen during chronic toxoplasmosis. These findings are very important for combating the disease, particularly in immunocompromised patients which could be life-threatening.
Repeated Exposure of Escherichia coli to High Ciprofloxacin Concentrations Selects gyrB Mutants That Show Fluoroquinolone-Specific Hyperpersistence
Authors: Perault Aurore , Turlan Catherine , Eynard Nathalie , Vallé Quentin , Bousquet-Mélou Alain , Giraud Etienne
Published: May 2022

Recent studies have shown that not only resistance, but also tolerance/persistence levels can evolve rapidly in bacteria exposed to repeated antibiotic treatments. We used in vitro evolution to assess whether tolerant/hyperpersistent Escherichia coli ATCC25922 mutants could be selected under repeated exposure to a high ciprofloxacin concentration. Among two out of three independent evolution lines, we observed the emergence of gyrB mutants showing an hyperpersistence phenotype specific to fluoroquinolones, but no significant MIC increase. The identified mutation gives rise to a L422P substitution in GyrB, that is, outside of the canonical GyrB QRDR. Our results indicate that mutations in overlooked regions of quinolone target genes may impair the efficacy of treatments via an increase of persistence rather than resistance level, and support the idea that, in addition to resistance, phenotypes of tolerance/persistence of infectious bacterial strains should receive considerations in the choice of antibiotic therapies.
Diagnosis of Amnesic Mild Cognitive Impairment Using MGS-WBC and VGBN-LM Algorithms
Authors: Cai Chunting , Cao Jiangsheng , Yang Chenhui , Chen E.
Published: May 2022

Computer-aided diagnosis (CAD) has undergone rapid development with the advent of advanced neuroimaging and machine learning methods. Nevertheless, how to extract discriminative features from the limited and high-dimensional data is not ideal, especially for amnesic mild cognitive impairment (aMCI) data based on resting-state functional magnetic resonance imaging (rs-fMRI). Furthermore, a robust and reliable system for aMCI detection is conducive to timely detecting and screening subjects at a high risk of Alzheimer’s disease (AD). In this scenario, we first develop the mask generation strategy based on within-class and between-class criterion (MGS-WBC), which primarily aims at reducing data redundancy and excavating multiscale features of the brain. Concurrently, vector generation for brain networks based on Laplacian matrix (VGBN-LM) is presented to obtain the global features of the functional network. Finally, all multiscale features are fused to further improve the diagnostic performance of aMCI. Typical classifiers for small data learning, such as naive Bayesian (NB), linear discriminant analysis (LDA), logistic regression (LR), and support vector machines (SVMs), are adopted to evaluate the diagnostic performance of aMCI. This study helps to reveal discriminative neuroimaging features, and outperforms the state-of-the-art methods, providing new insights for the intelligent construction of CAD system of aMCI.
Dual-Task Performance in Older Adults With and Without Idiopathic Normal Pressure Hydrocephalus
Authors: Lilja-Lund Otto , Nyberg Lars , Maripuu Martin , Laurell Katarina
Published: May 2022

Two of the main features of idiopathic normal pressure hydrocephalus (iNPH) are disturbed gait and cognition. These features are typically investigated separately, but here we combined walking with a cognitive task to investigate if older adults with iNPH were more susceptible to dual-task interference on walking than those without iNPH. In total, 95 individuals from the general population participated in our study. Of these, 20 were classified as Possible iNPH (median [interquartile range, IQR] 80 years [75–82.5]) and 75 as Unlikely iNPH (74 years [72–78]). Conversation, 10-m walking, semantic and phonemic verbal fluency were performed either combined or independently. “Stopping walking while talking” was noted. Pairwise comparisons and multiple logistic regression analyses were used. We found that the Possible iNPH group was older, stopped walking more frequently during the conversation, and had a slower single-task pace. The dual-task pace was slower for both groups. Only single-task walking pace could predict Possible iNPH when adjusted for age. We could establish a dual-task cost on gait performance in this sample of older adults from the general population, but the cost was not exclusive for individuals with Possible iNPH. To further assess the value of dual-task testing in iNPH, including observations of stopping walking while talking, a study of a clinical iNPH material with more severe symptoms would be valuable.
Evaluating Knee Mechanisms for Assistive Devices
Authors: Patrick Shawanee' , Anil Kumar Namita , Hur Pilwon
Published: May 2022

