bluuebunny/crossref_metadata_2025 huggingface dataset:
The Genetics of Autoimmune Myositis
Authors: Lamb Janine A.
Published: May 2022

The idiopathic inflammatory myopathies (IIM) are rare, heterogeneous systemic autoimmune disorders, characterized by inflammation of skeletal muscle and multi-organ involvement. Studies to identify genetic risk factors and dysregulated gene expression in IIM aim to increase our understanding of disease pathogenesis. Genome-wide association studies have confirmed the HLA region as the most strongly associated region in IIM, with different associations between clinically-defined subgroups. Associated genes are involved in both the innate and adaptive immune response, while identification of variants reported in other autoimmune disorders suggests shared biological pathways. Targeted imputation analysis has identified key associated amino acid residues within HLA molecules that may influence antigen recognition. These amino acids increase risk for specific clinical phenotypes and autoantibody subgroups, and suggest that serology-defined subgroups may be more homogeneous. Recent data support the contribution of rare genetic variation to disease susceptibility in IIM, including mitochondrial DNA variation in sporadic inclusion body myositis and somatic mutations and loss of heterozygosity in cancer-associated myositis. Gene expression studies in skeletal muscle, blood and skin from individuals with IIM has confirmed the role of interferon signalling and other dysregulated pathways, and identified cell-type specific signatures. These dysregulated genes differentiate IIM subgroups and identify potential biomarkers. Here, we review recent genetic studies in IIM, and how these inform our understanding of disease pathogenesis and provide mechanistic insights into biological pathways.
Genetic Variations Controlling Regulatory T Cell Development and Activity in Mouse Models of Lupus-Like Autoimmunity
Authors: Roach Tracoyia , Morel Laurence
Published: May 2022

Immune homeostasis is a constant balancing act between effector T cells and regulatory T cells defined by Foxp3 expression, the transcription factor that drives their differentiation and immunosuppressive activity. Immune homeostasis is altered when Treg cells are not generated or maintained in sufficient numbers. Treg cells rendered unstable by loss of Foxp3 expression, known as ex-Treg cells, gain pro-inflammatory functions. Treg cells may also become dysfunctional and lose their suppressive capabilities. These alterations can cause an imbalance between effector and regulatory subsets, which may ultimately lead to autoimmunity. This review discusses recent studies that identified genetic factors that maintain Treg cell stability as well as preserve their suppressive function. We focus on studies associated with systemic lupus erythematosus and highlight their findings in the context of potential therapeutic gene targeting in Treg cells to reverse the phenotypic changes and functional dysregulation inducing autoimmunity.
Improving Glucocorticoid Sensitivity of Brain-Homing CD4+ T Helper Cells by Steroid Hormone Crosstalk
Authors: Koetzier Steven C. , van Langelaar Jamie , Wierenga-Wolf Annet F. , Melief Marie-José , Pol Kim , Musters Suzanne , Lubberts Erik , Dik Willem A. , Smolders Joost , van Luijn Marvin M.
Published: May 2022

In early multiple sclerosis (MS), an IFN-γhighGM-CSFhighIL-17low CD4+ T-cell subset termed T helper 17.1 (Th17.1) reveals enhanced capacity to infiltrate the central nervous system. Th17.1 cells express high levels of multidrug resistance protein 1 (MDR1), which contributes to their poor glucocorticoid responsiveness. In this study, we explored whether glucocorticoid sensitivity of Th17.1 cells can generically be improved through synergy between steroid hormones, including calcitriol (1,25(OH)2D3), estradiol (E2) and progesterone (P4). We showed that human blood Th17.1 cells were less sensitive to 1,25(OH)2D3 than Th17 cells, as reflected by lower vitamin D receptor (VDR) levels and reduced modulation of MDR1, IFN-γ and GM-CSF expression after 1,25(OH)2D3 exposure. Upon T-cell activation, VDR levels were increased, but still lower in Th17.1 versus Th17 cells, which was accompanied by a 1,25(OH)2D3-mediated decline in MDR1 surface expression as well as secretion of IFN-γ and GM-CSF. In activated Th17.1 cells, 1,25(OH)2D3 amplified the suppressive effects of methylprednisolone (MP) on proliferation, MDR1 surface levels, secretion of IFN-γ and granzyme B, as well as expression of brain-homing markers CCR6 and VLA-4. The addition of P4 to 1,25(OH)2D3 further enhanced MP-mediated reduction in proliferation, CD25, CCR6 and CXCR3. Overall, this study indicates that glucocorticoid sensitivity of Th17.1 cells can be enhanced by treatment with 1,25(OH)2D3 and further improved with P4. Our observations implicate steroid hormone crosstalk as a therapeutic avenue in Th17.1-associated inflammatory diseases including MS.
Post-COVID-19 Fatigue and SARS-CoV-2 Specific Humoral and T-Cell Responses in Male and Female Outpatients
Authors: Meisinger Christa , Goßlau Yvonne , Warm Tobias D. , Leone Vincenza , Hyhlik-Dürr Alexander , Linseisen Jakob , Kirchberger Inge
Published: May 2022

Background

Information on the clinical characteristics and pathophysiological mechanisms underlying post-COVID-19 fatigue are scarce. The main objective of this study was to evaluate sex-specific humoral and T-cell responses associated with post-COVID-19 fatigue in a sample of individuals treated as outpatients.

