bluuebunny/crossref_metadata_2025 huggingface dataset:
Siglec15 is a prognostic indicator and a potential tumor-related macrophage regulator that is involved in the suppressive immunomicroenvironment in gliomas
Authors: Wang Jinchao , Xu Linzong , Ding Qian , Li Xiaoru , Wang Kai , Xu Shangchen , Liu Bin
Published: May 2023

Background

Siglec15 is rising as a promising immunotherapeutic target in bladder, breast, gastric, and pancreatic cancers. The aim of the present study is to explore the prognostic value and immunotherapeutic possibilities of Siglec15 in gliomas using bioinformatics and clinicopathological methods.

Methods

The bioinformatics approach was used to examine Siglec15 mRNA expression in gliomas based on TCGA, CGGA, and GEO datasets. Then, the predictive value of Siglec15 expression on progression-free survival time (PFST) and overall survival time (OST) in glioma patients was comprehensively described.The TCGA database was screened for differentially expressed genes (DEGs) between the high and low Siglec15 expression groups, and enrichment analysis of the DEGs was performed. The Siglec15 protein expression and its prognostic impact in 92 glioma samples were explored using immunohistochemistry Next, the relationships between Siglec15 expression and infiltrating immune cells, immune regulators and multiple immune checkpoints were analysed.

Results

Bioinformatics analyses showed that high Siglec15 levels predicted poor clinical prognosis and adverse recurrence time in glioma patients. In the immunohistochemical study serving as a validation set, Siglec15 protein overexpression was found in 33.3% (10/30) of WHO grade II, 56% (14/25) of WHO grade III, and 70.3% (26/37) of WHO grade IV gliomas respectively. Siglec15 protein overexpression was also found to be an independent prognostic indicator detrimental to the PFST and OST of glioma patients. Enrichment analysis showed that the DEGs were mainly involved in pathways associated with immune function, including leukocyte transendothelial migration, focal adhesion, ECM receptor interaction, and T-cell receptor signaling pathways. In addition, high Siglec15 expression was related to M2 tumor-associated macrophages (TAMs), N2 tumor-infiltrating neutrophils, suppressive tumor immune microenvironment, and multiple immune checkpoint molecules. Immunofluorescence analysis confirmed the colocalization of Siglec15 and CD163 on TAMs.

Conclusion

Siglec15 overexpression is common in gliomas and predicts an adverse recurrence time and overall survival time. Siglec15 is a potential target for immunotherapy and a potential TAMs regulator that is involved in the suppressed immunomicroenvironment in gliomas.
Osteopontin depletion in macrophages perturbs proteostasis via regulating UCHL1-UPS axis and mitochondria-mediated apoptosis
Authors: Rentsendorj Altan , Raedschelders Koen , Fuchs Dieu-Trang , Sheyn Julia , Vaibhav Vineet , Porritt Rebecca A. , Shi Haoshen , Dagvadorj Jargalsaikhan , de Freitas Germano Juliana , Koronyo Yosef , Arditi Moshe , Black Keith L. , Gaire Bhakta Prasad , Van Eyk Jennifer E. , Koronyo-Hamaoui Maya
Published: May 2023

Introduction

Osteopontin (OPN; also known as SPP1), an immunomodulatory cytokine highly expressed in bone marrow-derived macrophages (BMMΦ), is known to regulate diverse cellular and molecular immune responses. We previously revealed that glatiramer acetate (GA) stimulation of BMMΦ upregulates OPN expression, promoting an anti-inflammatory, pro-healing phenotype, whereas OPN inhibition triggers a pro-inflammatory phenotype. However, the precise role of OPN in macrophage activation state is unknown.

Methods

Here, we applied global proteome profiling via mass spectrometry (MS) analysis to gain a mechanistic understanding of OPN suppression versus induction in primary macrophage cultures. We analyzed protein networks and immune-related functional pathways in BMMΦ either with OPN knockout (OPNKO) or GA-mediated OPN induction compared with wild type (WT) macrophages. The most significant differentially expressed proteins (DEPs) were validated using immunocytochemistry, western blot, and immunoprecipitation assays.

Results and discussion

We identified 631 DEPs in OPNKO or GA-stimulated macrophages as compared to WT macrophages. The two topmost downregulated DEPs in OPNKO macrophages were ubiquitin C-terminal hydrolase L1 (UCHL1), a crucial component of the ubiquitin-proteasome system (UPS), and the anti-inflammatory Heme oxygenase 1 (HMOX-1), whereas GA stimulation upregulated their expression. We found that UCHL1, previously described as a neuron-specific protein, is expressed by BMMΦ and its regulation in macrophages was OPN-dependent. Moreover, UCHL1 interacted with OPN in a protein complex. The effects of GA activation on inducing UCHL1 and anti-inflammatory macrophage profiles were mediated by OPN. Functional pathway analyses revealed two inversely regulated pathways in OPN-deficient macrophages: activated oxidative stress and lysosome-mitochondria-mediated apoptosis (e.g., ROS, Lamp1-2, ATP-synthase subunits, cathepsins, and cytochrome C and B subunits) and inhibited translation and proteolytic pathways (e.g., 60S and 40S ribosomal subunits and UPS proteins). In agreement with the proteome-bioinformatics data, western blot and immunocytochemical analyses revealed that OPN deficiency perturbs protein homeostasis in macrophages—inhibiting translation and protein turnover and inducing apoptosis—whereas OPN induction by GA restores cellular proteostasis. Taken together, OPN is essential for macrophage homeostatic balance via the regulation of protein synthesis, UCHL1-UPS axis, and mitochondria-mediated apoptotic processes, indicating its potential application in immune-based therapies.
Effects of bariatric surgery on breast density in adult obese women: systematic review and meta-analysis
Authors: Sun Dezheng , Huang Zhiping , Dong Wenyan , Zhao Xiang , Liu Chaoqian , Sheng Yuan
Published: May 2023

Introduction

Bariatric surgery is one of the most effective methods for treating obesity. It can effectively reduce body weight and reduce the incidence of obesity-related breast cancer. However, there are different conclusions about how bariatric surgery changes breast density. The purpose of this study was to clarify the changes in breast density from before to after bariatric surgery.

