bluuebunny/crossref_metadata_2025 huggingface dataset:
Aberrant Gene Expression Profiling in Men With Sertoli Cell-Only Syndrome
Authors: Chen Tong , Wang Yichun , Tian Linlin , Guo Xuejiang , Xia Jiadong , Wang Zengjun , Song Ninghong
Published: June 2022

Sertoli cell-only syndrome (SCOS) is the most severe and common pathological type of non-obstructive azoospermia. The etiology of SCOS remains largely unknown to date despite a handful of studies reported in this area. According to the gene expression of testicular tissue samples in six datasets from the Gene Expression Omnibus, we detected 1441 differentially expressed genes (DEGs) between SCOS and obstructive azoospermia (OA) testicular tissue samples. Enriched GO terms and KEGG pathways for the downregulated genes included various terms and pathways related to cell cycle and reproduction, while the enrichment for the upregulated genes yielded many inflammation-related terms and pathways. In accordance with the protein-protein interaction (PPI) network, all genes in the most critical module belonged to the downregulated DEGs, and we obtained nine hub genes, including CCNB1, AURKA, CCNA2, BIRC5, TYMS, UBE2C, CDC20, TOP2A, and OIP5. Among these hub genes, six were also found in the most significant SCOS-specific module obtained from consensus module analysis. In addition, most of SCOS-specific modules did not have a consensus counterpart. Based on the downregulated genes, transcription factors (TFs) and kinases within the upstream regulatory network were predicted. Then, we compared the difference in infiltrating levels of immune cells between OA and SCOS samples and found a significantly higher degree of infiltration for most immune cells in SCOS than OA samples. Moreover, CD56bright natural killer cell was significantly associated with six hub genes. Enriched hallmark pathways in SCOS had remarkably more upregulated pathways than the downregulated ones. Collectively, we detected DEGs, significant modules, hub genes, upstream TFs and kinases, enriched downstream pathways, and infiltrated immune cells that might be specifically implicated in the pathogenesis of SCOS. These findings provide new insights into the pathogenesis of SCOS and fuel future advances in its theranostics.
Beneficial Immune Regulation by Biological Response Modifier Glucans in COVID-19 and Their Envisaged Potentials in the Management of Sepsis
Authors: Preethy Senthilkumar , Raghavan Kadalraja , Dedeepiya Vidyasagar Devaprasad , Surya Prakash Vaddi , Ikewaki Nobunao , Ikeue Yasunori , Nagataki Mitsuru , Iwasaki Masaru , Senthilkumar Rajappa , Abraham Samuel J. K.
Published: June 2022

Sepsis is a life-threatening condition caused by an abnormal immune response induced by infection with no approved or specific therapeutic options. We present our perspectives for the therapeutic management of sepsis through a four-way approach: (1) infection control through immune enhancement; (2) immune suppression during the initial hyper-inflammatory phase; (3) balanced immune-modulation to counter the later immune-paralysis phase; and (4) advantageous effects on metabolic and coagulation parameters throughout. COVID-19 is a virus-triggered, accelerated sepsis-like reaction that is associated with the rapid progress of an inflammatory cascade involving a cytokine storm and multiorgan failure. Here, we discuss the potential of the biological response modifiers, β-glucans (BRMGs), in the management of sepsis based on their beneficial effects on inflammatory-immune events in COVID-19 clinical studies. In COVID-19 patients, apart from metabolic regulation, BRMGs, derived from a black yeast, Aureobasidium pullulans strain AFO-202, have been reported to stimulate immune responses. BRMGs, produced by another strain (N-163) of A. pullulans, have been implicated in the beneficial regulation of inflammatory markers and immunity, namely IL-6, C-reactive protein (CRP), D-Dimer, ferritin, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCR), leucocyte-to-C-reactive protein ratio (LeCR), and leukocyte-to-IL-6 ratio (LeIR). Agents such as these β-glucans, which are safe as they have been widely consumed by humans for decades, have potential as adjuncts for the prevention and management of sepsis as they exert their beneficial effects across the spectrum of processes and factors involved in sepsis pathology, including, but not limited to, metabolism, infection, inflammation, immune modulation, immune enhancement, and gut microbiota.
Baseline Severity of Sacroiliitis and Extensive Fat Metaplasia Predicts the Progression of Backfill at the Sacroiliac Joint in Patients With Axial Spondyloarthritis
Authors: Zhang Yimeng , Guo Zikang , Wang Lisong , Zhan Ying , Qu Jin , Lei Xinwei
Published: June 2022

Objectives

Fat metaplasia in an erosion cavity, also known as backfill, is an essential intermediary in new bone formation in axial spondyloarthritis (axSpA) patients; however, the predictors of backfill progression are unknown. This longitudinal study aimed to assess the predictors of backfill progression in axSpA patients on magnetic resonance imaging (MRI).

Methods

Clinical and MRI data were collected at baseline and follow-up in 52 axSpA patients. Backfill progression was defined as the new or increased T1 hyperintensity within the SI joint space. Logistic regression analyses were performed to identify the predictors of the backfill progression.

