bluuebunny/crossref_metadata_2025 huggingface dataset:
Case report: Sequential therapy with dupilumab and baricitinib for severe alopecia areata with atopic dermatitis in children
Authors: Fang Huijuan , Zhang Fengchuan , Lin Wenjun , Jiang Yuqi , Liu Qingwu , Yang Dingquan
Published: June 2024

An 8-year-old female child presented with patchy hair loss for 1 year, accompanied by eyebrow loss for 6 months. Microscopic examination of the hair confirmed the features of active stage alopecia areata, with a Severity of Alopecia Tool (SALT) score of 70%. The diagnosis was severe alopecia areata. The patient had a history of atopic dermatitis since infancy, with recurrent episodes of scattered papules and pruritus for 8 years. Initial treatment involved subcutaneous injections of dupilumab 300mg every 2 weeks for 6 months, resulting in a reduction of SALT score to 20% and improvement of atopic dermatitis symptoms. Discontinuation of Dupilumab and initiation of daily oral Baricitinib at a dose of 2mg for a duration of 5 months. According to the SALT score evaluation, the severity of hair loss was less than 10% and there was significant regrowth of hair. No significant adverse reactions were observed during the treatment period.
Prognostic significance of programmed cell death ligand 1 blood markers in non-small cell lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis
Authors: Zhang Ningning , Chang Jianlan , Liu Ping , Tian Xiangyang , Yu Junyan
Published: June 2024

Background

Immune checkpoint inhibitors (ICIs) are effective for non-small cell lung cancer (NSCLC) treatment, but the response rate remains low. Programmed cell death ligand 1 (PD-L1) in peripheral blood, including soluble form (sPD-L1), expression on circulating tumor cells (CTCs PD-L1) and exosomes (exoPD-L1), are minimally invasive and promising markers for patient selection and management, but their prognostic significance remains inconclusive. Here, we performed a meta-analysis for the prognostic value of PD-L1 blood markers in NSCLC patients treated with ICIs.

Methods

Eligible studies were obtained by searching PubMed, EMBAS, Web of Science, and Cochrane Library prior to November 30, 2023. The associations between pre-treatment, post-treatment and dynamic changes of blood PD-L1 levels and progression-free survival (PFS)/over survival (OS) were analyzed by estimating hazard ratio (HR) and 95% confidence interval (CI).

Results

A total of 26 studies comprising 1606 patients were included. High pre- or post-treatment sPD-L1 levels were significantly associated with worse PFS (pre-treatment: HR=1.49, 95%CI 1.13–1.95; post-treatment: HR=2.09, 95%CI 1.40–3.12) and OS (pre-treatment: HR=1.83, 95%CI 1.25–2.67; post-treatment: HR=2.60, 95%CI 1.09–6.20, P=0.032). High pre-treatment exoPD-L1 levels predicted a worse PFS (HR=4.24, 95%CI 2.82–6.38, P<0.001). Pre-treatment PD-L1+ CTCs tended to be correlated with prolonged PFS (HR=0.63, 95%CI 0.39–1.02) and OS (HR=0.58, 95%CI 0.36–0.93). Patients with up-regulated exoPD-L1 levels, but not sPD-L1, after ICIs treatment had significantly favorable PFS (HR=0.36, 95%CI 0.23–0.55) and OS (HR=0.24, 95%CI 0.08–0.68).

Conclusion

PD-L1 blood markers, including sPD-L1, CTCs PD-L1 and exoPD-L1, can effectively predict prognosis, and may be potentially utilized for patient selection and treatment management for NSCLC patients receiving ICIs.
MAVS disruption impairs downstream signaling and results in higher virus replication levels of salmonid alphavirus subtype 3 but not infectious pancreatic necrosis virus in vitro
Authors: Xu Cheng , Gamil Amr A. A. , Wang Xiaolin , Munang’andu Hetron Mweemba , Evensen Øystein
Published: June 2024

The mitochondrial anti-viral signaling (MAVS) protein is an intermediary adaptor protein of retinoic acid-inducible gene-1 (RIG-I) like receptor (RLR) signaling, which activates the transcription factor interferon (IFN) regulatory factor 3 (IRF3) and NF-kB to produce type I IFNs. MAVS expression has been reported in different fish species, but few studies have shown its functional role in anti-viral responses to fish viruses. In this study, we used the transcription activator-like effector nuclease (TALEN) as a gene editing tool to disrupt the function of MAVS in Chinook salmon (Oncorhynchus tshawytscha) embryonic cells (CHSE) to understand its role in induction of interferon I responses to infections with the (+) RNA virus salmonid alphavirus subtype 3 (SAV-3), and the dsRNA virus infectious pancreatic necrosis virus (IPNV) infection. A MAVS-disrupted CHSE clone with a 7-aa polypeptide (GVFVSRV) deletion mutation at the N-terminal of the CARD domain infected with SAV-3 resulted in significantly lower expression of IRF3, IFNa, and ISGs and increased viral titer (1.5 log10) compared to wild-type. In contrast, the IPNV titer in MAVS-disrupted cells was not different from the wild-type. Furthermore, overexpression of salmon MAVS in MAVS-disrupted CHSE cells rescued the impaired type I IFN-mediated anti-viral effect against SAV-3.
Role of gut microbiota in regulating immune checkpoint inhibitor therapy for glioblastoma
Authors: Zhang Hao , Hong Ying , Wu Tingting , Ben Eyi , Li Shuai , Hu Liu , Xie Tao
Published: June 2024