Methods

The relevant literature was searched through PubMed and Embase to screen for studies. Meta-analysis was used to clarify the changes in breast density from before to after bariatric surgery.

Results

A total of seven studies were included in this systematic review and meta-analysis, including a total of 535 people. The average body mass index decreased from 45.3 kg/m2 before surgery to 34.4 kg/m2 after surgery. By the Breast Imaging Reporting and Data System score, the proportion of grade A breast density from before to after bariatric surgery decreased by 3.83% (183 vs. 176), grade B (248 vs. 263) increased by 6.05%, grade C (94 vs. 89) decreased by 5.32%, and grade D (1 vs. 4) increased by 300%. There was no significant change in breast density from before to after bariatric surgery (OR=1.27, 95% confidence interval (CI) [0.74, 2.20], P=0.38). By the Volpara density grade score, postoperative volumetric breast density increased (standardized mean difference = -0.68, 95% CI [-1.08, -0.27], P = 0.001).

Discussions

Breast density increased significantly after bariatric surgery, but this depended on the method of detecting breast density. Further randomized controlled studies are needed to validate our conclusions.
How to train your myeloid cells: a way forward for helminth vaccines?
Authors: Doolan Rory , Putananickal Namitha , Tritten Lucienne , Bouchery Tiffany
Published: May 2023

Soil-transmitted helminths affect approximately 1.5 billion people worldwide. However, as no vaccine is currently available for humans, the current strategy for elimination as a public health problem relies on preventive chemotherapy. Despite more than 20 years of intense research effort, the development of human helminth vaccines (HHVs) has not yet come to fruition. Current vaccine development focuses on peptide antigens that trigger strong humoral immunity, with the goal of generating neutralizing antibodies against key parasite molecules. Notably, this approach aims to reduce the pathology of infection, not worm burden, with only partial protection observed in laboratory models. In addition to the typical translational hurdles that vaccines struggle to overcome, HHVs face several challenges (1): helminth infections have been associated with poor vaccine responses in endemic countries, probably due to the strong immunomodulation caused by these parasites, and (2) the target population displays pre-existing type 2 immune responses to helminth products, increasing the likelihood of adverse events such as allergy or anaphylaxis. We argue that such traditional vaccines are unlikely to be successful on their own and that, based on laboratory models, mucosal and cellular-based vaccines could be a way to move forward in the fight against helminth infection. Here, we review the evidence for the role of innate immune cells, specifically the myeloid compartment, in controlling helminth infections. We explore how the parasite may reprogram myeloid cells to avoid killing, notably using excretory/secretory (ES) proteins and extracellular vesicles (EVs). Finally, learning from the field of tuberculosis, we will discuss how anti-helminth innate memory could be harnessed in a mucosal-trained immunity-based vaccine.
The multikinase inhibitor axitinib in the treatment of advanced hepatocellular carcinoma: the current clinical applications and the molecular mechanisms
Authors: Jiang Hao , Liao Jian , Wang Liezhi , Jin Chong , Mo Jinggang , Xiang Sheng
Published: May 2023

Advanced hepatocellular carcinoma (HCC) is a formidable public health problem with limited curable treatment options. Axitinib, an oral tyrosine kinase inhibitor, is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This anti-angiogenic drug was found to have promising activity in various solid tumors, including advanced HCC. At present, however, there is no relevant review article that summarizes the exact roles of axitinib in advanced HCC. In this review, 24 eligible studies (seven studies in the ClinicalTrials, eight experimental studies, and nine clinical trials) were included for further evaluation. The included randomized or single-arm phase II trials indicated that axitinib could not prolong the overall survival compared to the placebo for the treatment of advanced HCC, but improvements in progression free survival and time to tumor progression were observed. Experimental studies showed that the biochemical effects of axitinib in HCC might be regulated by its associated genes and affected signaling cascades (e.g. VEGFR2/PAK1, CYP1A2, CaMKII/ERK, Akt/mTor, and miR-509-3p/PDGFRA). FDA approved sorafenib combined with nivolumab (an inhibitor of PD-1/PD-L1) as the first line regimen for the treatment of advanced HCC. Since both axitinib and sorafenib are tyrosine kinase inhibitors as well as the VEGFR inhibitors, axitinib combined with anti-PDL-1/PD-1 antibodies may also exhibit tremendous potential in anti-tumoral effects for advanced HCC. The present review highlights the current clinical applications and the molecular mechanisms of axitinib in advanced HCC. To move toward clinical applications by combining axitinib and other treatments in advanced HCC, more studies are still warranted in the near future.
Genetic diagnosis of inborn errors of immunity using clinical exome sequencing
Authors: Kwon Soon Sung , Cho Youn Keong , Hahn Seungmin , Oh Jiyoung , Won Dongju , Shin Saeam , Kang Ji-Man , Ahn Jong Gyun , Lee Seung-Tae , Choi Jong Rak
Published: May 2023