Results

A total of 19 patients had “backfill” at baseline and 30 patients exhibited the backfill progression after follow-up. The mean disease duration and SPARCC scores at baseline were significantly different between patients with and without backfill progression (P<0.001, P=0.003, respectively). Patients with backfill progression had a higher frequency of backfill at baseline, a higher SSS score of fat metaplasia, and a higher SSS score of backfill than those without (P=0.001, P<0.001, and P=0.002, respectively). A higher fat fraction value in the fat metaplasia area at the baseline was more frequent in patients with, than without, backfill progression (P=0.019). In the univariate logistic regression analyses, a higher SPARCC score for inflammation and a higher SSS score for fat metaplasia at baseline were associated with backfill progression.

Conclusions

Severity of sacroiliitis and extensive fat metaplasia at baseline are predictors of the backfill progression in axSpA patients.
BTN3A Targeting Vγ9Vδ2 T Cells Antimicrobial Activity Against Coxiella burnetii-Infected Cells
Authors: Gay Laetitia , Mezouar Soraya , Cano Carla , Foucher Etienne , Gabriac Mélanie , Fullana Marie , Madakamutil Loui , Mège Jean-Louis , Olive Daniel
Published: June 2022

Vγ9Vδ2 T cells have been reported to participate to the immune response against infectious diseases such as the Q fever caused by Coxiella burnetii infection. Indeed, the number and proportion of Vγ9Vδ2 T cells are increased during the acute phase of Q fever. Human Vγ9Vδ2 T cell responses are triggered by phosphoantigens (pAgs) produced by pathogens and malignant cells, that are sensed via the membrane receptors butyrophilin-3A1 (BTN3A1) and -2A1 (BTN2A1). Here, by using CRISPR-Cas9 inactivation in THP-1 cells, we show that BTN3A and BTN2A are required to Vγ9Vδ2 T cell response to C. burnetii infection, though not directly involved in the infection process. Furthermore, C. burnetii-infected monocytes display increased BTN3A and BTN2A expression and induce Vγ9Vδ2 T cell activation that can be inhibited by specific antagonist mAb. More importantly, we show that the antimicrobial functions of Vγ9Vδ2 T cells towards C. burnetii are enhanced in the presence of an BTN3A activating antibody. This supports the role of Vγ9Vδ2 T cells in the control of C. burnetii infection and argues in favor of targeting these cells as an alternative treatment strategy for infectious diseases caused by intracellular bacteria.
High-Dimensional Immune Profiling by Mass Cytometry Revealed the Circulating Immune Cell Landscape in Patients With Intracranial Aneurysm
Authors: Ge Peicong , Liu Chenglong , Chan Liujia , Pang Yuheng , Li Hao , Zhang Qian , Ye Xun , Wang Jia , Wang Rong , Zhang Yan , Wang Wenjing , Zhang Dong , Zhao Jizong
Published: June 2022

Background

Increasing evidence supports a critical role of chronic inflammation in intracranial aneurysm (IA). Understanding how the immunological alterations in IA provides opportunities for targeted treatment. However, there is a lack of comprehensive and detailed characterization of the changes in circulating immune cells in IA.

Objective

To perform a comprehensive and detailed characterization of the changes in circulating immune cells in patients with IA.

Methods

Peripheral blood mononuclear cell samples from IA patients (n = 26) and age-and sex-matched healthy controls (HCs, n = 20) were analyzed using high dimensional mass cytometry, and the frequency and phenotype of immune cell subtypes were assessed.

Results

We identified 28 cell clusters and found that the immune signature of IA consists of cluster changes. IA patients exhibited dysfunction of immunity, with dysregulation of CD4+ T-cell clusters, increased B cells and monocytes, and decreased CD8+ T cells, DNT cells, and DPT cells. Moreover, compared with findings in HC, IA was associated with enhanced lymphocyte and monocyte immune activation, with a higher expression of HLA-DR, CXCR3, and CX3CR1. In addition, the expression of TLR4, p-STAT3, and the exhaustion marker PD1 was increased in T cells, B cells, and NK cells in IA patients.

Conclusions

Our data provide an overview of the circulating immune cell landscape of IA patients, and reveal that the dysfunction of circulating immunity may play a potential role in the development of IA.
Thiol Modifications in the Extracellular Space—Key Proteins in Inflammation and Viral Infection
Authors: Brücksken Kathrin A. , Loreto Palacio Paola , Hanschmann Eva-Maria
Published: June 2022

Posttranslational modifications (PTMs) allow to control molecular and cellular functions in response to specific signals and changes in the microenvironment of cells. They regulate structure, localization, stability, and function of proteins in a spatial and temporal manner. Among them, specific thiol modifications of cysteine (Cys) residues facilitate rapid signal transduction. In fact, Cys is unique because it contains the highly reactive thiol group that can undergo different reversible and irreversible modifications. Upon inflammation and changes in the cellular microenvironment, many extracellular soluble and membrane proteins undergo thiol modifications, particularly dithiol–disulfide exchange, S-glutathionylation, and S-nitrosylation. Among others, these thiol switches are essential for inflammatory signaling, regulation of gene expression, cytokine release, immunoglobulin function and isoform variation, and antigen presentation. Interestingly, also the redox state of bacterial and viral proteins depends on host cell-mediated redox reactions that are critical for invasion and infection. Here, we highlight mechanistic thiol switches in inflammatory pathways and infections including cholera, diphtheria, hepatitis, human immunodeficiency virus (HIV), influenza, and coronavirus disease 2019 (COVID-19).
Deep-Sea-Derived Fungi as Valuable Producers of Cytotoxic Secondary Metabolites and Their Leads Potential
Authors: Zhao Guangrong , Tang Wenli , Zhang Jianlong , Shi Peimin , Li Youzhi , Wang Jiao , Shen Qingqin , Si Haixia , Jiang Linlin , Yu Xin , Zhu Hongwei , Chen Guozhong , Zhang Xingxiao , Jia Hong
Published: June 2022