Methods

At a median time of 279 (179;325) days after the acute infection, a total of 281 individuals (45.9% men) aged 18-87 years old were included in the analysis. The participants were examined at the University Hospital of Augsburg, Southern Germany. Fatigue was assessed using the Fatigue Assessment Scale (FAS). Levels of anti-SARS-CoV2-spike IgG antibodies were measured by an enzyme-linked immunosorbent assay (ELISA), and for exploration of the SARS-CoV2-specific T-cell response, ex vivo ELISpot/FLUOROspot assays were conducted using an interferon-γ (IFN-γ) and interleukin-2 (IL-2) SARS-CoV-iSpot kit.

Results

Women more significantly suffered from post-COVID-19 fatigue in comparison to men (47.4% versus 25.6%, p=0.0002). Females but not males with fatigue showed a significantly lower number of T-cells producing IFN-γ, IL-2 or both IL-2 and IFNγ in comparison with females without fatigue. In both sexes, serum levels of anti-SARS-CoV2-spike IgG antibodies did not differ significantly between participants with or without fatigue.

Conclusions

Development of fatigue after acute COVID-19 disease might be associated with SARS-CoV-2-specific T-cell responses in women, but not men after a mild infection course treated outpatient.
The Antibiofilm Role of Biotics Family in Vaginal Fungal Infections
Authors: Boahen Angela , Than Leslie Thian Lung , Loke Yi-Linn , Chew Shu Yih
Published: May 2022

“Unity in strength” is a notion that can be exploited to characterize biofilms as they bestow microbes with protection to live freely, escalate their virulence, confer high resistance to therapeutic agents, and provide active grounds for the production of biofilms after dispersal. Naturally, fungal biofilms are inherently resistant to many conventional antifungals, possibly owing to virulence factors as their ammunitions that persistently express amid planktonic transition to matured biofilm state. These ammunitions include the ability to form polymicrobial biofilms, emergence of persister cells post-antifungal treatment and acquisition of resistance genes. One of the major disorders affecting vaginal health is vulvovaginal candidiasis (VVC) and its reoccurrence is termed recurrent VVC (RVVC). It is caused by the Candida species which include Candida albicans and Candida glabrata. The aforementioned Candida species, notably C. albicans is a biofilm producing pathogen and habitually forms part of the vaginal microbiota of healthy women. Latest research has implicated the role of fungal biofilms in VVC, particularly in the setting of treatment failure and RVVC. Consequently, a plethora of studies have advocated the utilization of probiotics in addressing these infections. Specifically, the excreted or released compounds of probiotics which are also known as postbiotics are being actively researched with vast potential to be used as therapeutic options for the treatment and prevention of VVC and RVVC. These potential sources of postbiotics are harnessed due to their proven antifungal and antibiofilm. Hence, this review discusses the role of Candida biofilm formation in VVC and RVVC. In addition, we discuss the application of pro-, pre-, post-, and synbiotics either individually or in combined regimen to counteract the abovementioned problems. A clear understanding of the role of biofilms in VVC and RVVC will provide proper footing for further research in devising novel remedies for prevention and treatment of vaginal fungal infections.
Mucosa-Colonizing Microbiota Correlate With Host Autophagy Signaling in Patients With Inflammatory Bowel Disease
Authors: Wang Wenxue , Liu Zhongjian , Yue Wei , Zhu Ling , Zhong Huijie , Yang Chao , He Tian , Wan Ping , Geng Jiawei
Published: May 2022

Both bacteria and autophagy are implicated in inflammatory bowel disease (IBD) pathogenesis. However, how bacteria crosstalk with autophagy signaling remains largely known, especially in intestinal mucosa. This study aimed to profile the internal complex autophagy signaling cascade and their external correlation with these bacteria, and consequently provide a systematic and precise target for future IBD diagnosis and therapy. We found the Ulcerative colitis (UC) patients exhibited more severe dysbiosis than the Crohn’s disease (CD) patients, as represented by alpha diversity, community phenotypes, and functional annotation compared with the control population. Meanwhile, CD patients showed greater transcriptional signaling activities of autophagy, endoplasmic reticulum (ER) stress, and bile acid production. Dominant bacteria (e.g., Rhodococcus, Escherichia, Shigella, and Enterococcus) were positively correlated and low-abundance bacteria (e.g., Bacillus, Acidovorax, Acinetobacter, and Stenotrophomonas) were negatively correlated with the autophagy signaling cascade (184 autophagy genes, 52 ER stress genes, and 22 bile acid production genes). Our observations suggested UC patients showed temporary and widespread microbiota turbulence and CD patients showed processive and local autophagy activity during IBD progression. Intestinal mucosa-colonizing bacteria were correlated with the bile/ER stress/autophagy signaling axis in IBD pathogenesis.
Evidence for Water-Borne Transmission of Highly Pathogenic Avian Influenza H5N1 Viruses
Authors: Zhang Hongbo , Yao Yanfeng , Li Yan , Chen Jianjun , Chen Ze
Published: May 2022

In this study, we isolated 10 H5N1 strains from water samples in Dongting Lake and 4 H5N1 strains from lakeside backyard poultry. These isolates belonged to three distinct clades (clade 2.3.2, 2.3.4, and 7). Phylogenetic analysis showed a diversified genome constellation. The genetic characteristics of some viruses isolated from water samples were extremely similar to those from lakeside poultry. Pathogenic experiments showed that selected represented isolates in this study were highly pathogenic for SPF chickens but had a diversified virulence in mice. The results of our study suggested the potential transmission of avian influenza (H5N1) between the poultry and wild waterfowls and water body around the habitat may play an important role.
Distinct Effects of the Apolipoprotein E ε4 Genotype on Associations Between Delayed Recall Performance and Resting-State Electroencephalography Theta Power in Elderly People Without Dementia
Authors: Wang Jing , Sun Tingting , Zhang Ying , Yu Xin , Wang Huali
Published: May 2022