Inborn errors of immunity (IEI) include a variety of heterogeneous genetic disorders in which defects in the immune system lead to an increased susceptibility to infections and other complications. Accurate, prompt diagnosis of IEI is crucial for treatment plan and prognostication. In this study, clinical utility of clinical exome sequencing (CES) for diagnosis of IEI was evaluated. For 37 Korean patients with suspected symptoms, signs, or laboratory abnormalities associated with IEI, CES that covers 4,894 genes including genes related to IEI was performed. Their clinical diagnosis, clinical characteristics, family history of infection, and laboratory results, as well as detected variants, were reviewed. With CES, genetic diagnosis of IEI was made in 15 out of 37 patients (40.5%). Seventeen pathogenic variants were detected from IEI-related genes, BTK, UNC13D, STAT3, IL2RG, IL10RA, NRAS, SH2D1A, GATA2, TET2, PRF1, and UBA1, of which four variants were previously unreported. Among them, somatic causative variants were identified from GATA2, TET2, and UBA1. In addition, we identified two patients incidentally diagnosed IEI by CES, which was performed to diagnose other diseases of patients with unrecognized IEI. Taken together, these results demonstrate the utility of CES for the diagnosis of IEI, which contributes to accurate diagnosis and proper treatments.
Lipid metabolism and rheumatoid arthritis
Authors: Lei Qian , Yang Jie , Li Li , Zhao Ning , Lu Cheng , Lu Aiping , He Xiaojuan
Published: May 2023

As a chronic progressive autoimmune disease, rheumatoid arthritis (RA) is characterized by mainly damaging the synovium of peripheral joints and causing joint destruction and early disability. RA is also associated with a high incidence rate and mortality of cardiovascular disease. Recently, the relationship between lipid metabolism and RA has gradually attracted attention. Plasma lipid changes in RA patients are often detected in clinical tests, the systemic inflammatory status and drug treatment of RA patients can interact with the metabolic level of the body. With the development of lipid metabolomics, the changes of lipid small molecules and potential metabolic pathways have been gradually discovered, which makes the lipid metabolism of RA patients or the systemic changes of lipid metabolism after treatment more and more comprehensive. This article reviews the lipid level of RA patients, as well as the relationship between inflammation, joint destruction, cardiovascular disease, and lipid level. In addition, this review describes the effect of anti-rheumatic drugs or dietary intervention on the lipid profile of RA patients to better understand RA.
Medication use and contextual factors associated with meeting guideline-based glycemic levels in diabetes among a nationally representative sample
Authors: McDaniel Cassidi C. , Lo-Ciganic Wei-Hsuan , Garza Kimberly B. , Kavookjian Jan , Fox Brent I. , Chou Chiahung
Published: May 2023

Introduction

Based on the long-lasting diabetes management challenges in the United States, the objective was to examine glycemic levels among a nationally representative sample of people with diabetes stratified by prescribed antihyperglycemic treatment regimens and contextual factors.

Methods

This serial cross-sectional study used United States population-based data from the 2015 to March 2020 National Health and Nutrition Examination Surveys (NHANES). The study included non-pregnant adults (≥20 years old) with non-missing A1C and self-reported diabetes diagnosis from NHANES. Using A1C lab values, we dichotomized the outcome of glycemic levels into <7% versus ≥7% (meeting vs. not meeting guideline-based glycemic levels, respectively). We stratified the outcome by antihyperglycemic medication use and contextual factors (e.g., race/ethnicity, gender, chronic conditions, diet, healthcare utilization, insurance, etc.) and performed multivariable logistic regression analyses.

Results

The 2042 adults with diabetes had a mean age of 60.63 (SE = 0.50), 55.26% (95% CI = 51.39–59.09) were male, and 51.82% (95% CI = 47.11–56.51) met guideline-based glycemic levels. Contextual factors associated with meeting guideline-based glycemic levels included reporting an “excellent” versus “poor” diet (aOR = 4.21, 95% CI = 1.92–9.25) and having no family history of diabetes (aOR = 1.43, 95% CI = 1.03–1.98). Contextual factors associated with lower odds of meeting guideline-based glycemic levels included taking insulin (aOR = 0.16, 95% CI = 0.10–0.26), taking metformin (aOR = 0.66, 95% CI = 0.46–0.96), less frequent healthcare utilization [e.g., none vs. ≥4 times/year (aOR = 0.51, 95% CI = 0.27–0.96)], being uninsured (aOR = 0.51, 95% CI = 0.33–0.79), etc.

Discussion

Meeting guideline-based glycemic levels was associated with medication use (taking vs. not taking respective antihyperglycemic medication classes) and contextual factors. The timely, population-based estimates can inform national efforts to optimize diabetes management.
Therapeutic prospect on umbilical cord mesenchymal stem cells in animal model with primary ovarian insufficiency: a meta-analysis
Authors: Wang Xinrun , Li Tianye , Bai Xuechai , Zhu Yun , Zhang Meiliang , Wang Liang
Published: May 2023

Background

Primary ovarian insufficiency (POI) leads to not only infertile but several adverse health events to women. Traditional treatment methods have their own set of limitations and drawbacks that vary in degree. Application of human umbilical cord mesenchymal stem cell (hUCMSC) is a promising strategy for POI. However, there is a lack of literatures on application of hUCMSC in human. Animal experimental model, however, can reflect the potential effectiveness of this employment. This study aimed to evaluate the curative effect of hUCMSC on animals with POI on a larger scale.

Methods

To gather data, Pubmed, Embase, and Cochrane Library were searched for studies published up to April 2022. Various indices, including the animals' estrous cycle, serum sex hormone levels, and follicle number in the ovary, were compared between the experimental group and those with Premature Ovarian Insufficiency (POI).