Cancer is the leading lethal disease worldwide. Natural products have contributed significantly to the development of approved therapeutic agents. Therefore, research into new bioactive naturally sourced metabolites with lead potential is urgently needed. It is well-known that marine microorganisms are by far one of the most notable and prolific sources of bioactive natural products. Among them, deep-sea-derived fungi are extraordinarily adapted and metabolically active under extreme environmental conditions, which enable them to produce a large number of novel secondary metabolites. Chemical examination of deep-sea-derived fungi has yielded enormous amounts of cytotoxic natural products and potential drug leads. This review summarizes a total of 229 cytotoxic compounds isolated from deep-sea-derived fungi from 2010 to 2021. The emphasis is on the unique chemical diversity of these metabolic products, together with their relevant cytotoxic properties. Among the isolated metabolites, 82 compounds have been found to possess moderate to potent cytotoxic activities. Meanwhile, we also highlight some compounds with potent cytotoxicities (namely “star molecules”) considering their high drug lead potential. This review reveals deep-sea-derived fungi as considerable resources for the development of new drugs and the potential of the newly discovered secondary metabolites as valuable antitumor lead compounds.
High Temperature Oxidation Behavior of Nano-Alumina–Modified NiAl Coating
Authors: Fang Yuqing , Shu Xiaoyong , Dong Shuhe
Published: June 2022

In this article, the nickel aluminide coating prepared by the chemical vapor deposition method has adhered deliberately with nano-alumina film on the surface by the electrophoresis method. The analysis results of oxidation behavior in the air at 1,000°C reported that the nano-alumina particles adhering to the nickel aluminide coating surface appear to be effective in facilitating the θ-Al2O3 to α-Al2O3 phase transformation. The fast θ to α phase transformation helps reduce the oxidation rate of the nickel–aluminum coating and prevents the cracking and peeling in the oxide scale. The research addressed a novel method to improve the high-temperature oxidation resistance of nickel aluminide coatings.
Global Research Trends in Irritable Bowel Syndrome: A Bibliometric and Visualized Study
Authors: Zhang Tai , Ma Xiangxue , Tian Wende , Zhang Jiaqi , Wei Yuchen , Zhang Beihua , Wang Fengyun , Tang Xudong
Published: June 2022

Background

There are about 10–23% of adults worldwide suffering from irritable bowel syndrome (IBS). Over the past few decades, there are many aspects of uncertainty regarding IBS leading to an ongoing interest in the topic as reflected by a vast number of publications, whose heterogeneity and variable quality may challenge researchers to measure their scientific impact, to identify collaborative networks, and to grasp actively researched themes. Accordingly, with help from bibliometric approaches, our goal is to assess the structure, evolution, and trends of IBS research between 2007 and 2022.

Methods

The documents exclusively focusing on IBS from 2007 to 2022 were retrieved from the Science Citation Index Expanded of the Web of Science Core Collection. The annual productivity of IBS research, and the most prolific countries or regions, authors, journals and resource-, intellectual- and knowledge-sharing in IBS research, as well as co-citation analysis of references and keywords were analyzed through Microsoft Office Excel 2019, CiteSpace, and VOSviewer.

Results

In total, 4,092 publications were reviewed. The USA led the list of countries with the most publications (1,226, 29.96%). Mayo Clinic contributed more publications than any other institution (193, 4.71%). MAGNUS SIMREN stood out as the most active and impactful scholar with the highest number of publications and the greatest betweenness centrality value. The most high-yield journal in this field was Neurogastroenterology and motility: the official journal of the European Gastrointestinal Motility Society (275, 6.72%). Gastroenterology had the most co-citations (3,721, 3.60%). Keywords with the ongoing strong citation bursts were chromogranin A, rat model, peptide YY, gut microbiota, and low-FODMAP diet, etc.

Conclusion

Through bibliometric analysis, we gleaned deep insight into the current status of literature investigating IBS for the first time. These findings will be useful to scholars interested in understanding the key information in the field, as well as identifying possible research frontiers.
Instillation of a Dry Powder in Nasal Casts: Parameters Influencing the Olfactory Deposition With Uni- and Bi-Directional Devices
Authors: Rigaut Clément , Deruyver Laura , Goole Jonathan , Haut Benoît , Lambert Pierre
Published: June 2022