Glioblastoma (GBM) is a highly malignant, invasive, and poorly prognosed brain tumor. Unfortunately, active comprehensive treatment does not significantly prolong patient survival. With the deepening of research, it has been found that gut microbiota plays a certain role in GBM, and can directly or indirectly affect the efficacy of immune checkpoint inhibitors (ICIs) in various ways. (1) The metabolites produced by gut microbiota directly affect the host’s immune homeostasis, and these metabolites can affect the function and distribution of immune cells, promote or inhibit inflammatory responses, affect the phenotype, angiogenesis, inflammatory response, and immune cell infiltration of GBM cells, thereby affecting the effectiveness of ICIs. (2) Some members of the gut microbiota may reverse T cell function inhibition, increase T cell anti-tumor activity, and ultimately improve the efficacy of ICIs by targeting specific immunosuppressive metabolites and cytokines. (3) Some members of the gut microbiota directly participate in the metabolic process of drugs, which can degrade, transform, or produce metabolites, affecting the effective concentration and bioavailability of drugs. Optimizing the structure of the gut microbiota may help improve the efficacy of ICIs. (4) The gut microbiota can also regulate immune cell function and inflammatory status in the brain through gut brain axis communication, indirectly affecting the progression of GBM and the therapeutic response to ICIs. (5) Given the importance of gut microbiota for ICI therapy, researchers have begun exploring the use of fecal microbiota transplantation (FMT) to transplant healthy or optimized gut microbiota to GBM patients, in order to improve their immune status and enhance their response to ICI therapy. Preliminary studies suggest that FMT may enhance the efficacy of ICI therapy in some patients. In summary, gut microbiota plays a crucial role in regulating ICIs in GBM, and with a deeper understanding of the relationship between gut microbiota and tumor immunity, it is expected to develop more precise and effective personalized ICI therapy strategies for GBM, in order to improve patient prognosis.
Toll-like receptors and integrins crosstalk
Authors: Alhamdan Fahd , Bayarsaikhan Ganchimeg , Yuki Koichi
Published: June 2024

Immune system recognizes invading microbes at both pathogen and antigen levels. Toll-like receptors (TLRs) play a key role in the first-line defense against pathogens. Major functions of TLRs include cytokine and chemokine production. TLRs share common downstream signaling pathways with other receptors. The crosstalk revolving around TLRs is rather significant and complex, underscoring the intricate nature of immune system. The profiles of produced cytokines and chemokines via TLRs can be affected by other receptors. Integrins are critical heterodimeric adhesion molecules expressed on many different cells. There are studies describing synergetic or inhibitory interplay between TLRs and integrins. Thus, we reviewed the crosstalk between TLRs and integrins. Understanding the nature of the crosstalk could allow us to modulate TLR functions via integrins.
Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D
Authors: Yang Xin , Huang Juan , Peng Jian , Wang Pai , Wong F. Susan , Wang Ruirui , Wang Dapeng , Wen Li
Published: June 2024

Introduction

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β cells. Toll-like receptor 9 (TLR9) plays a role in autoimmune diseases, and B cell-specific TLR9 deficiency delays T1D development. Gut microbiota are implicated in T1D, although the relationship is complex. However, the impact of B cell-specific deficiency of TLR9 on intestinal microbiota and the impact of altered intestinal microbiota on the development of T1D are unclear.

Objectives

This study investigated how gut microbiota and the intestinal barrier contribute to T1D development in B cell-specific TLR9-deficient NOD mice. Additionally, this study explored the role of microbiota in immune regulation and T1D onset.

Methods

The study assessed gut permeability, gene expression related to gut barrier integrity, and gut microbiota composition. Antibiotics depleted gut microbiota, and fecal samples were transferred to germ-free mice. The study also examined IL-10 production, Breg cell differentiation, and their impact on T1D development.

Results

B cell-specific TLR9-deficient NOD mice exhibited increased gut permeability and downregulated gut barrier-related gene expression. Antibiotics restored gut permeability, suggesting microbiota influence. Altered microbiota were enriched in Lachnospiraceae, known for mucin degradation. Transferring this microbiota to germ-free mice increased gut permeability and promoted IL-10-expressing Breg cells. Rag-/- mice transplanted with fecal samples from Tlr9fl/flCd19-Cre+ mice showed delayed diabetes onset, indicating microbiota’s impact.