Results

The administration of human umbilical cord-derived mesenchymal stem cells (hUCMSC) has been shown to significantly improve the estrous cycle (RR: 3.32, 95% CI: [1.80, 6.12], I2 = 0%, P = 0.0001), but robustly decrease its length (SMD: −1.97, 95% CI: [−2.58, −1.36], I2 = 0%, P < 0.00001). It can also strikingly increase levels of serum estradiol (SMD: 5.34, 95% CI: [3.11, 7.57], I2 = 93%, P < 0.00001) and anti-müllerian hormone (SMD: 1.92, 95% CI: [0.60, 3.25], I2 = 68%, P = 0.004). Besides, it lowers levels of serum follicle-stimulating hormone (SMD: −3.02, 95% CI: [−4.88, −1.16], I2 = 93%, P = 0.001) and luteinising hormone (SMD: −2.22, 95% CI: [−3.67, −0.76], I2 = 78%, P = 0.003), and thus collectively promotes folliculogenesis (SMD: 4.90, 95% CI: [3.92, 5.88], I2 = 0%, P < 0.00001).

Conclusions

Based on the presented findings, it is concluded that the administration of hUCMSC in animal models with POI can result in significant improvements in several key indicators, including estrous cycle recovery, hormone level modulation, and promotion of folliculogenesis. These positive outcomes suggest that hUCMSC may have potential as a treatment for POI in humans. However, further research is needed to establish the safety and efficacy of hUCMSC in humans before their clinical application.

Systematic review registration

https://inplasy.com/inplasy-2023-5-0075/, identifier: INPLASY202350075.
Large-scale analysis of putative plasmids in clinical multidrug-resistant Escherichia coli isolates from Vietnamese patients
Authors: Nguyen Quang Huy , Le Thi Thu Hang , Nguyen Son Thai , Nguyen Kieu-Oanh Thi , Quyen Dong Van , Hayer Juliette , Bañuls Anne-Laure , Tran Tam Thi Thanh
Published: May 2023

Introduction

In the past decades, extended-spectrum beta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Escherichia coli isolates have been detected in Vietnamese hospitals. The transfer of antimicrobial resistance (AMR) genes carried on plasmids is mainly responsible for the emergence of multidrug-resistant E. coli strains and the spread of AMR genes through horizontal gene transfer. Therefore, it is important to thoroughly study the characteristics of AMR gene-harboring plasmids in clinical multidrug-resistant bacterial isolates.

Methods

The profiles of plasmid assemblies were determined by analyzing previously published whole-genome sequencing data of 751 multidrug-resistant E. coli isolates from Vietnamese hospitals in order to identify the risk of AMR gene horizontal transfer and dissemination.

Results

The number of putative plasmids in isolates was independent of the sequencing coverage. These putative plasmids originated from various bacterial species, but mostly from the Escherichia genus, particularly E. coli species. Many different AMR genes were detected in plasmid contigs of the studied isolates, and their number was higher in CR isolates than in ESBL-producing isolates. Similarly, the blaKPC-2, blaNDM-5, blaOXA-1, blaOXA-48, and blaOXA-181 β-lactamase genes, associated with resistance to carbapenems, were more frequent in CR strains. Sequence similarity network and genome annotation analyses revealed high conservation of the β-lactamase gene clusters in plasmid contigs that carried the same AMR genes.

Discussion

Our study provides evidence of horizontal gene transfer in multidrug-resistant E. coli isolates via conjugative plasmids, thus rapidly accelerating the emergence of resistant bacteria. Besides reducing antibiotic misuse, prevention of plasmid transmission also is essential to limit antibiotic resistance.
Therapeutic interventions alter ecological interactions among cystic fibrosis airway microbiota
Authors: Ho Pok-Man , Nazeer Rahan Rudland , Welch Martin
Published: May 2023

The airways of people with cystic fibrosis (CF) often harbor a diverse microbiota and in recent years, much effort has been invested in cataloguing these. In spite of providing a wealth of insight, this cataloguing tells us little about how the organisms interact with one another in the CF airways. However, such relationships can be inferred using the theoretical framework of the Lotka-Volterra (LV) model. In the current work, we use a generalized Lotka-Volterra model to interrogate the nationwide data collected and curated by the UK CF Registry. This longitudinal dataset (covering the period 2008–2020) contains annual depositions that record the presence/absence of microbial taxa in each patient, their medication, and their CF genotype. Specifically, we wanted to identify trends in ecological relationships between the CF microbiota at a nationwide level, and whether these are potentially affected by medication. Our results show that some medications have a distinct influence on the microbial interactome, especially those that potentially influence the “gut-lung axis” or mucus viscosity. In particular, we found that patients treated with a combination of antimicrobial agents (targeting the airway microbiota), digestive enzymes (assisting in the assimilation of dietary fats and carbohydrates), and DNase (to reduce mucus viscosity) displayed a distinctly different airway interactome compared with patients treated separately with these medications.
Comparative analysis of phyto-fabricated chitosan, copper oxide, and chitosan-based CuO nanoparticles: antibacterial potential against Acinetobacter baumannii isolates and anticancer activity against HepG2 cell lines
Authors: Sarfraz Muhammad Hassan , Zubair Muhammad , Aslam Bilal , Ashraf Asma , Siddique Muhammad Hussnain , Hayat Sumreen , Cruz Jorrdy Neves , Muzammil Saima , Khurshid Mohsin , Sarfraz Muhammad Farrukh , Hashem Abeer , Dawoud Turki M. , Avila-Quezada Graciela Dolores , Abd_Allah Elsayed Fathi
Published: May 2023