Nose-to-brain delivery is a promising way to reach the central nervous system with therapeutic drugs. However, the location of the olfactory region at the top of the nasal cavity complexifies this route of administration. In this study, we used a 3D-printed replica of a nasal cavity (a so-called “nasal cast”) to reproduce in vitro the deposition of a solid powder. We considered two different delivery devices: a unidirectional device generating a classical spray and a bidirectional device that relies on the user expiration. A new artificial mucus also coated the replica. Five parameters were varied to measure their influence on the powder deposition pattern in the olfactory region of the cast: the administration device, the instillation angle and side, the presence of a septum perforation, and the flow rate of possible concomitant inspiration. We found that the unidirectional powder device is more effective in targeting the olfactory zone than the bi-directional device. Also, aiming the spray nozzle directly at the olfactory area is more effective than targeting the center of the nasal valve. Moreover, the choice of the nostril and the presence of a perforation in the septum also significantly influence the olfactory deposition. On the contrary, the inspiratory flow has only a minor effect on the powder outcome. By selecting the more efficient administration device and parameters, 44% of the powder can reach the olfactory region of the nasal cast.
Achieving Ammonium Removal Through Anammox-Derived Feammox With Low Demand of Fe(III)
Authors: Hu Lanlan , Cheng Xiaohui , Qi Guangxia , Zheng Min , Dang Yan , Li Jiyun , Xu Kangning
Published: June 2022

Feammox-based nitrogen removal technology can reduce energy consumption by aeration and emission of carbon dioxide. However, the huge theoretical demand for Fe(III) becomes a challenge for the further development of Feammox. This study investigated an anammox-derived Feammox process with an intermittent dosage of Fe2O3 and proposed a novel approach to reduce the Fe(III) consumption. The results showed that anammox genera Candidatus Brocadia and Candidatus Kuenenia in the seed anammox sludge significantly decreased after cultivation. The formation of N2 was the dominating pathway in Feammox while that of nitrite and nitrate could be neglected. Batch tests showed that specific Feammox activity of ammonium oxidation was 1.14–9.98 mg N/(g VSS·d). The maximum removal efficiency of ammonium reached 52.3% in the bioreactor with a low dosage of Fe(III) which was only 5.8% of the theoretical demand in Feammox. The removal of ammonium was mainly achieved through Feammox, while partial nitrification/anammox also played a role due to the non-power and unintentional oxygen leakage. The super-low oxygen also responded to the low demand of Fe(III) in the bioreactor because it could trigger the cycle of Fe(III)/Fe(II) by coupling Feammox and chemical oxidation of Fe(II) to Fe(III). Therefore, anammox-derived Feammox can achieve the removal of ammonium with low Fe(III) demand at super-low oxygen.
Bacillus Calmette–Guérin in Immuno-Regulation of Alzheimer’s Disease
Authors: Klein Benjamin Y. , Greenblatt Charles L. , Gofrit Ofer N. , Bercovier Hervé
Published: June 2022

Bacillus Calmette–Guérin is frequently the treatment of choice of superficial bladder cancer. Exposing the urinary bladder of elderly patients with bladder cancer to the BCG vaccine reduced the risk of Alzheimer’s disease (AD) substantially. Vaccines against other infectious microorganisms by other vaccination methods showed a similar but a lesser effect. This suggests that immune effects on AD are antigenically non-specific, likely being a metabolic result of immune system activation, similar to that shown for Juvenile diabetes. In this mini review we point to the benefit of BCG vaccine. We then briefly highlight the pathological involvement of the immune system in the AD both, in the peripheral and the central (brain) compartments. Given the uncertain prophylactic mechanism of the BCG effect against AD we propose to take advantage of the therapeutically planned bladder exposure to BCG. Based on pathological aggregation of wrongly cleaved amyloid precursor protein (APP) resistant to the unfolded protein response (UPR) which results in amyloid beta plaques we predict that BCG may impact the UPR signaling cascade. In addition pathways of innate immunity training concerned with energy metabolism, predict capability of activated immune cells to substitute deranged astrocytes that fail to support neuronal energy metabolism. This mini review points to ways through which immune cells can mediate between BCG vaccination and AD to support the wellness of the central nervous system.
Parkinsonian Syndromes in Motor Neuron Disease: A Clinical Study
Authors: Pasquini Jacopo , Trogu Francesca , Morelli Claudia , Poletti Barbara , Girotti Floriano , Peverelli Silvia , Brusati Alberto , Ratti Antonia , Ciammola Andrea , Silani Vincenzo , Ticozzi Nicola
Published: June 2022

Background

Parkinsonian syndromes may rarely occur in motor neuron disease (MND). However, previous studies are heterogeneous and mostly case reports or small case series. Therefore, we aimed to identify and characterize patients with concurrent parkinsonian syndromes extracted from a cohort of 1,042 consecutive cases diagnosed with MND at a tertiary Italian Center.

Methods

Diagnosis of Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) was made according to current criteria. Clinical characterization included: upper and lower motor neuron disease features, typical and atypical parkinsonian features, oculomotor disorders, cognitive testing, MRI features, and, when available molecular neuroimaging. Genetic testing was carried out for major MND and PD-associated genes.

Results

Parkinsonian syndromes were diagnosed in 18/1042 (1.7%) of MND patients (7 PD, 6 PSP, 3 CBS, 2 other parkinsonisms). Based on phenotype, patients could be categorized into amyotrophic lateral sclerosis (ALS)-parkinsonism and primary lateral sclerosis (PLS)-parkinsonism clusters. Across the whole database, parkinsonism was significantly more common in PLS than in other MND phenotypes (12.1 vs. 1.1%, p = 5.0 × 10−10). MND patients with parkinsonian features had older age of onset, higher frequency of oculomotor disorders, cognitive impairment, and family history of parkinsonism or dementia. Two patients showed pathogenic mutations in TARDBP and C9orf72 genes.