Conclusion

B cell-specific TLR9 deficiency alters gut microbiota, increasing gut permeability and promoting IL-10-expressing Breg cells, which delay T1D. This study uncovers a link between TLR9, gut microbiota, and immune regulation in T1D, with implications for microbiota-targeted T1D therapies.
Defining operational objectives for nature-inclusive marine infrastructure to achieve system-scale impact
Authors: ter Hofstede Remment , van Koningsveld Mark
Published: June 2024

The marine environment faces continuous anthropogenic pressures, including infrastructural developments at a global scale. Integration of nature-inclusive measures in the design of infrastructural development is increasingly encouraged, but a lack of coordination results in fragmentation of project-based measures, failing to meet the desired overall effects. To realize impact at system-scale, i.e. the seascape dimension required to achieve the set objective for a selected ecosystem component, overarching policies with shared targets towards effective nature-inclusive marine infrastructure are needed. We present a stepwise approach to work towards operational objectives for promoting selected ecosystem components that can be species, habitats or ecosystem processes, in which ruling policies, environmental conditions and the use of infrastructural development are aligned, and agreement on achievable ambitions is reached. Having clear targets will provide guidance to project developers in designing the infrastructure nature-inclusive, and in setting up relevant monitoring programs to evaluate the measures taken. We demonstrate how this stepwise approach could be applied to derive operational objectives for the design of nature-inclusive marine infrastructure in the context of offshore windfarm development in the North Sea, currently one of the most prominent infrastructure developments that changes the marine environment drastically. The European flat oyster Ostrea edulis has been selected as target species in the case study, as its once abundant population is now nearly extinct from the North Sea due to human disturbances, and there’s growing interest to restore its reefs. The application of the stepwise approach indicates the potential for oyster reef restoration in the area, based upon a clear match between ruling policy, environmental conditions, and habitat suitability within offshore wind farms. An agreement between the main stakeholders on achievable ambitions can likely be established and would translate into the operational objective to actively introduce oysters to reach an initial critical mass and optimize settlement habitat in all future offshore wind farms in an area with suitable habitat characteristics. Such an agreement on overarching objectives is crucial to align separate initiatives to promote targeted ecosystem components and to jointly become most effective, which is ultimately in the best interest of the larger community using the system.
Identification of potential shared gene signatures between gastric cancer and type 2 diabetes: a data-driven analysis
Authors: Xia Bingqing , Zeng Ping , Xue Yuling , Li Qian , Xie Jianhui , Xu Jiamin , Wu Wenzhen , Yang Xiaobo
Published: June 2024

Background

Gastric cancer (GC) and type 2 diabetes (T2D) contribute to each other, but the interaction mechanisms remain undiscovered. The goal of this research was to explore shared genes as well as crosstalk mechanisms between GC and T2D.

Methods

The Gene Expression Omnibus (GEO) database served as the source of the GC and T2D datasets. The differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) were utilized to identify representative genes. In addition, overlapping genes between the representative genes of the two diseases were used for functional enrichment analysis and protein–protein interaction (PPI) network. Next, hub genes were filtered through two machine learning algorithms. Finally, external validation was undertaken with data from the Cancer Genome Atlas (TCGA) database.

Results

A total of 292 and 541 DEGs were obtained from the GC (GSE29272) and T2D (GSE164416) datasets, respectively. In addition, 2,704 and 336 module genes were identified in GC and T2D. Following their intersection, 104 crosstalk genes were identified. Enrichment analysis indicated that “ECM-receptor interaction,” “AGE-RAGE signaling pathway in diabetic complications,” “aging,” and “cellular response to copper ion” were mutual pathways. Through the PPI network, 10 genes were identified as candidate hub genes. Machine learning further selected BGN, VCAN, FN1, FBLN1, COL4A5, COL1A1, and COL6A3 as hub genes.

Conclusion

“ECM-receptor interaction,” “AGE-RAGE signaling pathway in diabetic complications,” “aging,” and “cellular response to copper ion” were revealed as possible crosstalk mechanisms. BGN, VCAN, FN1, FBLN1, COL4A5, COL1A1, and COL6A3 were identified as shared genes and potential therapeutic targets for people suffering from GC and T2D.
Estimated plasma volume status as a simple and accessible predictor of 28-day mortality in septic shock: insights from a retrospective study of the MIMIC-IV database
Authors: Gao Beijun , Chen Rongping , Zhao Hua , Zhang Hongmin , Wang Xiaoting , Liu Dawei
Published: June 2024

Background

Assessing volume status in septic shock patients is crucial for tailored fluid resuscitation. Estimated plasma volume status (ePVS) has emerged as a simple and effective tool for evaluating patient volume status. However, the prognostic value of ePVS in septic shock patients remains underexplored.