The aim of this study was to provide a comparative analysis of chitosan (CH), copper oxide (CuO), and chitosan-based copper oxide (CH-CuO) nanoparticles for their application in the healthcare sector. The nanoparticles were synthesized by a green approach using the extract of Trianthema portulacastrum. The synthesized nanoparticles were characterized using different techniques, such as the synthesis of the particles, which was confirmed by UV–visible spectrometry that showed absorbance at 300 nm, 255 nm, and 275 nm for the CH, CuO, and CH-CuO nanoparticles, respectively. The spherical morphology of the nanoparticles and the presence of active functional groups was validated by SEM, TEM, and FTIR analysis. The crystalline nature of the particles was verified by XRD spectrum, and the average crystallite sizes of 33.54 nm, 20.13 nm, and 24.14 nm were obtained, respectively. The characterized nanoparticles were evaluated for their in vitro antibacterial and antibiofilm potential against Acinetobacter baumannii isolates, where potent activities were exhibited by the nanoparticles. The bioassay for antioxidant activity also confirmed DPPH scavenging activity for all the nanoparticles. This study also evaluated anticancer activities of the CH, CuO, and CH-CuO nanoparticles against HepG2 cell lines, where maximum inhibitions of 54, 75, and 84% were recorded, respectively. The anticancer activity was also confirmed by phase contrast microscopy, where the treated cells exhibited deformed morphologies. This study demonstrates the potential of the CH-CuO nanoparticle as an effective antibacterial agent, having with its antibiofilm activity, and in cancer treatment.
Network meta-analysis of comparative efficacy of animal-assisted therapy vs. pet-robot therapy in the management of dementia
Authors: Du Hongdi , Bo Lin , Lai Xiaoxing , Zhu Hongwei , Huo Xiaopeng
Published: May 2023

Objective

This network meta-analysis aimed to compare and rank the efficacy of animal-assisted therapy (AAT) and pet-robotic therapy (PRT) in the management of dementia.

Methods

Relevant studies were identified by searching PubMed, EMBASE, the Cochrane Library, SCOPUS, and Web of Science (WoS) until October 13, 2022. Traditional meta-analysis was first conducted based on the random-effects model, then random network meta-analysis was conducted to determine the relative efficacy and rank probability of AAT and PRT.

Results

Nineteen randomized controlled trials (RCTs) were included in this network meta-analysis. Network meta-analysis revealed that PRT marginally benefited agitation alleviation compared with control (standard mean difference [SMD]: −0.37, 95% confidence interval [95%CI]: −0.72 to −0.01) although both AAT and PRT did not improve cognitive function, reduce depression, and improve Quality of Life (QoL). The SUCRA probabilities indicated that PRT ranked better than AAT in agitation, cognitive function, and QoL, although there were no differences between the two therapies.

Conclusion

The present network meta-analysis reveals that PRT may help alleviate agitated behaviors in people with dementia. However, future studies are warranted to establish evidence of the effectiveness of PRT and further evaluate the differences between different robot types in managing dementia.
Hoehn and Yahr Stage and Striatal Dat-SPECT Uptake Are Predictors of Parkinson’s Disease Motor Progression
Authors: Jackson Holly , Anzures-Cabrera Judith , Taylor Kirsten I. , Pagano Gennaro ,   PASADENA Investigators,   Prasinezumab Study Group
Published: May 2023

Currently, no treatments available for Parkinson’s disease (PD) can slow PD progression. At the early stage of the disease, only a subset of individuals with PD progress quickly, while the majority have a slowly progressive form of the disease. In developing treatments that aim to slow PD progression, clinical trials aim to include individuals who are likely to progress faster, such that a treatment effect, if one exists, can be identified easier and earlier. The aim of the present study was to identify baseline predictors of clinical progression in early PD. We analyzed 12-month data acquired from the PASADENA trial Part 1 (NCT03100149, n = 76 participants who were allocated to the placebo arm and did not start symptomatic therapy) and the Parkinson’s Progression Markers Initiative (PPMI) study (n = 139 demographically and clinically matched participants). By using ridge regression models including clinical characteristics, imaging, and non-imaging biomarkers, we found that Hoehn and Yahr stage and dopamine transporter single-photon emission computed tomography specific binding ratios (Dat-SPECT SBR) in putamen ipsilateral to the side of motor symptom onset predicted PD progression at the early stage of the disease. Further studies are needed to confirm the validity of these predictors to identify with high accuracy individuals with early PD with a faster progression phenotype.
The effect of seed location on functional connectivity: evidence from an image-based meta-analysis
Authors: Li Meng-Ting , Sun Jia-Wei , Zhan Lin-Lin , Antwi Collins Opoku , Lv Ya-Ting , Jia Xi-Ze , Ren Jun
Published: May 2023

Introduction

Default mode network (DMN) is the most involved network in the study of brain development and brain diseases. Resting-state functional connectivity (rsFC) is the most used method to study DMN, but different studies are inconsistent in the selection of seed. To evaluate the effect of different seed selection on rsFC, we conducted an image-based meta-analysis (IBMA).

Methods

We identified 59 coordinates of seed regions of interest (ROIs) within the default mode network (DMN) from 11 studies (retrieved from Web of Science and Pubmed) to calculate the functional connectivity; then, the uncorrected t maps were obtained from the statistical analyses. The IBMA was performed with the t maps.

Results

We demonstrate that the overlap of meta-analytic maps across different seeds’ ROIs within DMN is relatively low, which cautions us to be cautious with seeds’ selection.