Conclusion

Specific patterns in MND-parkinsonism were observed, with PLS patients often showing atypical parkinsonian syndromes and ALS patients more frequently showing typical PD. Systematic clinical, genetic, and neuropathologic characterization may provide a better understanding of these phenotypes.
Visually Perceived Negative Emotion Enhances Mismatch Negativity but Fails to Compensate for Age-Related Impairments
Authors: Chen Jiali , Huang Xiaomin , Wang Xianglong , Zhang Xuefei , Liu Sishi , Ma Junqin , Huang Yuanqiu , Tang Anli , Wu Wen
Published: June 2022

Objective: Automatic detection of auditory stimuli, represented by the mismatch negativity (MMN), facilitates rapid processing of salient stimuli in the environment. The amplitude of MMN declines with ageing. However, whether automatic detection of auditory stimuli is affected by visually perceived negative emotions with normal ageing remains unclear. We aimed to evaluate how fearful facial expressions affect the MMN amplitude under ageing.

Methods: We used a modified oddball paradigm to analyze the amplitude of N100 (N1) and MMN in 22 young adults and 21 middle-aged adults.

Results: We found that the amplitude of N1 elicited by standard tones was smaller under fearful facial expressions than neutral facial expressions and was more negative for young adults than middle-aged adults. The MMN amplitude under fearful facial expressions was greater than neutral facial expressions, but the amplitude in middle-aged adults was smaller than in young adults.

Conclusion: Visually perceived negative emotion promotes the extraction of auditory features. Additionally, it enhances the effect of auditory change detection in middle-aged adults but fails to compensate for this decline with normal ageing.

Significance: The study may help to understand how visually perceived emotion affects the early stage of auditory information processing from an event process perspective.
Decoding Intracranial EEG With Machine Learning: A Systematic Review
Authors: Mirchi Nykan , Warsi Nebras M. , Zhang Frederick , Wong Simeon M. , Suresh Hrishikesh , Mithani Karim , Erdman Lauren , Ibrahim George M.
Published: June 2022

Advances in intracranial electroencephalography (iEEG) and neurophysiology have enabled the study of previously inaccessible brain regions with high fidelity temporal and spatial resolution. Studies of iEEG have revealed a rich neural code subserving healthy brain function and which fails in disease states. Machine learning (ML), a form of artificial intelligence, is a modern tool that may be able to better decode complex neural signals and enhance interpretation of these data. To date, a number of publications have applied ML to iEEG, but clinician awareness of these techniques and their relevance to neurosurgery, has been limited. The present work presents a review of existing applications of ML techniques in iEEG data, discusses the relative merits and limitations of the various approaches, and examines potential avenues for clinical translation in neurosurgery. One-hundred-seven articles examining artificial intelligence applications to iEEG were identified from 3 databases. Clinical applications of ML from these articles were categorized into 4 domains: i) seizure analysis, ii) motor tasks, iii) cognitive assessment, and iv) sleep staging. The review revealed that supervised algorithms were most commonly used across studies and often leveraged publicly available timeseries datasets. We conclude with recommendations for future work and potential clinical applications.
Tumor Microenvironment Characterization in Breast Cancer and an Immune Cell Infiltration Score Development, Validation, and Application
Authors: Li Lang
Published: June 2022

The tumor microenvironment (TME) refers to the cellular environment in which tumors exist. An increasing number of reports have emphasized its role in tumor progression, prognosis, relapse, metastasis, and therapeutic response with breast cancer (BRCA). Few studies have revealed a systematic landscape of immune cell infiltration (ICI) in BRCA. In this study, we comprehensively analyzed the immune cells infiltrating TME in BRCA. Three ICI patterns were identified through an unsupervised clustering method and an ICI score was developed by a principal component analysis (PCA). A Kaplan-Meier survival with log-rank test revealed a significant overall survival (OS) difference of BRCA patients with these three ICI patterns. We also found that a high ICI score was characterized by an elevated tumor mutation burden (TMB), effector T-cell infiltration, INF-γ-related cytotoxicity, and cytolytic activity score. An independent cohort validated that this ICI score could be a prognostic indicator for BRCA. Two immunotherapeutic cohorts and two chemotherapeutic cohorts confirmed that patients with higher ICI scores showed significant chemotherapeutic and immunotherapeutic advantages. In summary, these results suggest that the ICI patterns could act as a prognostic indicator and that the ICI score could precisely predict the clinical outcome for BRCA patients.
Multiplex Immunofluorescence and the Digital Image Analysis Workflow for Evaluation of the Tumor Immune Environment in Translational Research
Authors: Rojas Frank , Hernandez Sharia , Lazcano Rossana , Laberiano-Fernandez Caddie , Parra Edwin Roger
Published: June 2022