Methods

The study cohort consisted of septic shock patients admitted to the ICU, sourced from the MIMIC-IV database. Patients were categorized into two groups based on 28-day survival outcomes, and their baseline characteristics were compared. According to the ePVS (6.52 dL/g) with a hazard ratio of 1 in the restricted cubic spline (RCS) analysis, patients were further divided into high and low ePVS groups. A multivariable Cox regression model was utilized to evaluate the association between ePVS and 28-day mortality rate. The Kaplan–Meier survival curve was plotted, and all-cause mortality was compared between the high and low groups using the log-rank test.

Results

A total of 7,607 septic shock patients were included in the study, among whom 2,144 (28.2%) died within 28 days. A J-shaped relationship was observed between ePVS at ICU admission and 28-day mortality, with an increase in mortality risk noted when ePVS exceeded 6.52 dL/g. The high ePVS group exhibited notably higher mortality rates compared to the low ePVS group (28-day mortality: 26.2% vs. 30.2%; 90-day mortality: 35% vs. 42.3%). After adjustment for confounding factors, ePVS greater than 6.52 dL/g independently correlated with an increased risk of 28-day mortality (HR: 1.20, 95% CI: 1.10–1.31, p < 0.001) and 90-day mortality (HR: 1.25, 95% CI: 1.15–1.35, p < 0.001). Kaplan–Meier curves demonstrated a heightened risk of mortality associated with ePVS values exceeding 6.52 dL/g.

Conclusion

A J-shaped association was observed between ePVS and 28-day mortality in septic shock patients, with higher ePVS levels associated with increased risk of mortality.
White root rot of Bletilla striata: the pathogen, biological characterization, and fungicide screening
Authors: Liang Fang , Jiang Xuejing , Liu Lijuan , Wang Feihu , Liu Feng , Hu Saixue , Tan Lijun , Chen Xiao , Xu Yixuan , Xu Xiulan , Jiang Liqiong , Liu Yinggao , Yang Chunlin
Published: June 2024

Bletilla striata is an endangered traditional medicinal herb in China. In May 2020, the emergence of white root rot severely impacted the quality and yield of B. striata, affecting about 5% of the plants at plant nurseries of the Chengdu Academy of Agricultural and Forestry Sciences. Through a series of experiments and evaluations, the pathogen was identified as Fusarium solani. This is the first report of B. striata white root rot caused by F. solani in Sichuan, China. To better understand this disease and provide data support for its control, a combination of morphological, molecular characterisation and pathogenicity determination was used in this study for assessment. Meanwhile, the effects of different carbon and nitrogen sources, culture medium, temperature, photoperiod and pH on mycelial growth and spore production of F. solani were investigated. In addition, effective fungicides were screened and the concentration ratios of fungicides were optimized using response surface methodology (RSM). The experimental results showed that sucrose was the optimum carbon source for the pathogen, and the optimum temperature and pH were 25°C and pH 7, respectively, while light did no significant effect. Effective fungicides were screened, among which difenoconazole showed the strongest inhibition with EC50 of 142.773 µg/mL. The optimum fungicide concentration scheme (difenoconazole, pyraclostrobin, and thiophanate-methyl at 395.42, 781.03, and 561.11 µg/mL, respectively) was obtained using response surface methodology (RSM) to improve the inhibition rate of 92.24 ± 0.34%. This study provides basic data for the pathogen characterization of B. striata white root rot and its potential fungicides in Sichuan, China. In addition, the optimal fungicide concentration ratios were obtained through response surface methodology (RSM) optimization, which significantly enhanced the fungicidal effect and provided a scientific basis for the future control of B. striata white root rot.
Lactiplantibacillus plantarum N4 ameliorates lipid metabolism and gut microbiota structure in high fat diet-fed rats
Authors: Deng Manqi , Zhang Shuaiying , Wu Siying , Jiang Qiunan , Teng Wenyao , Luo Tao , Ouyang Yerui , Liu Jiantao , Gu Bing
Published: June 2024