Discussion

Future studies using the seed-based functional connectivity method should take the reproducibility of different seeds into account. The choice of seed may significantly affect the connectivity results.
The contralateral organization of the human nervous system as a quantum unfolded, holographic-like, artifactual representation of the underlying dynamics of a fundamentally two-dimensional universe
Authors: Zukauskis Ronald L.
Published: May 2023

A working hypothesis is put forward in this article that the contralateral organization of the human nervous system appears to function like a quantum unfolded holographic apparatus by appearing to invert and reverse quantum unfolded visual and non-visual spatial information. As such, the three-dimensional contralateral organization would be an artifactual representation of the underlying dynamics of a fundamentally two-dimensional universe. According to the holographic principle, nothing that is experienced as three-dimensional could have been processed in a three-dimensional brain. Everything we would experience at a two-dimensional level would appear as a three-dimensional holographic representation, including the architecture of our brains. Various research observations reported elsewhere are reviewed and interpreted here as they may be related in a process that is fundamental to the underlying two-dimensional dynamics of the contralateral organization. The classic holographic method and characteristics of image formation contained by a holograph are described as they relate to the working hypothesis. The double-slit experiment is described and its relevance to the working hypothesis.
C1ql4 regulates breast cancer cell stemness and epithelial-mesenchymal transition through PI3K/AKT/NF-κB signaling pathway
Authors: Xu Fan , Wang Jiali , Zhen Shuman , Duan Yuqing , Li Qingshan , Liu Lihua
Published: May 2023

Background

The stemness characteristic of breast cancer (BC) is a crucial factor underlying cancer recurrence and metastasis after operative therapy and chemoradiotherapy. Understanding the potential mechanism of breast cancer stem cells (BCSCs) may ameliorate the prognosis of patients.

Methods

We collected clinical specimens of BC patients for staining and statistical analysis to verify the expression status and clinical significance of complement C1q-like 4 (C1ql4). Western blot and qRT-PCR were employed to detect the expression of molecules. Flow cytometry was used to examine cell cycle, cell apoptosis and the portion of BCSCs. Wound healing and Transwell assays were used to detect cell metastasis. The effect of C1ql4 on breast cancer progression in vivo was examined in a nude mouse tumor bearing model.

Results

Our clinical analysis showed that C1ql4 was highly expressed in BC tissues and cell lines, and the high expression of C1ql4 was significantly corelated with the malignancy of BC patients. Moreover, we also found that C1ql4 was overexpressed in BCSCs. C1ql4 knockdown suppressed the BCSC and EMT properties, promoted cell cycle progression, enhanced BC cell apoptosis, and inhibited cell migration and invasion, whereas the C1ql4 overexpression exhibited the opposite effects. Mechanistically, C1ql4 promoted the activation and nuclear location of NF-κB and the expression of downstream factors TNF-α and IL-1β. Moreover, inhibition of PI3K/AKT signaling suppressed the C1ql4-induced stemness and EMT.

Conclusions

Our findings suggest that C1ql4 promotes the BC cell stemness and EMT via modulating the PI3K/AKT/NF-κB signaling, and provides a promising target for BC treatment.
Juvenile idiopathic arthritis with systemic onset with inflammatory bone lesions: two case reports of patients successfully treated with canakinumab and experience gained from literature
Authors: Alexeeva Ekaterina I. , Dvoryakovskaya Tatyana M. , Tsulukiya Irina T. , Kondrateva Natalia M. , Solomatina Natalia M. , Kondratiev Gleb V. , Peshekhonova Luliia V. , Kostik Mikhail M.
Published: May 2023

Non-bacterial osteomyelitis (NBO) is a rare chronic inflammatory bone disease related to immune system dysregulation. This disease belongs to a family of autoinflammatory diseases. It often coexists with other TNF-α-mediated immune-mediated diseases such as juvenile idiopathic arthritis (JIA) and inflammatory bowel diseases. Previously, interleukin-1-driven inflammation was described predominantly in monogenic cases of NBO, such as DIRA syndrome or Majeed syndrome. However, the association between NBO and JIA with systemic onset (soJIA) has not been described yet.

Herein, we describe the cases of two patients with soJIA with inflammatory bone lesions wherein canakinumab (anti-interleukin-1β antibodies) caused remission.

Case descriptions

Patient 1–A 6-month-old boy with typical soJIA suffered a destruction of the 7th to 9th ribs and the left pubic bone. Antibiotics, IVIG, and cyclosporine proved ineffective. Corticosteroids were effective, but due to the factor of corticosteroid dependence, which has some disadvantages, canakinumab with a dosage of 4 mg/kg was initiated every 4 weeks, which completely controlled the disease and allowed to taper corticosteroids.

Patient 2—A 2-year-old girl developed chronic non-bacterial osteomyelitis of the 5th rib 2 months after taking corticosteroids prescribed for typical soJIA. She underwent surgical debridement removal, and several courses of antibiotics proved ineffective. She developed macrophage activation syndrome, following which anakinra was prescribed, which resulted in only temporary improvement. Therefore, this drug was switched to canakinumab, which caused corticosteroid-free remission.