State-of-the-art knee braces use a polycentric mechanism with a predefined locus of the instantaneous center of rotation (centrode) and most exoskeleton devices use a knee mechanism with a single axis of rotation. However, human knees do not share a common centrode nor do they have a single axis. This leads to misalignment between the assistive device's joint axis and the user's knee axis, resulting in device migration and interaction forces, which can lead to sores, pain, and abandonment of the device over time. There has been some research into self-aligning knee mechanisms; however, there is a lack of consensus on the benefit of these mechanisms. There is no research that looked purely at the impact of the knee mechanisms, either. In this article, we compare three different knee brace mechanisms: single axis (SA), polycentric with predefined centrode (PPC), and polycentric with a self-aligning center of rotation (PSC). We designed and conducted an experiment to evaluate different joint mechanisms on device migration and interaction forces. Brace material, weight, size, cuff design, fitment location, and tightness were consistent across trials, making the knee joint mechanism the sole variable. The brace mechanisms had no significant effect on walking kinematics or kinetics. However, the PPC brace had greater interaction forces on the top brace strap than the SA and PSC. The PSC and SA had significantly lower interaction forces on the bottom strap compared to the PPC brace. The PSC had significantly less migration than both the SA and PPC braces. These results show that a PPC mechanism may not be beneficial for a wide range of users. This also shows that the PSC mechanisms may improve mechanism alignment and lessen device migration.
Sit-to-Stand (STS) Movement Analysis of the Center of Gravity for Human–Robot Interaction
Authors: Wang Haiyan , Xu Shanshan , Fu Jiayu , Xu Xiangrong , Wang Zhixiong , Na Ri Su
Published: May 2022

As the aging process is springing up around the whole world, the problem of sit-to-stand (STS) for the elderly has become the focal point of older people themselves, their families, and society. The key challenge in solving this problem is developing and applying the technology of auxiliary robots for standing up and auxiliary stands. The research is not only to find the appropriate fundamentals from a healthcare perspective in the center of gravity movement (COM) curve of the elderly during STS but also to meet the psychological needs of the elderly during STS in a comfortable, pleasant, and safe way. To obtain the skeleton tracking technology used in this study, we used the Vicon optical motion capture system and automatic moving target indicator (AMTI) 3-D force measuring table to obtain a COM curve of the elderly during STS. The stationary process, speed, and sitting posture analysis during STS were combined in this paper to seek a solution to the psychological needs of the elderly. The analysis is conducted with the integration of medicine, engineering, art, and science into this research. Finally, a movement curve and related dynamic parameters that can truly reflect the STS of the elderly are obtained, and the discussion is provided. The research result can provide theoretical and technical support for the later development of auxiliary robots for standing up and auxiliary stands technology products, so that the elderly can STS comfortably, happily, and safely with the assistance of human–robot interaction.
Procedural and Methodological Quality in Preclinical Stroke Research–A Cohort Analysis of the Rat MCAO Model Comparing Periods Before and After the Publication of STAIR/ARRIVE
Authors: Friedrich Jacqueline , Lindauer Ute , Höllig Anke
Published: May 2022