A robust understanding of the tumor immune environment has important implications for cancer diagnosis, prognosis, research, and immunotherapy. Traditionally, immunohistochemistry (IHC) has been regarded as the standard method for detecting proteins in situ, but this technique allows for the evaluation of only one cell marker per tissue sample at a time. However, multiplexed imaging technologies enable the multiparametric analysis of a tissue section at the same time. Also, through the curation of specific antibody panels, these technologies enable researchers to study the cell subpopulations within a single immunological cell group. Thus, multiplexed imaging gives investigators the opportunity to better understand tumor cells, immune cells, and the interactions between them. In the multiplexed imaging technology workflow, once the protocol for a tumor immune micro environment study has been defined, histological slides are digitized to produce high-resolution images in which regions of interest are selected for the interrogation of simultaneously expressed immunomarkers (including those co-expressed by the same cell) by using an image analysis software and algorithm. Most currently available image analysis software packages use similar machine learning approaches in which tissue segmentation first defines the different components that make up the regions of interest and cell segmentation, then defines the different parameters, such as the nucleus and cytoplasm, that the software must utilize to segment single cells. Image analysis tools have driven dramatic evolution in the field of digital pathology over the past several decades and provided the data necessary for translational research and the discovery of new therapeutic targets. The next step in the growth of digital pathology is optimization and standardization of the different tasks in cancer research, including image analysis algorithm creation, to increase the amount of data generated and their accuracy in a short time as described herein. The aim of this review is to describe this process, including an image analysis algorithm creation for multiplex immunofluorescence analysis, as an essential part of the optimization and standardization of the different processes in cancer research, to increase the amount of data generated and their accuracy in a short time.
The Role and Therapeutic Perspectives of Sirtuin 3 in Cancer Metabolism Reprogramming, Metastasis, and Chemoresistance
Authors: Zhao QingYi , Zhou Jing , Li Feng , Guo Sen , Zhang Liang , Li Jing , Qi Qin , Shi Yin
Published: June 2022

Sirtuin 3 (SIRT3), the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, acts as a metabolic modulator mainly located in mitochondria via regulating the process of the relevant biochemical processes by targeting crucial mediators. Recently, owing to its dual role in cancer, SIRT3 has attracted extensive attention. Cancer cells have different metabolic patterns from normal cells, and SIRT3-mediated metabolism reprogramming could be critical in the cancer context, which is closely related to the mechanism of metabolism reprogramming, metastasis, and chemoresistance in tumor cells. Therefore, it is crucial to elucidate the relevant pathological mechanisms and take appropriate countermeasures for the progression of clinical strategies to inhibit the development of cancer. In this review, existing available data on the regulation of cancer metabolism reprogramming, metastasis, and chemoresistance progression of SIRT3 are detailed, as well as the status quo of SIRT3 small molecule modulators is updated in the application of cancer therapy, aiming to highlight strategies directly targeting SIRT3-mediated tumor-suppressing and tumor-promoting, and provide new approaches for therapy application. Furthermore, we offer an effective evidence-based basis for the evolvement of potential personalized therapy management strategies for SIRT3 in cancer settings.
Association Between Metabolic Syndrome and Risk of Renal Cell Cancer: A Meta-Analysis
Authors: Du Wurong , Guo Kaibo , Jin Huimin , Sun Leitao , Ruan Shanming , Song Qiaoling
Published: June 2022

Background

Metabolic syndrome (MetS) has been related to increased risks of a variety of cancers. However, the association between MetS and the risk of renal cell cancer (RCC) remains not fully determined. This meta-analysis was conducted to investigate whether MetS is independently associated with the risk of RCC in adults.

Methods

Relevant observational studies were obtained by searching PubMed, Embase, Cochrane’s Library, and Web of Science databases. Study characteristics and outcome data were extracted independently by two authors. The random-effect model was used for meta-analysis considering the possible influence of between-study heterogeneity. Predefined subgroup analyses were used to evaluate the possible influences of study characteristics on the outcome.

Results

Eight studies involving 10,601,006 participants contributed to the meta-analysis. Results showed that MetS was independently associated with a higher risk of RCC in adult population (risk ratio [RR]: 1.62, 95% confidence interval [CI]: 1.41 to 1.87, p<0.001; I2 = 85%). Subgroup analyses showed consistent association in men (RR: 1.52, 95% CI: 1.23 to 1.89, p<0.001) and in women (RR: 1.71, 95% CI: 1.28 to 2.27, p<0.001), in Asians (RR: 1.51, 95% CI: 1.25 to 1.83, p<0.001) and in Caucasians (RR: 1.76, 95% CI: 1.46 to 2.12, p<0.001), and in community derived (RR: 1.56, 95% CI: 1.34 to 1.82, p<0.001) and non-community derived population (RR: 1.87, 95% CI: 1.71 to 2.04, p<0.001). Differences in study design or quality score also did not significantly affect the association (p for subgroup difference both >0.05).

Conclusions

MetS may be independently associated with RCC in adult population.
Lesson Learned From Hospital Palliative Care Service in a Cancer Research Center in Italy: Results of 5 Years of Experience
Authors: Alquati Sara , Peruselli Carlo , Turrà Caterina , Tanzi Silvia
Published: June 2022

Background

International studies have documented that over a third of all hospital beds are occupied by patients with palliative care needs in their last year of life. Experiences of Palliative Care Services that take place prevalently or exclusively in hospital settings are very few in Italy.

Objective

Describe clinical, educational and research activities performed by a hospital PCS and discussing opportunities and critical issues encountered in an Italian Cancer Center.

Method

Retrospective data regarding adults with advanced stage diseases referred from January 2015 to December 2019.