Lowing blood lipid levels with probiotics has good application prospects. This study aimed to isolate probiotics with hypolipidemic efficacy from homemade na dish and investigate their mechanism of action. In vitro experiments were conducted to determine the cholesterol-lowering ability of five isolates, with results showing that Lactiplantibacillus plantarum N4 exhibited a high cholesterol-lowering rate of 50.27% and significant resistance to acid (87%), bile salt (51.97%), and pepsin (88.28%) in simulated gastrointestinal fluids, indicating promising application prospects for the use of probiotics in lowering blood lipids. The findings from the in vivo experiment demonstrated that the administration of N4 effectively attenuated lipid droplet accumulation and inflammatory cell infiltration in the body weight and liver of hyperlipidemic rats, leading to restoration of liver tissue morphology and structure, as well as improvement in lipid and liver biochemical parameters. 16S analysis indicated that the oral administration of N4 led to significant alterations in the relative abundance of various genera, including Sutterella, Bacteroides, Clostridium, and Ruminococcus, in the gut microbiota of hyperlipidemia rats. Additionally, fecal metabolomic analysis identified a total of 78 metabolites following N4 intervention, with carboxylic acids and their derivatives being the predominant compounds detected. The transcriptomic analysis revealed 156 genes with differential expression following N4 intervention, leading to the identification of 171 metabolic pathways through Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Notably, the glutathione metabolism pathway, PPAR signaling pathway, and bile secretion pathway emerged as the primary enrichment pathways. The findings from a comprehensive multi-omics analysis indicate that N4 influences lipid metabolism and diminishes lipid levels in hyperlipidemic rats through modulation of fumaric acid and γ-aminobutyric acid concentrations, as well as glutathione and other metabolic pathways in the intestinal tract, derived from both the gut microbiota and the host liver. This research offers valuable insights into the therapeutic potential of probiotics for managing lipid metabolism disorders and their utilization in the development of functional foods.
Utilisation of Lactiplantibacillus plantarum and propionic acid to improve silage quality of amaranth before and after wilting: fermentation quality, microbial communities, and their metabolic pathway
Authors: Zhao Muqier , Bao Jian , Wang Zhijun , Sun Pengbo , Liu Jingyi , Yan Yuting , Ge Gentu
Published: June 2024

Objective

The aim of this study was to investigate the effects of Lactiplantibacillus plantarum (L. plantarum) and propionic acid (PA) on fermentation characteristics and microbial community of amaranth (Amaranthus hypochondriaus) silage with different moisture contents.

Methods

Amaranth was harvested at maturity stage and prepared for ensiling. There were two moisture content gradients (80%: AhG, 70%: AhS; fresh material: FM) and three treatments (control: CK, L. plantarum: LP, propionic acid: PA) set up, and silages were opened after 60 d of ensiling.

Results

The results showed that the addition of L. plantarum and PA increased lactic acid (LA) content and decreased pH of amaranth after fermentation. In particular, the addition of PA significantly increased crude protein content (p < 0.05). LA content was higher in wilted silage than in high-moisture silage, and it was higher with the addition of L. plantarum and PA (p < 0.05). The dominant species of AhGLP, AhSCK, AhSLP and AhSPA were mainly L. plantarum, Lentilactobacillus buchneri and Levilactobacillus brevis. The dominant species in AhGCK include Enterobacter cloacae, and Xanthomonas oryzae was dominated in AhGPA, which affected fermentation quality. L. plantarum and PA acted synergistically after ensiling to accelerate the succession of dominant species from gram-negative to gram-positive bacteria, forming a symbiotic microbial network centred on lactic acid bacteria. Both wilting and additive silage preparation methods increased the degree of dominance of global and overview maps and carbohydrate metabolism, and decreased the degree of dominance of amino acid metabolism categories.

Conclusion

In conclusion, the addition of L. plantarum to silage can effectively improve the fermentation characteristics of amaranth, increase the diversity of bacterial communities, and regulate the microbial community and its functional metabolic pathways to achieve the desired fermentation effect.
Active myeloperoxidase: a promising biomarker to differentiate “acute” and “low-grade” peri-prosthetic joint infections from aseptic failures
Authors: Maritati Martina , De Rito Giuseppe , Rosta Valentina , Cervellati Carlo , Manfrinato Maria Cristina , Zanoli Gustavo Alberto , De Giorgio Roberto , Guarino Matteo , Costanzini Anna , Contini Carlo , Ning Yu , Trampuz Andrej , Trentini Alessandro
Published: June 2024

Introduction

The accurate distinction between periprosthetic joint infections (PJI) and aseptic failures (AF) is of paramount importance due to differences in treatment. However, this could be challenging by using the current criteria. Various synovial fluid biomarkers are being assessed to improve the diagnostic accuracy. Myeloperoxidase (MPO), an enzyme contained in the granules of neutrophils, may be a promising biomarker for PJI.

Methods

Synovial fluids of 99 patients (n = 65 PJI according to EBJIS criteria; n = 34 AF) were collected in two specialized orthopedic centers. PJI were divided into acute (n = 33) and low-grade (n = 32) according to previously published classification. An activity assay specific for active MPO was performed in each sample. Ability of MPO to correctly discriminate patients with PJI from AF was determined by ROC analysis. The best discriminating cut-off value was determined by calculating the J Youden index. For all analyses, a P value < 0.05 was considered statistically significant.