The translation of preclinical stroke research into successful human clinical trials remains a challenging task. The first Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for preclinical research and several other guidelines were published to address these challenges. Most guidelines recommend the use of physiological monitoring to detect the occurrence of undesired pathologies such as subarachnoid hemorrhage and to limit the variability of the infarct volume and–therefore-homogenize the experimental result for complete reporting particularly with respect to transparency and methodological rigor. From the years 2009 and 2019, 100 published articles each using a rat stroke model were analyzed to quantify parameters related to anesthesia, physiological monitoring, stroke model type, ischemia verification, and overall study quality over time. No significant difference in the frequency of cerebral blood flow (CBF) measurements over time (28/34% for 2009/2019) was found. Notably, significantly fewer studies reported temperature, blood pressure, and blood gas monitoring data in 2019 compared to 2009. On the other hand, an increase in general study quality parameters (e.g., randomization, reporting of approval) was seen. In conclusion, the frequency of periinterventional monitoring has decreased over time. Some general methodological quality aspects, however, partially have increased. CBF measurement–the gold standard for ischemia verification-was applied rarely. Despite the growing recognition of current guidelines such as STAIR and ARRIVE (both widely approved in 2019) reporting, methods and procedures mostly do not follow these guidelines. These deficits may contribute to the translational failure of preclinical stroke research in search for neuroprotective therapies.
Small Unruptured Intracranial Aneurysms Can Be Effectively Treated With Flow-Diverting Devices
Authors: Li Li , Gao Bu-Lang , Shao Qiu-Ji , Zhang Guang-Lin , Wang Zi-Liang , Li Tian-Xiao , Zhu Liang-Fu
Published: May 2022

Purpose

To investigate the effect and safety of flow diverters in the management of small (<10 mm in diameter) unruptured intracranial aneurysms.

Materials and Methods

One hundred and ten patients with 145 small intracranial aneurysms treated with flow diverters were retrospectively enrolled. The clinical, endovascular, and follow-up data were analyzed.

Results

One hundred twenty-one flow diverters were deployed for the treatment of 145 small intracranial aneurysms in 110 patients, and the stenting success rate was 99.1%. In 133 (91.7%) aneurysms, only flow-diverting devices were deployed, and in the rest 12 (8.3%) of aneurysms, coils were used to loosely pack the aneurysm after deployment of a flow-diverting device. Five patients (4.5%) experienced ischemic complications, but no hemorrhagic complications were occurred. All patients had clinical follow-up 6–18 (median 12) after the procedure, with the modified Rankin scale score (mRS) 0 in 101 patients, 1 in four patients, 2 in three patients, 4 in one patient, and 5 in one patient. Digital subtraction angiography was performed at follow-up in 90 (81.8%) patients with 118 (81.4%) aneurysms 6–18 months (median 12) after the procedure, with the Raymond grade I in 90 (76.2%) aneurysms and Raymond grade III in 28 (23.7%). Eighteen patients with 22 partially occluded aneurysms at the first angiographic follow-up experienced the second digital subtraction angiography 12–36 months (median 26) after the procedure, and 21 (95.5%) aneurysms were completely occluded. Two patients had asymptomatic in-stent stenosis.

Conclusion

Treatment of small unruptured intracranial aneurysms with flow diverters can be performed safely and effectively with satisfactory outcomes.
The Eye Pupil Adjusts to Illusorily Expanding Holes
Authors: Laeng Bruno , Nabil Shoaib , Kitaoka Akiyoshi
Published: May 2022

Some static patterns evoke the perception of an illusory expanding central region or “hole.” We asked observers to rate the magnitudes of illusory motion or expansion of black holes, and these predicted the degree of dilation of the pupil, measured with an eye tracker. In contrast, when the “holes” were colored (including white), i.e., emitted light, these patterns constricted the pupils, but the subjective expansions were also weaker compared with the black holes. The change rates of pupil diameters were significantly related to the illusory motion phenomenology only with the black holes. These findings can be accounted for within a perceiving-the-present account of visual illusions, where both the illusory motion and the pupillary adjustments represent compensatory mechanisms to the perception of the next moment, based on shared experiences with the ecological regularities of light.
Single Blind Randomized Controlled Trial of Modified Constraint-Induced Movement Therapy in Infants With the Sequelas of Unilateral Brachial Plexus Injury
Authors: Cui Zhenzhen , Liu Le , Chen Xi , Zeng Haiyan , Zheng Shizhu , Wu De
Published: May 2022

Objective

To explore the effect of modified constraint-induced movement therapy (mCIMT) on upper limbs residual dysfunction for infancy with the sequelas of unilateral brachial plexus injury (uBPI).