Results

Clinical activity - The PCS performed 2422 initial consultations with an average of 484 initial consultations per year. A majority of patients had advanced cancer, from 85% to 72%, with an average of 2583 total consultations per year and an average of 4.63 consultations per patient. The penetrance has increased over time from 6.3% to 15.75%. Educational and research activity - Since 2015, PCS has provided training to health professionals (HPs) of different departments of our hospital. Most of the educational projects for HPs were part of research projects, for example the communication training program, management of pain and end-of-life symptoms and the training program for PC-based skills.

Conclusion

Our data suggests that a PCS able to provide palliative care to inpatients and outpatient and continuous training support to other hospital specialists can relatively quickly improve the level of its penetrance in hospital activities.
Dexmedetomidine in Children on Extracorporeal Membrane Oxygenation: Pharmacokinetic Data Exploration Using Previously Published Models
Authors: Thibault Céline , Zuppa Athena F.
Published: June 2022

Background

Dexmedetomidine is a sedative and analgesic increasingly used in children supported with extracorporeal membrane oxygenation (ECMO). No data is available to describe the pharmacokinetics (PK) of dexmedetomidine in this population.

Methods

We performed a single-center prospective PK study. Children <18 years old, supported with ECMO, and on a dexmedetomidine infusion as part of their management were prospectively included. PK samples were collected. Dexmedetomidine dosing remained at the discretion of the clinical team. Six population PK models built in pediatrics were selected. Observed concentrations were compared with population predicted concentrations using the PK models.

Results

Eight children contributed 30 PK samples. None of the PK models evaluated predicted the concentrations with acceptable precision and bias. Four of the six evaluated models overpredicted the concentrations. The addition of a correction factor on clearance improved models' fit. Two of the evaluated models were not applicable to our whole population age range because of their structure.

Conclusion

Most of the evaluated PK models overpredicted the concentrations, potentially indicating increased clearance on ECMO. Population PK models applicable to a broad spectrum of ages and pathologies are more practical in pediatric critical care settings but challenging to develop.
Continual Deletion of Spinal Microglia Reforms Astrocyte Scar Favoring Axonal Regeneration
Authors: Xia Longkuo , Qi Jianhuan , Tang Mingming , Liu Jing , Zhang Da , Zhu Yanbing , Hu Baoyang
Published: June 2022

Astrocyte scar formation after spinal cord injury (SCI) efficiently limits the accurate damage but physically restricts the following axon regeneration. Lately, fine tuning scar formation is becoming a novel strategy to develop SCI treatment, yet how to leverage these opposite effects remains challenging. Here, utilizing an improved drug administration approach, we show that in a mouse model of spinal cord injury, continual deletion of microglia, especially upon scar formation, by pexidartinib decreases the amount of microglia-derived collagen I and reforms the astrocyte scar. The astrocytes become less compacted in the scar, which permits axon regeneration and extension. Although continual microglia deletion did not significantly improve the locomotive performance of the SCI mice, it did ameliorate their weight loss, possibly by improving their relevant health conditions. We thus identified a novel approach to regulate astrocyte scars for improved axon regeneration, which is indicative of the clinical treatment of SCI patients.
A Multi-Centre Prospective Study of the Efficacy and Safety of Alglucosidase Alfa in Chinese Patients With Infantile-Onset Pompe Disease
Authors: Zhu Diqi , Zhu Jiacong , Qiu Wenjuan , Wang Benzhen , Liu Lin , Yu Xiaodan , Ou Zhenheng , Shan Guangsong , Wang Jian , Li Bin , Chen Xiaokang , Liu Cong , Li Zipu , Fu Lijun
Published: June 2022

Background: A high prevalence of infantile-onset Pompe disease (IOPD) in the Chinese population has been noted, but there are currently no reported clinical trials of enzyme replacement therapy (ERT) for IOPD in this population. The purpose of this study was to evaluate the efficacy and safety of alglucosidase alfa in Chinese patients with IOPD.

Materials and Methods: A multicentre, single-arm, prospective, open-label clinical trial was performed at 4 sites in China. Eligible Chinese subjects with IOPD received an infusion of alglucosidase alfa at a dose of 20 mg/kg every 2 weeks for up to 52 weeks. The primary endpoints of clinical efficacy were the survival rate and changes in the left ventricular mass index (LVMI). The safety assessment was based on the incidence of adverse events (AEs).

Results: A total of 10 eligible subjects were enrolled in the study. The mean age at the start of ERT was 5.36 ± 1.56 months. Nine subjects had survived after 52 weeks of treatment. One subject discontinued the study and died after mechanical ventilation was withdrawn. The intent-to-treat analysis demonstrated that the survival rate was 90.0% (95% confidence interval: 55.5–99.7%). The mean LVMI at week 52 was 70.59 ± 39.93 g/m2 compared to that of 298.02 ± 178.43 g/m2 at baseline, with a difference of -227.60 ± 155.99 g/m2. All subjects had left ventricular mass (LVM) Z scores >10 at baseline, and eight subjects (80%) achieved Z scores <5 at week 52. No treatment-related AEs were observed, and no AEs led to the discontinuation of treatment.