Background

Abnormal electroencephalography (EEG) activity has been demonstrated in mild cognitive impairment (MCI), and theta rhythm might be inversely related to memory. The apolipoprotein E (ApoE) epsilon 4 (ε4) allele, as a genetic vulnerability factor for pathologic and normal age-related cognitive decline, may influence different patterns of cognitive dysfunction. Therefore, the present study primarily aimed to verify the role of resting theta rhythm in delayed recall deficits, and further explore the effects of the ApoE genotype on the associations between the resting theta power and delayed recall performance in the elderly individuals without dementia.

Methods

A total of 47 individuals without dementia, including 23 MCI and 24 healthy subjects (HCs), participated in the study. All subjects were administered the Hopkins Verbal Learning Test–Revised (HVLT-R) to measure delayed recall performance. Power spectra based on resting-state EEG data were used to examine brain oscillations. Linear regression was used to examine the relationships between EEG power and delayed recall performance in each subgroup.

Results

The increased theta power in the bilateral central and temporal areas (Ps = 0.02–0.044, uncorrected) was found in the patients with MCI, and were negatively correlated with delayed recall performance (rs = −0.358 to −0.306, Ps = 0.014–0.036, FDR corrected) in the elderly individuals without dementia. The worse delayed recall performance was associated with higher theta power in the left central and temporal areas, especially in ApoE ε4 non-carriers and not in carriers (rs = −0.404 to −0.369, Ps = 0.02–0.035, uncorrected).

Conclusion

Our study suggests that theta disturbances might contribute to delayed recall memory decline. The ApoE genotype may have distinct effects on EEG-based neural correlates of episodic memory performance.
Neu1 Is Released From Activated Microglia, Stimulating Microglial Phagocytosis and Sensitizing Neurons to Glutamate
Authors: Allendorf David H. , Brown Guy C.
Published: May 2022

Neuraminidase 1 (Neu1) hydrolyses terminal sialic acid residues from glycoproteins and glycolipids, and is normally located in lysosomes, but can be released onto the surface of activated myeloid cells and microglia. We report that endotoxin/lipopolysaccharide-activated microglia released Neu1 into culture medium, and knockdown of Neu1 in microglia reduced both Neu1 protein and neuraminidase activity in the culture medium. Release of Neu1 was reduced by inhibitors of lysosomal exocytosis, and accompanied by other lysosomal proteins, including protective protein/cathepsin A, known to keep Neu1 active. Extracellular neuraminidase or over-expression of Neu1 increased microglial phagocytosis, while knockdown of Neu1 decreased phagocytosis. Microglial activation caused desialylation of microglial phagocytic receptors Trem2 and MerTK, and increased binding to Trem2 ligand galectin-3. Culture media from activated microglia contained Neu1, and when incubated with neurons induced their desialylation, and increased the neuronal death induced by low levels of glutamate. Direct desialylation of neurons by adding sialidase or inhibiting sialyltransferases also increased glutamate-induced neuronal death. We conclude that activated microglia can release active Neu1, possibly by lysosomal exocytosis, and this can both increase microglial phagocytosis and sensitize neurons to glutamate, thus potentiating neuronal death.
Inhibitory NPY Neurons Provide a Large and Heterotopic Commissural Projection in the Inferior Colliculus
Authors: Anair Justin D. , Silveira Marina A. , Mirjalili Pooyan , Beebe Nichole L. , Schofield Brett R. , Roberts Michael T.
Published: May 2022

Located in the midbrain, the inferior colliculus (IC) plays an essential role in many auditory computations, including speech processing and sound localization. The right and left sides of the IC are interconnected by a dense fiber tract, the commissure of the IC (CoIC), that provides each IC with one of its largest sources of input (i.e., the contralateral IC). Despite its prominence, the CoIC remains poorly understood. Previous studies using anterograde and retrograde tract-tracing showed that IC commissural projections are predominately homotopic and tonotopic, targeting mirror-image locations in the same frequency region in the contralateral IC. However, it is unknown whether specific classes of neurons, particularly inhibitory neurons which constitute ~10%–40% of the commissural projection, follow this pattern. We, therefore, examined the commissural projections of Neuropeptide Y (NPY) neurons, the first molecularly identifiable class of GABAergic neurons in the IC. Using retrograde tracing with Retrobeads (RB) in NPY-hrGFP mice of both sexes, we found that NPY neurons comprise ~11% of the commissural projection. Moreover, focal injections of Retrobeads showed that NPY neurons in the central nucleus of the IC exhibit a more divergent and heterotopic commissural projection pattern than non-NPY neurons. Thus, commissural NPY neurons are positioned to provide lateral inhibition to the contralateral IC. Through this circuit, sounds that drive activity in limited regions on one side of the IC likely suppress activity across a broader region in the contralateral IC.
Whole-Brain Network Models: From Physics to Bedside
Authors: Pathak Anagh , Roy Dipanjan , Banerjee Arpan
Published: May 2022