Results

Active MPO was higher in PJI than AF (P < 0.0001). The ROC analysis revealed a significant area under the curve (AUC: 0.86; 95% CI: 0.78–0.93, P < 0.0001). A cut-off value of 561.9 U/mL, with good sensitivity (0.69) and specificity (0.88), discriminated between AF and PJI (accuracy 75.76%, 95% CI: 66.11–83.81%, positive likelihood ratio 5.88, 95% CI: 2.31–14.98 and negative likelihood ratio 0.35, 95%CI: 0.24–0.51). No difference in MPO levels was found between acute and chronic low-grade PJI.

Conclusion

The proposed assay appears to be a reliable and affordable tool for detecting the active MPO in synovial fluid, with promising characteristics of sensitivity and specificity in discriminating both acute and low-grade PJI from AF. Further studies are needed to confirm MPO diagnostic cut-off values and validate their use in the routine clinical practice.
Therapeutic effects of a novel synthetic α-secretase
Authors: Kim Sung Bin , Mun Bo-Ram , Kim Sung Yoon , Elangovan Muthukumar , Park Euy Jun , Choi Won-Seok , Park Woo Jin
Published: June 2024

Excessive accumulation of amyloid-β (Aβ) has been associated with the pathogenesis of Alzheimer’s disease (AD). Clinical studies have further proven that elimination of Aβ can be a viable therapeutic option. In the current study, we conceptualized a fusion membrane protein, referred to as synthetic α-secretase (SAS), that can cleave amyloid precursor protein (APP) and Aβ specifically at the α-site. In mammalian cells, SAS indeed cleaved APP and Aβ at the α-site. Overexpression of SAS in the hippocampus was achieved by direct injection of recombinant adeno-associated virus serotype 9 (AAV9) that expresses SAS (AAV9-SAS) into the bilateral ventricles of mouse brains. SAS enhanced the non-amyloidogenic processing of APP, thus reducing the levels of soluble Aβ and plaques in the 5xFAD mice. In addition, SAS significantly attenuated the cognitive deficits in 5xFAD mice, as demonstrated by novel object recognition and Morris water maze tests. Unlike other Aβ-cleaving proteases, SAS has highly strict substrate specificity. We propose that SAS can be an efficient modality to eliminate excessive Aβ from diseased brains.
Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications
Authors: Lin Cui , Kong Yu , Chen Qian , Zeng Jixiang , Pan Xiaojin , Miao Jifei
Published: June 2024

Soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2) plays a crucial role in the pathogenesis of Alzheimer’s disease (AD). This review comprehensively examines sTREM2’s involvement in AD, focusing on its regulatory functions in microglial responses, neuroinflammation, and interactions with key pathological processes. We discuss the dynamic changes in sTREM2 levels in cerebrospinal fluid and plasma throughout AD progression, highlighting its potential as a therapeutic target. Furthermore, we explore the impact of genetic variants on sTREM2 expression and its interplay with other AD risk genes. The evidence presented in this review suggests that modulating sTREM2 activity could influence AD trajectory, making it a promising avenue for future research and drug development. By providing a holistic understanding of sTREM2’s multifaceted role in AD, this review aims to guide future studies and inspire novel therapeutic strategies.
Ravulizumab use for acetylcholine receptor-positive generalized myasthenia gravis in clinical practice
Authors: Katyal Nakul , Govindarajan Raghav , Goyal Neelam , Muley Suraj , Muppidi Srikanth
Published: June 2024

Purpose

To describe the early experience of ravulizumab use in acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ve gMG).

Methods

This multicenter retrospective study included AChR+ve gMG patients who were treated with ravulizumab and had both pre- and post-ravulizumab myasthenia gravis activities of daily living (MG-ADL) scores. Clinical information regarding MG history, concomitant treatment(s), MG-ADL, other MG-specific measures, and adverse events were recorded.

Results

A total of 18 patients with mean age of 61.83 (±16.08, n = 18) years were included in this cohort. In 10 complement inhibitor naive patients, a clinically meaningful reduction in mean Mg-ADL (baseline: 6.6 (±3.58) vs. 4.4 (±2.28), post ravulizumab) was seen. 6 out of 10 patients (60%) had clinically meaningful reduction post ravulizumab and two achieved minimum symptom expression (MSE). In 8 patients switched from eculizumab to ravulizumab, further reduction was noted in post ravulizumab mean MG-ADL (Baseline: 3.25 (±3.34) vs. 1.5 (±2.34) post ravulizumab). None of the patients who switched from eculizumab to ravulizumab experienced worsening symptoms. Eleven out of 14 (78.5%) patients on prednisone therapy were able to reduce their prednisone dose post-ravulizumab. None of the patients experienced any major side effects.