Conclusion

This is the first description of a rare association of soJIA with inflammatory bone lesions with the proven efficacy of IL-1 blockade. The association of two autoinflammatory conditions should indicate IL-1-driven mechanisms and a possible genetic basis. Follow-up genetic and functional studies are required to better understand the pathogenesis of such overlapping diseases.
Early changes in cerebral metabolism after perinatal hypoxia-ischemia: a study in normothermic and hypothermic piglets
Authors: Andelius Ted C. K. , Bøgh Nikolaj , Pedersen Mette V. , Omann Camilla , Andersen Mads , Andersen Hannah B. , Hjortdal Vibeke E. , Pedersen Michael , Rasmussen Martin B. , Kyng Kasper J. , Henriksen Tine B.
Published: May 2023

Introduction

Hypoxic ischemic encephalopathy (HIE) after a perinatal insult is a dynamic process that evolves over time. Therapeutic hypothermia (TH) is standard treatment for severe to moderate HIE. There is a lack of evidence on the temporal change and interrelation of the underlying mechanisms that constitute HIE under normal and hypothermic conditions. We aimed to describe early changes in intracerebral metabolism after a hypoxic-ischemic insult in piglets treated with and without TH and in controls.

Methods

Three devices were installed into the left hemisphere of 24 piglets: a probe measuring intracranial pressure, a probe measuring blood flow and oxygen tension, and a microdialysis catheter measuring lactate, glucose, glycerol, and pyruvate. After a standardized hypoxic ischemic insult, the piglets were randomized to either TH or normothermia.

Results

Glycerol, a marker of cell lysis, increased immediately after the insult in both groups. There was a secondary increase in glycerol in normothermic piglets but not in piglets treated with TH. Intracerebral pressure, blood flow, oxygen tension, and extracellular lactate remained stable during the secondary increase in glycerol.

Conclusion

This exploratory study depicted the development of the pathophysiological mechanisms in the hours following a perinatal hypoxic-ischemic insult with and without TH and controls.
Caudal block vs. transversus abdominis plane block for pediatric surgery: a systematic review and meta-analysis
Authors: Hafeman Michael , Greenspan Seth , Rakhamimova Emiliya , Jin Zhaosheng , Moore Robert P. , Al Bizri Ehab
Published: May 2023

Background

The caudal block and transversus abdominis plane block (TAP) are commonly used in combination with general anesthesia for pediatric lower abdominal, inguinal, and genitourinary surgeries. There is limited data directly comparing the impact of these techniques on recovery. In this meta-analysis, we compare the duration of postoperative analgesia between these two techniques.

Objective

This review examined the duration of analgesia in pediatric patients (age 0–18 years) undergoing surgery who received caudal or TAP block after induction of general anesthesia. The primary outcome was duration of analgesia, defined as the time to first rescue analgesic dose. Secondary outcomes included number of rescue analgesic doses, acetaminophen usage within 24 h postoperatively, 24 h pain score area under the curve, and postoperative nausea and vomiting.

Evidence review

We systematically searched Pubmed, Central, EMBASE, CINAHL, Google Scholar, Web of Science citation index, the US clinical trials register, and abstracts from prominent 2020–2022 anesthesia conferences for randomized controlled trials that compared these blocks and reported analgesia duration.

Findings

Twelve RCTs inclusive of 825 patients were identified. TAP block was associated with longer analgesia duration (Mean difference = 1.76 h, 95% CI: 0.70–2.81, p = 0.001) and reduced doses of rescue analgesic within 24 h (Mean difference = 0.50 doses, 95% CI: 0.02–0.98, p = 0.04). No statistically significant differences were detected in other outcomes.

Conclusion

This meta-analysis suggests that TAP block provides greater duration of analgesia than caudal block after pediatric surgeries. TAP block was also associated with fewer rescue analgesic doses in the first 24 h without increased pain scores.

Systematic review registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=380876, identifier: CRD42022380876.
Identification of serum biomarkers for necrotizing enterocolitis using aptamer-based proteomics
Authors: Mackay Stephen , Frazer Lauren C. , Bailey Grace K. , Miller Claire M. , Gong Qingqing , Dewitt Olivia N. , Singh Dhirendra K. , Good Misty
Published: May 2023

Introduction

Necrotizing enterocolitis (NEC) is a potentially fatal intestinal disease primarily affecting preterm infants. Early diagnosis of neonates with NEC is crucial to improving outcomes; however, traditional diagnostic tools remain inadequate. Biomarkers represent an opportunity to improve the speed and accuracy of diagnosis, but they are not routinely used in clinical practice.

Methods

In this study, we utilized an aptamer-based proteomic discovery assay to identify new serum biomarkers of NEC. We compared levels of serum proteins in neonates with and without NEC and identified ten differentially expressed serum proteins between these groups.

Results

We detected two proteins, C-C motif chemokine ligand 16 (CCL16) and immunoglobulin heavy constant alpha 1 and 2 heterodimer (IGHA1 IGHA2), that were significantly increased during NEC and eight that were significantly decreased. Generation of receiver operating characteristic (ROC) curves revealed that alpha-fetoprotein (AUC = 0.926), glucagon (AUC = 0.860), and IGHA1 IGHA2 (AUC = 0.826) were the proteins that best differentiated patients with and without NEC.

Discussion

These findings indicate that further investigation into these serum proteins as a biomarker for NEC is warranted. In the future, laboratory tests incorporating these differentially expressed proteins may improve the ability of clinicians to diagnose infants with NEC rapidly and accurately.
Safety and effectiveness of the combination of remimazolam tosilate and propofol in gastroscopy: a multicenter, randomized controlled, single-blind clinical trial
Authors: Wang Chunyan , Gao Yangzheng , Li Jie , Zhang Linlin , Li Qing , Li Yize , Lu Yuechun , Sun Jiangang , Zhang Yang , Cheng Yaobei , Zhang Shidong , Wang Guolin , Yu Yonghao
Published: May 2023