Computational neuroscience has come a long way from its humble origins in the pioneering work of Hodgkin and Huxley. Contemporary computational models of the brain span multiple spatiotemporal scales, from single neuronal compartments to models of social cognition. Each spatial scale comes with its own unique set of promises and challenges. Here, we review models of large-scale neural communication facilitated by white matter tracts, also known as whole-brain models (WBMs). Whole-brain approaches employ inputs from neuroimaging data and insights from graph theory and non-linear systems theory to model brain-wide dynamics. Over the years, WBM models have shown promise in providing predictive insights into various facets of neuropathologies such as Alzheimer's disease, Schizophrenia, Epilepsy, Traumatic brain injury, while also offering mechanistic insights into large-scale cortical communication. First, we briefly trace the history of WBMs, leading up to the state-of-the-art. We discuss various methodological considerations for implementing a whole-brain modeling pipeline, such as choice of node dynamics, model fitting and appropriate parcellations. We then demonstrate the applicability of WBMs toward understanding various neuropathologies. We conclude by discussing ways of augmenting the biological and clinical validity of whole-brain models.
Metabolomics of Cerebrospinal Fluid in Multiple Sclerosis Compared With Healthy Controls: A Pilot Study
Authors: Židó Michal , Kačer David , Valeš Karel , Svobodová Zuzana , Zimová Denisa , Štětkárová Ivana
Published: May 2022

Background

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) leading to the loss of myelin and axons. Diagnosis is based on clinical findings, MRI, and analysis of cerebrospinal fluid (CSF). CSF is an ultrafiltrate of plasma and reflects inflammatory processes in the CNS. The aim of this study was to perform metabolomics analysis of CSF in patients after the first attack of MS and healthy controls and try to find new specific analytes for MS including those potentially predicting disease activities at the onset.

Methods

We collected CSF from 19 patients (16 females, aged 19–55 years) after the first attack of clinical symptoms who fulfilled revised McDonald criteria of MS and CSF of 19 controls (16 females, aged 19–50 years). Analyses of CSF samples were provided using the high-performance liquid chromatography system coupled with a mass spectrometer with a high-resolution detector (TripleTOF 5600, AB Sciex, Canada).

Results

Approximately 130 selected analytes were identified, and 30 of them were verified. During the targeted analysis, a significant decrease in arginine and histidine and a less significant decrease in the levels of asparagine, leucine/isoleucine, and tryptophan, together with a significant increase of palmitic acid in the patient group, were found.

Conclusion

We observed significant differences in amino and fatty acids in the CSF of newly diagnosed patients with MS in comparison with controls. The most significant changes were observed in levels of arginine, histidine, and palmitic acid that may predict inflammatory disease activity. Further studies are necessary to support these findings as potential biomarkers of MS.
Secreted Amyloid Precursor Protein Alpha, a Neuroprotective Protein in the Brain Has Widespread Effects on the Transcriptome and Proteome of Human Inducible Pluripotent Stem Cell-Derived Glutamatergic Neurons Related to Memory Mechanisms
Authors: Peppercorn Katie , Kleffmann Torsten , Jones Owen , Hughes Stephanie , Tate Warren
Published: May 2022

Secreted amyloid precursor protein alpha (sAPPα) processed from a parent human brain protein, APP, can modulate learning and memory. It has potential for development as a therapy preventing, delaying, or even reversing Alzheimer’s disease. In this study a comprehensive analysis to understand how it affects the transcriptome and proteome of the human neuron was undertaken. Human inducible pluripotent stem cell (iPSC)-derived glutamatergic neurons in culture were exposed to 1 nM sAPPα over a time course and changes in the transcriptome and proteome were identified with RNA sequencing and Sequential Window Acquisition of All THeoretical Fragment Ion Spectra-Mass Spectrometry (SWATH-MS), respectively. A large subset (∼30%) of differentially expressed transcripts and proteins were functionally involved with the molecular biology of learning and memory, consistent with reported links of sAPPα to memory enhancement, as well as neurogenic, neurotrophic, and neuroprotective phenotypes in previous studies. Differentially regulated proteins included those encoded in previously identified Alzheimer’s risk genes, APP processing related proteins, proteins involved in synaptogenesis, neurotransmitters, receptors, synaptic vesicle proteins, cytoskeletal proteins, proteins involved in protein and organelle trafficking, and proteins important for cell signalling, transcriptional splicing, and functions of the proteasome and lysosome. We have identified a complex set of genes affected by sAPPα, which may aid further investigation into the mechanism of how this neuroprotective protein affects memory formation and how it might be used as an Alzheimer’s disease therapy.
Extruded Wheat Bran Consumption Increases Serum Short-Chain Fatty Acids but Does Not Modulate Psychobiological Functions in Healthy Men: A Randomized, Placebo-Controlled Trial
Authors: Dalile Boushra , La Torre Danique , Kalc Polona , Zoppas Francesca , Roye Chiara , Loret Chrystel , Lamothe Lisa , Bergonzelli Gabriela , Courtin Christophe M. , Vervliet Bram , Oudenhove Lukas Van , Verbeke Kristin
Published: May 2022

Background

Incorporation of wheat bran (WB) into food products increases intake of dietary fiber, which has been associated with improved mood and cognition and a lower risk for psychiatric disorders such as depression, with short-chain fatty acids (SCFAs) as candidate mediators of these effects. Modifying WB using extrusion cooking increases SCFA productionin vitrorelative to unmodified WB.