Conclusion

In our clinical practice, 60% of AChR+ve gMG complement inhibitor naive patients experienced a clinically meaningful improvement in MG-ADL scores with ravulizumab. Patients were safely switched from eculizumab to ravulizumab and had further improvement in their mean MG-ADL scores. Of those on prednisone therapy, the majority were able to reduce their prednisone dosage.
Ultrasound guided platelet rich plasma injections for post-traumatic greater occipital neuralgia following concussion: a pilot randomized controlled trial
Authors: Stone Jacqueline E. , Campbell Christina , Tabor Jason B. , Bonfield Stephan , Machan Matthew , Shan Rodney Li Pi , Debert Chantel T.
Published: June 2024

Background

Treatment for post-traumatic greater occipital neuralgia (GON) includes serial injections of steroid/anesthetic. While these injections can alleviate pain, effects can be transient, frequently lasting only 1 month. As a potential alternative, platelet-rich plasma (PRP) injections are an emerging biological treatment with beneficial effects in peripheral nerve disorders. We investigated the feasibility, safety, and effectiveness of a single PRP injection for post-traumatic GON in comparison to saline or steroid/anesthetic injection.

Methods

In this pilot randomized, double-blinded, placebo-controlled trial, 32 adults with post-traumatic GON were allocated 1:1:1 to receive a single ultrasound-guided injection of (1) autologous PRP (2) steroid/anesthetic or (3) normal saline. Our primary outcome was feasibility (recruitment, attendance, retention) and safety (adverse events). Exploratory measures included headache intensity and frequency (daily headache diaries) and additional questionnaires (headache impact, and quality of life) assessed at pre-injection, 1 week, 1 month, and 3 months post-injection.

Results

We screened 67 individuals, 55% were eligible and 95% of those participated. Over 80% of daily headache diaries were completed with 91% of participants completing the 3-month outcome questionnaires. No serious adverse events were reported. There were no significant differences between groups for headache intensity or frequency. Headache impact on function test-6 scores improved at 3 month in the PRP (β = −9.7, 95% CI [−15.6, −3.74], p = 0.002) and saline (β = −6.7 [−12.7, −0.57], p = 0.033) groups but not steroid/anesthetic group (p = 0.135).

Conclusion

PRP is a feasible and safe method for treating post-traumatic GON with comparable results to saline and steroid/anaesthetic. Further trials with larger sample sizes are required.

Clinical trial registration:https://clinicaltrials.gov/, identifier NCT04051203.
The association between declining lung function and stroke risk: insights from an observational study and Mendelian randomization
Authors: Wang Jiadong , Lin Junjie , Zheng Yujie , Hua Minxia , Wang Kunyi , Lu Kexin , Zhang Yu , Zheng Weijun , Chen Rucheng , Lin Fuquan
Published: June 2024

Background

Stroke, prevalent globally, particularly impacts low- and middle-income countries. Decreased lung function is one of the risk factors for stroke, and there is a lack of sufficient research on the association between the two, especially based on evidence from representative large samples. We aimed to explore the association between lung function and stroke incidence.

Methods

We collected data from 13,371 participants from the 2007–2012 U.S. national cross-sectional study and 11,192 participants from the Chinese national cohort study during the 2011–2018 follow-up period. Multivariate logistic regression and Cox proportional hazards regression were used to assess cross-sectional and longitudinal associations of peak expiratory flow with stroke risks. Additionally, we used publicly available GWAS data from a European population to conduct Mendelian randomization analysis, further exploring the potential causal relationship.

Results

The results of the cross-sectional study suggest that a decline in peak expiratory flow may be associated with an increased risk of stroke. The cohort study revealed that, compared to the first tertile group, the risk of stroke incidence in the second and third tertile groups of PEF decreased by 19% (hazard ratio (HR) = 0.810, 95%CI = 0.684–0.960) and 21.4% (HR = 0.786, 95%CI = 0.647–0.956), respectively. Mendelian randomization analysis clarified that higher PEF levels are significantly associated with a reduced risk of stroke (OR = 0.852, 95%CI = 0.727–0.997).

Conclusion

Decreased lung function is a risk factor for stroke. As a simple and accurate indicator of lung function, PEF can be used to monitor lung function in community populations and patients for primary stroke prevention.
Primary malignant melanoma of the parotid gland, a rare case arising from a duct: a case report and literature review
Authors: Aung Moe Thu Zar , Kim Jo-Eun , Yoon Hye-Jung , Huh Kyoung-Hoe , Yi Won-Jin , Heo Min-Suk , Lee Sam-Sun
Published: June 2024

Malignant melanoma of the parotid gland is an unusual tumor in the head and neck region, and most parotid melanoma is reported as a metastatic lesion of cutaneous malignant melanoma. We report a case of primary malignant melanoma arising in the parotid gland duct with diagnostic challenge. The patient was a 68-year-old man who complained of repeated right facial swelling that presented 3 months prior. Swelling was detected along the Stensen’s duct of the cheek, and brown-colored saliva-like fluid was aspirated. On MR and CT images, a fluid-filled duct with small nodule and heterogeneously enhancing mass in the parotid parenchyma was detected. The nodular mass on the ductal wall grew rapidly, and the hyperintense T1 signal became significant on follow-up images. The final diagnosis via histopathologic examination using biopsy and parotidectomy specimen revealed the lesion as malignant melanoma of the duct and pleomorphic adenoma of the parenchyma. Even if the incidence of primary malignant melanoma is very low among tumors occurring in the parotid gland, efforts supporting an early diagnosis using imaging characteristics are important.
Development of esophagogastroduodenoscopy in China: results from the national census in 2013 and 2020
Authors: Zhou Siwei , Chen Zheran , Jiao Yunfei , Cheng Zhiyuan , Gao Ye , Wang Tianjiao , Xin Lei , Wan Rong , Wang Luowei
Published: June 2024