Methods

Single blind randomized controlled trial of mCIMT vs. standard care. An enrolling 31 infants with a uBPI exhibiting residual dysfunction of the affected upper limb for over 6 months was conducted. And functional outcomes pertaining to the affected upper limb were assessed via AMS, GRES, RHS, and MSS at 0, 3, and 6 months after treatment.

Results

No differences were found in baseline (acquisition phase) AMS, MSS, GRES, or RHS between the control and mCIMT groups [F(1, 14) = 0.062, P = 0.086; F(1, 14) = 0.483, P = 0.499; F(1, 14) = 0.272, P = 0.610; Z = −0.336, P = 7.373]. At the 3- and 6-month follow-up time points, AMS, MSS, and GRES scores were significantly improved over baseline in both groups [mCIMT: F(2, 30) = 183.750, 128.614, 110.085, P < 0.05; Control: F(2, 28) = 204.007, 75.246, 51.070, P < 0.05]. No significant differences were found between two treatment groups at the 3-month follow-up time point [F(1, 14) = 0.565, P = 0.465; F(1, 14) = 0.228, P = 0.641; F(1, 14) = 0.713, P = 0.413; Z = −0.666, P = 0.505]. However, at the 6-month follow-up time point, AMS and MSS scores were significantly improved in the mCIMT group relative to the control group [F(1, 14) = 8.077, P = 0.013; F(1, 14) = 18.692, P = 0.001].

Conclusion

mCIMT may benefit the rehabilitation of residual upper limb dysfunction associated with a uBPI in infants.

Clinical Trial Registration

[www.chictr.org.cn], identifier [ChiCTR1900022119].
Enhanced Non-Associative Long-Term Potentiation in Immature Granule Cells in the Dentate Gyrus of Adult Rats
Authors: Simonova Natalia A. , Volgushev Maxim A. , Malyshev Alexey Y.
Published: May 2022

The dentate gyrus is one of the few sites of neurogenesis in the adult brain. Integration of new-generated granule cells into the hippocampal circuitry provides a substrate for structural plasticity, fundamental for normal function of adult hippocampus. However, mechanisms of synaptic plasticity that mediate integration of new-generated granule cells into the existing circuitry remain poorly understood. Especially mechanisms of plasticity at GABA-ergic synapses remain elusive. Here, we show that postsynaptic spiking without presynaptic activation can induce heterosynaptic, non-associative plasticity at GABA-ergic inputs to both immature and mature granule cells. In both immature and mature neurons, plastic changes were bidirectional and individual inputs could express long-term potentiation (LTP) or long-term depression (LTD), or do not change. However, properties of non-associative plasticity dramatically change with maturation of newly generated granule cells: while in immature cells there was a clear predominance of non-associative LTP and net potentiation across the inputs, in mature neurons, potentiation and depression were balanced with no net change on average. We conclude that GABA-ergic inputs to granule cells are plastic, and that the rules for induction of non-associative plasticity change with maturation. We propose that potentiation-biased non-associative plasticity of GABA-ergic transmission might help to counter-balance an increase of excitatory drive that is facilitated by enhanced LTP at glutamatergic synapses in maturating granule cells. Such mechanism might help to build a strong GABA-ergic input to surviving active new cells, necessary for normal function of mature granule cells, which operate under a tight inhibitory control and generate sparse spiking activity.
Imaging Findings and Clinical Features of Primary Spinal Epithelioid Hemangioendothelioma
Authors: Liang Pan , Zhu Bing-Bing , Ren Xiu-Chun , Gao Jian-Bo
Published: May 2022

Rationale and Objectives

Primary spinal epithelioid hemangioendothelioma (SEHE) is an extremely rare angiocentric vascular neoplasm with inherent metastatic potential, which pursues a clinical course intermediate between hemangioma and angiosarcoma. The present study sought to present computed tomography (CT) and magnetic resonance imaging (MRI) findings and clinical features of primary SEHE and review the literature.