Objective

The aim of this study was to evaluate the effects of extruded WB on psychobiological functioning and the mediating role of SCFAs.

Methods

In a randomized, triple-blind, placebo-controlled trial, 69 healthy male participants consumed 55 g of breakfast cereal containing either extruded WB or placebo daily for 28 days. At pre- and post-intervention visits, the cortisol response to experimentally induced stress was measured as a primary outcome. In addition, serum SCFAs and brain-derived neurotrophic factors were quantified as potential mediators. Secondary psychobiological outcomes included subjective stress responses, responses to experimentally induced fear, cortisol awakening response, heart rate variability, and retrospective subjective mood ratings. Intestinal permeability, fecal SCFAs, and stool consistency were measured as secondary biological outcomes.

Results

Extruded WB increased serum acetate and butyrate (p< 0.05). None of the primary or secondary outcomes were affected by the intervention. Participants who consumed a placebo exhibited an increase in the percentage of fecal dry weight but did not report increased constipation. Despite these statistically significant effects, these changes were small in magnitude.

Conclusions

Extruded WB consumption increased serum short-chain fatty acids but did not modulate psychobiological functions in healthy men. Effective modulation of psychobiological functions may require greater increases in SCFAs than those achieved following extruded WB consumption. Rather than attempting to induce health benefits with a single fiber-rich food, combinations of different fibers, particularly highly fermentable ones, might be needed to further increase SCFA production and uptake in the systemic circulation to observe an effect on psychobiological processes.
Identification and Validation of Novel Immune-Related Alternative Splicing Signatures as a Prognostic Model for Colon Cancer
Authors: Liu Yunze , Xu Lei , Hao Chuanchuan , Wu Jin , Jia Xianhong , Ding Xia , Lin Changwei , Zhu Hongmei , Zhang Yi
Published: May 2022

Background

Individual immune-related alternative splicing (AS) events have been found to be significant in immune regulation and cancer prognosis. However, a comprehensive analysis of AS events in cancer cells based on immune-related genes (IRGs) has not been performed, and its clinical value is unknown.

Methods

Colon cancer cases with AS data were obtained from TCGA, and then, we identified overall survival-related AS events (OS-ASEs) based on IRGs by univariate analyses. Using Lasso regression, multivariate Cox regression, Kaplan–Meier analysis and nomograms, we constructed an AS risk model based on the calculated risk score. Furthermore, associations of the risk score with clinical and immune features were confirmed through the Wilcoxon rank sum test, association analysis, etc. Finally, by qRT–PCR, cell coculture and CCK-8 analyses, we validated the significance of OS-ASEs in colon cancer cell lines and clinical samples.

Results

A total of 3,119 immune-related AS events and 183 OS-ASEs were identified, and 9 OS-ASEs were ultimately used to construct a comprehensive risk model for colon cancer patients. Low-risk patients had better OS and DFS rates than high risk patients. Furthermore, a high risk score corresponded to high numbers of multiple tumour-infiltrating immune cells and high expression of HLA-D region genes and immune checkpoint genes. Notably, we identified for the first time that anti-PD-L1 or anti-CTLA-4 antibodies may decrease the OS of specific colon cancer patients in the low-risk group. Additionally, the in vitro experiment validated that CD46-9652-ES and PSMC5-43011-ES are positively correlated with the infiltration of immune cells and promote the growth of colon cancer cells. CD46-9652-ES can contribute to T cell-mediated tumour cell killing. PSMC5-43011-ES was observed to induce M2 polarization of macrophages.

Conclusions

This study identified and validated immune-related prognostic AS signatures that can be used as a novel AS prognostic model and provide a novel understanding of the relationship between the immune microenvironment and clinical outcomes.
Imprime PGG Enhances Anti-Tumor Effects of Tumor-Targeting, Anti-Angiogenic, and Immune Checkpoint Inhibitor Antibodies
Authors: Chan Anissa S. H. , Kangas Takashi O. , Qiu Xiaohong , Uhlik Mark T. , Fulton Ross B. , Ottoson Nadine R. , Gorden Keith B. , Yokoyama Yumi , Danielson Michael E. , Jevne Trinda M. , Michel Kyle S. , Graff Jeremy R. , Bose Nandita
Published: May 2022

Imprime PGG (Imprime) is in late-stage clinical development as a combinatorial agent with several therapeutic modalities. Here we present pre-clinical mechanistic data supportive of Imprime, a soluble yeast β-1,3/1,6-glucan pathogen-associated molecular pattern able to prime innate immune cells in a Dectin-1dependent manner. In tumor-free mice, Imprime evoked broad innate immune responses (type I interferon signature, mobilization of myeloid cells, dendritic cell and monocyte/macrophage expression of co-stimulatory ligands like CD86, and activation of natural killer cells). Imprime-mediated activation of myeloid cells also resulted in functional priming of antigen-specific CD8 T cell response. In tumor-bearing mice, Imprime monotherapy further resulted in activation of systemic and tumor infiltrating macrophages and enhanced cytotoxic CD8 T cell trafficking. Imprime enhanced the anti-tumor activity of several combinatorial agents in mouse cancer models; anti-tyrosinase-related protein 1 antibody in B16F10 melanoma experimental lung metastasis model, anti-vascular endothelial growth factor receptor 2 antibody in H1299 and H441 lung cancer, and anti-programmed cell death protein 1 antibody in MC38 colon cancer models. Mechanistically, combining Imprime with these combinatorial therapeutic agents elicited enhanced innate immune activation, supporting immunological synergy. Finally, Imprime treatment induced similar in vitro phenotypic and functional activation of human innate immune cells. Collectively, these data demonstrate Imprime’s potential to orchestrate a broad, yet coordinated, anti-cancer immune response and complement existing cancer immunotherapies.
Is There Another Posterior Approach for Presacral Tumors Besides the Kraske Procedure? — A Study on the Feasibility and Safety of Surgical Resection of Primary Presacral Tumors via Transsacrococcygeal Transverse Incision
Authors: Zhao Xudong , Zhou Sixin , Liu Na , Li Peiyu , Chen Lin
Published: May 2022

Background

The aim of the present study was to explore the feasibility and safety of the surgical resection of presacral tumors via a transsacrococcygeal transverse incision.