Remimazolam tosilate (RT) is a new short-acting γ-aminobutyric acid A (GABAA) receptors agonist. However, its optimal use mode and dosage still remain unclear. This study aimed to examine the safety and effectiveness of the combination of RT and propofol in gastroscopy. This was a prospective, single-blind, randomized, multicenter, parallel-group study. All eligible 256 patients were randomized into the following 3 groups. Patients were anesthetized with propofol (Group P), RT (Group R) or the combination of RT and propofol (Group RP). The primary efficacy endpoints were: body movement score; satisfaction of gastroscopy doctors; success rate of sedation and effects on sleep status. Sedation induction time, time to be fully alert and adverse events were also recorded. The probability of complete immobility was lower in group R (33.73%) than in group P (86.67%) and RP (83.13%). The rate of doctors’ satisfaction was much lower in group R (28.92%) than in group P (77.78%) and RP (72.29%). The success rate of sedation and sleep outcome score has no difference in the three groups. The time to adequate sedation was longer in group RP (77.27 ± 18.63 s) than in group P (64.47 ± 24.36 s), but much shorter than that in group R (102.84 ± 46.43s). The time to be fully alert was shorter in group R (6.30 ± 1.52 min) and RP (6.54 ± 1.13 min) than in group P (7.87 ± 1.08 min). The proportion of sedative hypotension was significantly higher in group P (41.11%) than in group R (1.20%) and group RP (3.61%) (p < 0.001). The incidence of respiratory depression was much higher in group P (17.78%) than in group R (no patient) and group RP (1.2%). The incidence of adverse events was lower in groups R (4.82%) and RP (9.64%) than in group P (31.11%). The combination of RT and propofol takes effect quickly, makes patients alert quickly, provides a sufficient depth of sedation, reduces body movement, does not inhibit circulation and respiratory function, does not affect sleep, and is the preferred mode for gastroscopy doctors and anesthesiologists.
The dilemma of antibiotic susceptibility and clinical decision-making in a multi-drug-resistant Pseudomonas aeruginosa bloodstream infection
Authors: Chen Long , Qu Xingyi , Su Jingqian , Yao Haijun , Yuan Qiang , Wang Yu , Li Nanyang , Wu Gang , Liu Xiaofen , Hu Jin , Zhang Jing
Published: May 2023

Objective: How to choose the appropriate antibiotics and dosage has always been a difficult issue during the treatment of multi-drug-resistant bacterial infections. Our study aims to resolve this difficulty by introducing our multi-disciplinary treatment (MDT) clinical decision-making scheme based on rigorous interpretation of antibiotic susceptibility tests and precise therapeutic drug monitoring (TDM)-guided dosage adjustment.

Method: The treatment course of an elderly patient who developed a multi-drug-resistant Pseudomonas aeruginosa (MDRPA) bloodstream infection from a brain abscess was presented.

Results: In the treatment process, ceftazidime–avibactam (CAZ–AVI) was used empirically for treating the infection and clinical symptoms improved. However, the follow-up bacterial susceptibility test showed that the bacteria were resistant to CAZ–AVI. Considering the low fault tolerance of clinical therapy, the treatment was switched to a 1 mg/kg maintenance dose of susceptible polymyxin B, and TDM showed that the AUC24h, ss of 65.5 mgh/L had been achieved. However, clinical symptoms were not improved after 6 days of treatment. Facing the complicated situation, the cooperation of physicians, clinical pharmacologists, and microbiologists was applied, and the treatment finally succeeded with the pathogen eradicated when polymyxin B dose was increased to 1.4 mg/kg, with the AUC24h, ss of 98.6 mgh/L.

Conclusion: MDT collaboration on the premise of scientific and standardized drug management is helpful for the recovery process in patients. The empirical judgment of doctors, the medication recommendations from experts in the field of TDM and pharmacokinetics/pharmacodynamics, and the drug susceptibility results provided by the clinical microbiology laboratory all provide the direction of treatment.
Effects of lumacaftor—ivacaftor therapy on cystic fibrosis transmembrane conductance regulator function in F508del homozygous patients with cystic fibrosis aged 2–11 years
Authors: Berges Julian , Graeber Simon Y. , Hämmerling Susanne , Yu Yin , Krümpelmann Arne , Stahl Mirjam , Hirtz Stephanie , Scheuermann Heike , Mall Marcus A. , Sommerburg Olaf
Published: May 2023

Rationale: Lumacaftor/ivacaftor was approved for the treatment of patients with cystic fibrosis who are homozygous for F508del aged 2 years and older following positive results from phase three trials. However, the improvement in CFTR function associated with lumacaftor/ivacaftor has only been studied in patients over 12 years of age, while the rescue potential in younger children is unknown.

Methods: In a prospective study, we aimed to evaluate the effect of lumacaftor/ivacaftor on the CFTR biomarkers sweat chloride concentration and intestinal current measurement as well as clinical outcome parameters in F508del homozygous CF patients 2–11 years before and 8–16 weeks after treatment initiation.

Results: A total of 13 children with CF homozygous for F508del aged 2–11 years were enrolled and 12 patients were analyzed. Lumacaftor/ivacaftor treatment reduced sweat chloride concentration by 26.8 mmol/L (p = 0.0006) and showed a mean improvement in CFTR activity, as assessed by intestinal current measurement in the rectal epithelium, of 30.5% compared to normal (p = 0.0015), exceeding previous findings of 17.7% of normal in CF patients homozygous for F508del aged 12 years and older.

Conclusion: Lumacaftor/ivacaftor partially restores F508del CFTR function in children with CF who are homozygous for F508del, aged 2–11 years, to a level of CFTR activity seen in patients with CFTR variants with residual function. These results are consistent with the partial short-term improvement in clinical parameters.