Materials and Methods

Clinical data of four patients with primary SEHE confirmed by pathology from January 2011 to May 2020 were analyzed retrospectively. Two cases underwent CT scan, while 3 cases underwent MRI scan. Image observation included the tumor location, bone changes, morphology, density/signal characteristics, and enhanced features.

Results

The four patients were all women who ranged in age from 25 to 74 years. Four cases of the lesions were in the vertebral body; among them, two cases involved the accessory of the vertebra. Soap bubble appearance was detected in 2 cases, honeycomb osteolytic appearance in 2 cases, a sclerotic margin in 3 cases, and accompanying vertebral compression fracture in 1 case. CT showed a slightly inhomogeneous low density with punctate high-density foci. MRI showed an inhomogeneous low signal on T1-weighted image (T1WI) and a high signal on T2WI. Contrast-enhanced CT/MRI demonstrated moderate to intensive inhomogeneous enhancement of the lesions. The discs were normal. In one case, lesions presented a dural tail sign.

Conclusions

Primary SEHE is so rare in the clinic as an aggressive vascular tumor. The relatively typical clinical features and radiographic findings can help in preoperative diagnosis.
Lymph Node Metastasis Spread Patterns and the Effectiveness of Prophylactic Neck Irradiation in Sinonasal Squamous Cell Carcinoma (SNSCC)
Authors: Liu Qian , Qu Yuan , Wang Kai , Wu Runye , Zhang Ye , Huang Xiaodong , Zhang Jianghu , Chen Xuesong , Wang Jingbo , Xiao Jianping , Yi Junlin , Xu Guozhen , Luo Jingwei
Published: May 2022

Objectives

To analyze the incidence and spread of lymph node metastasis (LNM) and the effectiveness of prophylactic neck irradiation in patients with SNSCC.

Methods

A total of 255 patients with SNSCC were retrospectively reviewed. The LNM spread pattern was revealed. The clinical parameters related to LNM, and the prognostic value of elective neck irradiation (ENI) were assessed. A 1:1 matching with propensity scores was performed between ENI group and observation (OBS) group.

Results

The initial LNM rate was 20.8%, and the regional recurrence (RR) rate was 7.5%. Lymphatic spreading in SNSCC followed the common trajectories: a. level Ib ➔ level II ➔ level Va/level III/IV lymph nodes (LNs); b. retropharyngeal lymph nodes (RPLNs) ➔ level II LNs. The most frequently involved site was level II LNs (16.1%), followed by level Ib LNs (10.2%), RPLNs (4.7%), level III LNs (3.2%), level Va LNs (1.6%), level IVa LNs (1.4%) and level VIII LNs (0.8%). The median follow-up time was 105 months. The 5-year overall survival (OS) was 55.7% for N0 patients and 38.5% for patients with initial N+ or N- relapse (p = 0.009). After PSM, the 5-year regional recurrence-free survival was 71.6% and 94.7% (p = 0.046) in OBS and ENI group, respectively. The multivariate analysis showed that ENI (p = 0.013) and absence of nasopharynx involvement (p = 0.026) were associated with a significantly lower RR rate.

Conclusions

Patients with LNM had poorer survival than those who never experienced LNM. Lymphatic spread in SNSCC followed predictable patterns. ENI effectively reduced the RR rate in patients at high risk.
Protein Kinase C Epsilon Overexpression Is Associated With Poor Patient Outcomes in AML and Promotes Daunorubicin Resistance Through p-Glycoprotein-Mediated Drug Efflux
Authors: Nicholson Rachael , Menezes Ana Catarina , Azevedo Aleksandra , Leckenby Adam , Davies Sara , Seedhouse Claire , Gilkes Amanda , Knapper Steve , Tonks Alex , Darley Richard L.
Published: May 2022