Methods

The clinical data and prognoses of patients with presacral tumors who underwent surgery at the Chinese People’s Liberation Army (PLA) General Hospital between January 2009 and December 2018 were retrospectively reviewed and analyzed.

Results

A total of 110 patients with presacral tumors were included in this study, including 82 female patients and 28 male patients, with a female-to-male ratio of 2.9:1. A posterior approach (transsacrococcygeal transverse incision) was utilized in 105 patients, an anterior approach (transabdominal excision) was utilized in 1 patient, and a combined (posterior plus anterior) approach was utilized in 4 patients. The mean tumor size was 8.72 ± 4.28 cm. More than half of the patients (n=59/110) with presacral tumors were asymptomatic. Twenty-six pathological types were observed in our study, including 97 benign lesions and 13 malignant lesions. The intraoperative complication rate was 42.7% (n=47/110), whereas the postoperative morbidity rate was 3.6% (n=4/110). The length of hospital stay for patients treated with the posterior approach was shorter than that of patients treated with the anterior and combined approaches. After a mean follow-up of 90.13 ± 31.22 months, 11 patients had local presacral tumor recurrence, and 1 patient had distant metastasis, with a combined recurrence rate of 10.9% (n=12/110).

Conclusions

The surgical resection of primary presacral tumors via a transsacrococcygeal transverse incision is feasible and safe, with acceptable oncological therapeutic outcomes and a low postoperative morbidity rate, making it worth popularizing in clinical practice.
Ultrasound Instead of X-Ray to Diagnose Neonatal Fractures: A Feasibility Study Based on a Case Series
Authors: Liu Jing , Zhang Li , Qiu Ru-Xin
Published: May 2022

Background

Fracture is a common birth injury in neonates, and its diagnosis mainly depends on chest X-ray examination, while ultrasound is typically not included in the diagnostic work-up of neonatal fractures. The aim of this study was to investigate the feasibility of using ultrasound to replace X-rays for the diagnosis of fractures in newborns and to determine the ultrasound characteristics of such fractures.

Methods

Bedside ultrasound with an appropriate probe and scanning angle was performed on 52 newborn infants with suspected fractures based on physical examination findings, and the ultrasound results were compared with the X-ray examination results.

Results

All 52 infants (100%) showed typical signs of fracture on ultrasound, including 46 cases of clavicle fracture, 3 cases of skull fracture, 2 cases of rib fracture, and 1 case of humerus fracture. Ultrasound was able to detect interrupted cortical continuity, displacement or angulation at the broken end, and callus formation during the recovery period. Chest X-ray examination was performed on 30 patients and identified 96.7% (29/30) of fractures, and the coincidence rate between ultrasound and X-ray was 100%. However, the sensitivity of ultrasound was higher than that of X-ray.

Conclusion

Ultrasound diagnosis of neonatal fracture is accurate, reliable, simple, and feasible. Therefore, it can replace X-ray examinations for the routine diagnosis of common types of neonatal bone fractures.
The Role of GLI in the Regulation of Hepatic Epithelial–Mesenchymal Transition in Biliary Atresia
Authors: Siyu Pu , Junxiang Wang , Qi Wang , Yimao Zhang , Shuguang Jin
Published: May 2022

Objective

To study the regulatory role of GLI1/GLI2, a nuclear transcription factor of the Sonic hedgehog (Shh) signaling pathway, in epithelial–mesenchymal transition (EMT) related to hepatic fibrosis in patients with biliary atresia (BA).

Methods

The messenger RNA (mRNA) and protein expression levels of GLI1/GLI2, Snail/Slug, and other Shh- and EMT-related cytokines were tested in the liver tissues of BA patients and animals. Then, GLI1/GLI2 was silenced and overexpressed in mouse intrahepatic bile duct epithelial cells (mIBECs) and BA animals to investigate changes in the mRNA and protein expression of EMT key factors and liver fibrosis indicators. After silencing and overexpression of GLI1/GLI2, immunofluorescence was used to detect the expression of cytokeratin-19 (CK19) and α-smooth muscle actin (α-SMA) in mIBECs, and hematoxylin and eosin (HE) staining and Masson staining were used to observe the degree of liver fibrosis in the BA animals.

Results

Compared with the control, the mRNA and protein expression levels of GLI2, Snail, vimentin, and α-SMA were significantly increased and those of E-cadherin were significantly decreased in liver tissue from BA patients and animals. Overexpression of GLI2 increased the mRNA and protein expression levels of Snail, vimentin, and α-SMA and that of E-cadherin was significantly decreased in mIBECs and BA animals. After GLI2 silencing, the opposite pattern was observed. Immunofluorescence detection showed enhanced expression of the bile duct epithelial cell marker CK19 in mIBECs after GLI2 silencing and enhanced expression of the mesenchymal cell marker α-SMA after GLI2 overexpression. HE and Masson staining suggested that the GLI2-overexpressing group had a significantly higher degree of fibrosis.