Conclusions: This clinical trial is the first study of ERT for IOPD in China, indicating that alglucosidase alfa has favourable efficacy and safety for the treatment of Chinese patients with IOPD (ClinicalTrials.gov number, NCT03687333).
The Potential Use of Antibiotics Against Helicobacter pylori Infection: Biopharmaceutical Implications
Authors: Miri Amir Hossein , Kamankesh Mojtaba , Llopis-Lorente Antoni , Liu Chenguang , Wacker Matthias G. , Haririan Ismaeil , Asadzadeh Aghdaei Hamid , Hamblin Michael R. , Yadegar Abbas , Rad-Malekshahi Mazda , Zali Mohammad Reza
Published: June 2022

Helicobacter pylori (H. pylori) is a notorious, recalcitrant and silent germ, which can cause a variety of debilitating stomach diseases, including gastric and duodenal ulcers and gastric cancer. This microbe predominantly colonizes the mucosal layer of the human stomach and survives in the inhospitable gastric microenvironment, by adapting to this hostile milieu. In this review, we first discuss H. pylori colonization and invasion. Thereafter, we provide a survey of current curative options based on polypharmacy, looking at pharmacokinetics, pharmacodynamics and pharmaceutical microbiology concepts, in the battle against H. pylori infection.
TAZ Induces Migration of Microglia and Promotes Neurological Recovery After Spinal Cord Injury
Authors: Hu Xuyang , Huang Jinxin , Li Yiteng , Dong Lei , Chen Yihao , Ouyang Fangru , Li Jianjian , Li Ziyu , Jing Juehua , Cheng Li
Published: June 2022

Following spinal cord injury (SCI), microglia gradually migrate to the edge of the lesion, interweaving around the border of the lesion to form the microglial scar, which performs inflammatory limiting and neuroprotective functions. Recent reports showed that Yes-associated protein (YAP) was expressed in astrocytes and promoted the formation of astrocytic scars, while YAP was not expressed in microglia after SCI. YAP and its paralogue transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, which have a similar functional role as both are negatively regulated by the Hippo signalling pathway. However, the expression and function of TAZ after SCI are unclear. Our research group previously found that Fascin-1 was highly expressed in microglia and promoted migration of microglia after SCI, and that, there was a close regulatory relationship between Fascin-1 and YAP/TAZ. In this study, we demonstrated that TAZ was significantly upregulated and mainly expressed in microglia after SCI, and accumulated in the nuclei of microglia in the spinal cord at 14 days post-SCI. Moreover, TAZ was upregulated and accumulated in the nuclei of anti-inflammatory M2-like (M2-L) polarized or myelin-treated microglia. Additionally, XMU-MP-1 (an inhibitor of the Hippo kinase MST1/2 to active TAZ) promoted the aggregation of microglia around the lesion core, resulting in the formation of microglial scars and the functional recovery of mice after SCI. Our findings also indicated that TAZ promoted microglial migration in vitro. Mechanistically, Fascin-1 interacted with TAZ, which upregulated TAZ expression and induced TAZ nuclear accumulation in microglia to promote microglial migration. These findings revealed that TAZ mediated microglial migration to the edge of the lesion core, promoting the formation of microglial scars and functional recovery after SCI. Moreover, TAZ was downstream of Fascin-1, which positively regulated microglial migration after SCI.
Challenges of Future Accelerators for Particle Physics Research
Authors: Gourlay Stephen , Raubenheimer Tor , Shiltsev Vladimir
Published: June 2022

For over half a century, high-energy particle accelerators have been a major enabling technology for particle and nuclear physics research as well as sources of X-rays for photon science research in material science, chemistry and biology. Particle accelerators for energy and intensity Frontier research in particle and nuclear physics continuously push the accelerator community to invent ways to increase the energy and improve the performance of accelerators, reduce their cost, and make them more power efficient. The accelerator community has demonstrated imagination and creativity in developing a plethora of future accelerator ideas and proposals. The technical maturity of the proposed facilities ranges from shovel-ready to those that are still largely conceptual. At this time, over 100 contributed papers have been submitted to the Accelerator Frontier of the US particle physics decadal community planning exercise known as Snowmass’2021. These papers cover a broad spectrum of topics: beam physics and accelerator education, accelerators for neutrinos, colliders for Electroweak/Higgs studies and multi-TeV energies, accelerators for Physics Beyond Colliders and rare processes, advanced accelerator concepts, and accelerator technology for Radio Frequency cavities (RF), magnets, targets and sources. This paper provides an overview of the present state of accelerators for particle physics and gives a brief description of some of the major facilities that have been proposed, their perceived advantages and some of the remaining challenges.
Te Film as a Saturable Absorber for the Mid-Infrared Er3+-Doped ZBLAN Fiber Laser
Authors: Zhang Min , Kang Liu , Ma Zhijian , Yan Peiguang , Hou Shaodong
Published: June 2022

We demonstrate a Q-switched Er3+-doped ZBLAN fiber laser at 2.8 µm mid-infrared (mid-IR) region achieved by adopting Te as the saturable absorber mirror (SAM). The modulation depth and saturation intensity of the Te-SAM were measured to be ∼7.2% and 10.81 MW∕cm2, respectively. Stable Q-switched laser pulses with the maximum pulse energy of 3.05 µJ and the minimum pulse width of 0.457 µs at the launched pump power of 4.51 W were obtained. Maximum average output power of 357 mW with repetition rate of 116.98 kHz were achieved. The signal-to-noise ratio (SNR) is 52 dB, which is higher than that of most 2.8 µm mid-infrared Q-switched fiber lasers reported so far. To the best of our knowledge, this is the first demonstration from a Q-switched fiber laser at 2.8 µm based on a Te-SAM.