The protein kinase C (PKC) family of serine/threonine kinases are pleiotropic signaling regulators and are implicated in hematopoietic signaling and development. Only one isoform however, PKCϵ, has oncogenic properties in solid cancers where it is associated with poor outcomes. Here we show that PKCϵ protein is significantly overexpressed in acute myeloid leukemia (AML; 37% of patients). In addition, PKCϵ expression in AML was associated with a significant reduction in complete remission induction and disease-free survival. Examination of the functional consequences of PKCϵ overexpression in normal human hematopoiesis, showed that PKCϵ promotes myeloid differentiation, particularly of the monocytic lineage, and decreased colony formation, suggesting that PKCϵ does not act as an oncogene in hematopoietic cells. Rather, in AML cell lines, PKCϵ overexpression selectively conferred resistance to the chemotherapeutic agent, daunorubicin, by reducing intracellular concentrations of this agent. Mechanistic analysis showed that PKCϵ promoted the expression of the efflux pump, P-GP (ABCB1), and that drug efflux mediated by this transporter fully accounted for the daunorubicin resistance associated with PKCϵ overexpression. Analysis of AML patient samples also showed a link between PKCϵ and P-GP protein expression suggesting that PKCϵ expression drives treatment resistance in AML by upregulating P-GP expression.
The Effect of Tumor Characteristics and Location on the Extent of Lymph Node Metastases of Head and Neck Cutaneous Squamous Cell Carcinoma
Authors: van Leer Bram , Leus Alet J. G. , van Dijk Boukje A. C. , van Kester Marloes S. , Halmos Gyorgy B. , Diercks Gilles F.H. , van der Vegt Bert , Vister Jeroen , Rácz Emoke , Plaat Boudewijn E. C.
Published: May 2022

Background

The extent of a neck dissection for patients with metastasis of cutaneous squamous cell carcinoma of the head and neck (HNcSCC) is still subject to debate and clear guidelines are lacking. Tumor characteristics like size, differentiation and tumor location are known risk factors for lymph node metastasis (LNM). There is some evidence that, depending on tumor location, LNM follows a specific pattern. This study aims to identify which tumor characteristics can predict the pattern and extent of LNM.

Method

In this cohort study 80 patients were included, who underwent a primary neck dissection for LNM of HNcSCC between 2003 and 2018 at the University Medical Center Groningen, the Netherlands. Retrospective data was collected for primary tumor characteristics and LNM and included surgical and follow-up data. Influence of tumor characteristics on the extent of LNM was analyzed using non-parametric tests. Logistic regression analysis were used to identify a metastasis pattern based on the primary tumor location.

Results

Only primary tumor location was associated with the pattern of LNM. HNcSCC of the ear metastasized to level II (OR = 2.6) and the parotid gland (OR = 3.6). Cutaneous lip carcinoma metastasized to ipsilateral and contralateral level I (OR = 5.3). Posterior scalp tumors showed a metastasis pattern to level II (OR = 5.6); level III (OR = 11.2), level IV (OR = 4.7) and the parotid gland (OR = 10.8). Ear canal tumors showed a low risk of LNM for all levels. The extent of LNM was not related to age or any tumor characteristics i.e. tumor diameter, infiltration depth, differentiation grade, perineural growth and vascular invasion.

Conclusion

Primary tumor location determines the LNM pattern. Whereas known unfavorable tumor characteristics did not relate to the extent of LNM. Location guided limited neck dissection combined with parotidectomy will treat most patients adequately.
Integrative Analysis Identifies Cell-Type-Specific Genes Within Tumor Microenvironment as Prognostic Indicators in Hepatocellular Carcinoma
Authors: Huang Zi-Li , Xu Bin , Li Ting-Ting , Xu Yong-Hua , Huang Xin-Yu , Huang Xiu-Yan
Published: May 2022

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, but effective early detection and prognostication methods are lacking.

Methods

The Cox regression model was built to stratify the HCC patients. The single-cell RNA sequencing data analysis and gene set enrichment analysis were employed to investigate the biological function of identified markers. PLCB1 gain- or loss-of-function experiments were performed, and obtained HCC samples were analyzed using quantitative real-time PCR and immunohistochemistry assay to validate the biological function of identified markers.