Conclusion

The Shh signaling pathway plays an important role in fibrogenesis in BA. GLI2 can significantly regulate EMT in mIBECs and livers of BA mice.
Exome Sequencing Identifies the Extremely Rare ITGAV and FN1 Variants in Early Onset Inflammatory Bowel Disease Patients
Authors: Al-Numan Huda Husain , Jan Rana Mohammed , Al-Saud Najla bint Saud , Rashidi Omran M. , Alrayes Nuha Mohammad , Alsufyani Hadeel A. , Mujalli Abdulrahman , Shaik Noor Ahmad , Mosli Mahmoud Hisham , Elango Ramu , Saadah Omar I. , Banaganapalli Babajan
Published: May 2022

Background

Molecular diagnosis of early onset inflammatory bowel disease (IBD) is very important for adopting suitable treatment strategies. Owing to the sparse data available, this study aims to identify the molecular basis of early onset IBD in Arab patients.

Methods

A consanguineous Arab family with monozygotic twins presenting early onset IBD was screened by whole exome sequencing (WES). The variants functional characterization was performed by a series of computational biology methods. The IBD variants were further screened in in-house whole exome data of 100 Saudi cohorts ensure their rare prevalence in the population.

Results

Genetic screening has identified the digenic autosomal recessive mode of inheritance of ITGAV (G58V) and FN1 (G313V) variants in IBD twins with early onset IBD. Findings from pathogenicity predictions, stability and molecular dynamics have confirmed the deleterious nature of both variants on structural features of the corresponding proteins. Functional biology data suggested that both genes show abundant expression in gastrointestinal tract and immune organs, involved in immune cell restriction, regulation of different immune related pathways. Data from knockout mouse models for ITGAV gene has revealed that the dysregulated expression of this gene impacts intestinal immune homeostasis. The defective ITGAV and FN1 involved in integrin pathway, are likely to induce intestinal inflammation by disturbing immune homeostasis.

Conclusions

Our findings provide novel insights into the molecular etiology of pediatric onset IBD and may likely pave way in developing genomic medicine.
Antidiabetic Effect of Rehmanniae Radix Based on Regulation of TRPV1 and SCD1
Authors: Liu Ye , Zhu Ruizheng , Liu Bei , Wang Wuqing , Yang Ping , Cao Zhonglian , Yang Xiaolei , Du Wandi , Yang Qing , Liang Jingru , Hu Jiarong , Ma Guo
Published: May 2022

Purpose: This study aimed to disclose the antidiabetic mechanisms of Rehmanniae Radix (RR).

Methods: The antidiabetic effect of RR was studied in Streptozocin (STZ)–induced diabetes mellitus (DM) rats and HepG2 cells with insulin resistance (IR). Antidiabetic targets and signaling pathways of RR were confirmed by the network pharmacology and transcriptome analysis as well as HK2 cells induced by high glucose (HG).

Results: After the DM rats were administrated RR extract (RRE) for 4 weeks, their body weight was 10.70 ± 2.00% higher than those in the model group, and the fasting blood glucose (FBG), AUC of the oral glucose tolerance test, and insulin sensitivity test values were 73.23 ± 3.33%, 12.31 ± 2.29%, and 13.61 ± 5.60% lower in the RRE group, respectively. When compared with the model group, an increase of 45.76 ± 3.03% in the glucose uptake of HepG2 cells with IR was seen in the RRE group. The drug (RR)–components–disease (DM)–targets network with 18 components and 58 targets was established. 331 differentially expressed genes (DEGs) were identified. TRPV1 and SCD1 were important DEGs by the intersectional analysis of network pharmacology and renal transcriptome. The TRPV1 overexpression significantly inhibited apoptosis and oxidative stress of the HK2 cells induced by HG, while SCD1 overexpression induced apoptosis and oxidative stress of the HK2 cells induced by low and high glucose. When compared to the HG group, the mRNA and protein expressions of TRPV1 in the presence of RRE (100 μg/ml) increased by 3.94 ± 0.08 and 2.83 ± 0.40 folds, respectively.

Conclusion: In summary, RR displayed an inspiring antidiabetic effect by reducing FBG and IR, upregulating the mRNA and protein expressions of TRPV1, and downregulating mRNA expression of SCD1. Induction of TRPV1 and inhibition of SCD1 by RR was possibly one of its antidiabetic mechanisms.
Appropriateness of Antibiotic Prescribing in Hospitalized Children: A Focus on the Real-World Scenario of the Different Paediatric Subspecialties
Authors: Nasso Chiara , Scarfone Alessandro , Pirrotta Igor , Rottura Michelangelo , Giorgi Domenico Antonio , Pallio Giovanni , Irrera Natasha , Squadrito Violetta , Squadrito Francesco , Irrera Pierangela , Arcoraci Vincenzo , Altavilla Domenica
Published: May 2022

Background: Antibiotics are prescribed for children both in hospital and community settings, particularly at preschool age. Italy shows a high rate of inappropriate antibiotic prescriptions which may represent a serious problem in the hospital scenario. Thus, the aim of this study was to investigate appropriateness of antibiotic prescribing in the context of different paediatric subspecialties in a hospital setting.