Results

In this study, we developed a model using optimized markers for HCC recurrence prediction. Specifically, we screened out 8 genes through a series of data analyses, and built a multivariable Cox model based on their expression. The risk stratifications using the Eight-Gene Cox (EGC) model were closely associated with the recurrence-free survivals (RFS) in both training and three validation cohorts. We further demonstrated that this risk stratification could serve as an independent predictor in predicting HCC recurrence, and that the EGC model could outperform other models. Moreover, we also investigated the cell-type-specific expression patterns of the eight recurrence-related genes in tumor microenvironment using single-cell RNA sequencing data, and interpreted their functional roles from correlation and gene set enrichment analyses, in vitro and in vivo experiments. Particularly, PLCB1 and SLC22A7 were predominantly expressed in malignant cells, and they were predicted to promote angiogenesis and to help maintain normal metabolism in liver, respectively. In contrast, both FASLG and IL2RB were specifically expressed in T cells, and were highly correlated with T cell marker genes, suggesting that these two genes might assist in maintaining normal function of T cell-mediated immune response in tumor tissues.

Conclusion

In conclusion, the EGC model and eight identified marker genes could not only facilitate the accurate prediction of HCC recurrence, but also improve our understanding of the mechanisms behind HCC recurrence.
p53-Mediated Indirect Regulation on Cellular Metabolism: From the Mechanism of Pathogenesis to the Development of Cancer Therapeutics
Authors: Wang Chen-Yun , Chao Chi-Hong
Published: May 2022

The transcription factor p53 is the most well-characterized tumor suppressor involved in multiple cellular processes, which has expanded to the regulation of metabolism in recent decades. Accumulating evidence reinforces the link between the disturbance of p53-relevant metabolic activities and tumor development. However, a full-fledged understanding of the metabolic roles of p53 and the underlying detailed molecular mechanisms in human normal and cancer cells remain elusive, and persistent endeavor is required to foster the entry of drugs targeting p53 into clinical use. This mini-review summarizes the indirect regulation of cellular metabolism by wild-type p53 as well as mutant p53, in which mechanisms are categorized into three major groups: through modulating downstream transcriptional targets, protein-protein interaction with other transcription factors, and affecting signaling pathways. Indirect mechanisms expand the p53 regulatory networks of cellular metabolism, making p53 a master regulator of metabolism and a key metabolic sensor. Moreover, we provide a brief overview of recent achievements and potential developments in the therapeutic strategies targeting mutant p53, emphasizing synthetic lethal methods targeting mutant p53 with metabolism. Then, we delineate synthetic lethality targeting mutant p53 with its indirect regulation on metabolism, which expands the synthetic lethal networks of mutant p53 and broadens the horizon of developing novel therapeutic strategies for p53 mutated cancers, providing more opportunities for cancer patients with mutant p53. Finally, the limitations and current research gaps in studies of metabolic networks controlled by p53 and challenges of research on p53-mediated indirect regulation on metabolism are further discussed.
Effects of N6-Methyladenosine Modification on Cancer Progression: Molecular Mechanisms and Cancer Therapy
Authors: Zhu Yong-fu , Wang Shu-Jie , Zhou Jie , Sun Ye-han , Chen You-mou , Ma Jia , Huo Xing-xing , Song Hang
Published: May 2022

N6-methyladenosine (m6A) is a major internal epigenetic modification in eukaryotic mRNA, which is dynamic and reversible. m6A is regulated by methylases (“writers”) and demethylases (“erasers”) and is recognized and processed by m6A-binding proteins (“readers”), which further regulate RNA transport, localization, translation, and degradation. It plays a role in promoting or suppressing tumors and has the potential to become a therapeutic target for malignant tumors. In this review, we focus on the mutual regulation of m6A and coding and non-coding RNAs and introduce the molecular mechanism of m6A methylation involved in regulation and its role in cancer treatment by taking common female malignant tumors as an example.