Methods: Antibiotics prescribing was retrospectively analysed in paediatric patients (0–18 years) admitted in the emergency paediatrics, general paediatrics, paediatric nephrology and rheumatology units between January and December 2019. Patients were stratified by age in neonates, infants, toddlers, children and adolescents. Assessments were conducted by trained local assessors and appropriateness was classified as appropriate, inappropriate and not assessable.

Results: Empirical antibiotics were mainly prescribed following a diagnosis of respiratory, gastrointestinal and/or urinary infection. A total of 825 antibiotic prescriptions were recorded in the three subspecialties; 462 antibiotic prescriptions (56%) out of 825 were assessed as inappropriate and 55 prescriptions (6.7%) were not assessable. Inappropriateness considerably varied within subspecialties: the risk of inappropriate antibiotic prescribing was higher in emergency paediatrics and general paediatric than in children, according to age. Ceftriaxone and clarithromycin were the most inappropriate prescribed antibiotics in the emergency paediatrics whereas amoxicillin/clavulanic acid represented the most inappropriate antibiotic prescribed in general paediatrics.

Conclusion: The present data may be useful in order to reduce inappropriate antibiotic prescribing in the paediatric setting; antibiotic stewardship and clinical improvement programs in hospital paediatric care are strongly recommended.
Recent Advances in Clinical Diagnosis and Pharmacotherapy Options of Membranous Nephropathy
Authors: Wang Yan-Ni , Feng Hao-Yu , Nie Xin , Zhang Ya-Mei , Zou Liang , Li Xia , Yu Xiao-Yong , Zhao Ying-Yong
Published: May 2022

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome among adults, which is the leading glomerular disease that recurs after kidney transplantation. Treatment for MN remained controversial and challenging, partly owing to absence of sensitive and specific biomarkers and effective therapy for prediction and diagnosis of disease activity. MN starts with the formation and deposition of circulating immune complexes on the outer area in the glomerular basement membrane, leading to complement activation. The identification of autoantibodies against the phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing protein 7A (THSD7A) antigens illuminated a distinct pathophysiological rationale for MN treatments. Nowadays, detection of serum anti-PLA2R antibodies and deposited glomerular PLA2R antigen can be routinely applied to MN. Anti-PLA2R antibodies exhibited much high specificity and sensitivity. Measurement of PLA2R in immune complex deposition allows for the diagnosis of PLA2R-associated MN in patients with renal biopsies. In the review, we critically summarized newer diagnosis biomarkers including PLA2R and THSD7A tests and novel promising therapies by using traditional Chinese medicines such as Astragalus membranaceus, Tripterygium wilfordii, and Astragaloside IV for the treatment of MN patients. We also described unresolved questions and future challenges to reveal the diagnosis and treatments of MN. These unprecedented breakthroughs were quickly translated to clinical diagnosis and management. Considerable advances of detection methods played a critical role in diagnosis and monitoring of treatment.
Effects of Intermittent Hypoxia-Hyperoxia Exposure Prior to Aerobic Cycling Exercise on Physical and Cognitive Performance in Geriatric Patients—A Randomized Controlled Trial
Authors: Behrendt Tom , Bielitzki Robert , Behrens Martin , Glazachev Oleg S. , Schega Lutz
Published: May 2022

Background: It was recently shown that intermittent hypoxic-hyperoxic exposure (IHHE) applied prior to a multimodal training program promoted additional improvements in cognitive and physical performance in geriatric patients compared to physical training only. However, there is a gap in the literature to which extent the addition of IHHE can enhance the effects of an aerobic training. Therefore, the aim of this study was to investigate the efficacy of IHHE applied prior to aerobic cycling exercise on cognitive and physical performance in geriatric patients.

Methods: In a randomized, two-armed, controlled, and single-blinded trial, 25 geriatric patients (77–94 years) were assigned to two groups: intervention group (IG) and sham control group (CG). Both groups completed 6 weeks of aerobic training using a motorized cycle ergometer, three times a week for 20 min per day. The IG was additionally exposed to intermittent hypoxic and hyperoxic periods for 30 min prior to exercise. The CG followed the similar procedure breathing sham hypoxia and hyperoxia (i.e., normoxia). Within 1 week before and after the interventions, cognitive performance was assessed with the Dementia-Detection Test (DemTect) and the Clock Drawing Test (CDT), while physical performance was measured using the Timed “Up and Go” Test (TUG) and the Short-Physical-Performance-Battery (SPPB).

Results: No interaction effect was found with respect to the DemTect (ηp2 = 0.02). An interaction effect with medium effect size (ηp2 = 0.08) was found for CDT performance with a higher change over time for IG (d = 0.57) compared to CG (d = 0.05). The ANCOVA with baseline-adjustment indicated between-group differences with a large and medium effect size at post-test for the TUG (ηp2 = 0.29) and SPPB (ηp2 = 0.06) performance, respectively, in favour of the IG. Within-group post-hoc analysis showed that the TUG performance was worsened in the CG (d = 0.65) and remained unchanged in the IG (d = 0.19). Furthermore, SPPB performance was increased (d = 0.58) in IG, but no relevant change over time was found for CG (d = 0.00).

Conclusion: The current study suggests that an additional IHHE prior to aerobic cycling exercise seems to be more effective to increase global cognitive functions as well as physical performance and to preserve functional mobility in geriatric patients in comparison to aerobic exercise alone after a 6-week intervention period.