Background

Given the significant burden of upper digestive diseases, there has been a substantial increase in the utilization of esophagogastroduodenoscopy (EGD) in China from 2012 to 2019. The objective of this study is to investigate the development, practice, and factors influencing the widespread use of EGD during this period.

Methods

Two national censuses were conducted among all hospitals in mainland China that perform gastrointestinal endoscopy. These censuses aimed to extract information on the infrastructure, volume, and quality of EGD. The analysis of potential factors influencing EGD practice was based on real-world data from open access sources.

Results

From 2012 to 2019, the number of hospitals performing EGD in mainland China increased from 1,518 to 2,265 (1.49-fold) in tertiary hospitals and from 3,633 to 4,097 (1.12-fold) in secondary hospitals, respectively. The national utilization rate of EGD also increased from 1,643.53 to 2,018.06 per 100,000 inhabitants, indicating a 1.23-fold increase. Regions with more endoscopists per 100,000 inhabitants (OR 9.61, P<0.001), more tertiary hospitals performing EGD per million inhabitants (OR 2.43, P<0.001), higher incidence of esophageal and gastric cancer (OR 2.09, P=0 016), and higher number of hospitals performing EGD per million inhabitants (OR 1.77, P=0.01) tended to provided more numerous and qualitied EGD. And hospital grading, regional GDP, incidence of esophageal and gastric cancer and the volume of EGD were observed as the significantly relevant factors of malignant dictation rate (MDR) (P<0.05), but not the number and educational background of endoscopists.

Conclusion

Over the past seven years, China has made significant progress in EGD. However, challenges persist in terms of quality and inequality.
Novel pretreatment nomograms based on pan-immune-inflammation value for predicting clinical outcome in patients with head and neck squamous cell carcinoma
Authors: Chen Qian , Wang Shi-Yang , Chen Yue , Yang Ming , Li Kai , Peng Zi-Yang , Xu Chong-Wen , Yao Xiao-Bao , Li Hong-Hui , Zhao Qian , Cao Yu-Dan , Bai Yan-Xia , Li Xiang
Published: June 2024

Background

The prognostic value of an effective biomarker, pan-immune-inflammation value (PIV), for head and neck squamous cell carcinoma (HNSCC) patients after radical surgery or chemoradiotherapy has not been well explored. This study aimed to construct and validate nomograms based on PIV to predict survival outcomes of HNSCC patients.

Methods

A total of 161 HNSCC patients who underwent radical surgery were enrolled retrospectively for development cohort. The cutoff of PIV was determined using the maximally selected rank statistics method. Multivariable Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to develop two nomograms (Model A and Model B) that predict disease-free survival (DFS). The concordance index, receiver operating characteristic curves, calibration curves, and decision curve analysis were used to evaluate the nomograms. A cohort composed of 50 patients who received radiotherapy or chemoradiotherapy (RT/CRT) alone was applied for generality testing of PIV and nomograms.

Results

Patients with higher PIV (≥123.3) experienced a worse DFS (HR, 5.01; 95% CI, 3.25–7.72; p<0.0001) and overall survival (OS) (HR, 5.23; 95% CI, 3.34–8.18; p<0.0001) compared to patients with lower PIV (<123.3) in the development cohort. Predictors of Model A included age, TNM stage, neutrophil-to-lymphocyte ratio (NLR), and PIV, and that of Model B included TNM stage, lymphocyte-to-monocyte ratio (LMR), and PIV. In comparison with TNM stage alone, the two nomograms demonstrated good calibration and discrimination and showed satisfactory clinical utility in internal validation. The generality testing results showed that higher PIV was also associated with worse survival outcomes in the RT/CRT cohort and the possibility that the two nomograms may have a universal applicability for patients with different treatments.

Conclusions

The nomograms based on PIV, a simple but useful indicator, can provide prognosis prediction of individual HNSCC patients after radical surgery and may be broadly applicated for patients after RT/CRT alone.
Safety and efficacy of Holmium-166 selective internal radiotherapy of primary and secondary liver cancer confirmed by real-world data
Authors: Schulze-Zachau Victor , Verset Gontran , De Bondt Pieter , De Keukeleire Katrien , Gühne Falk , Heuschkel Martin , Hoffmann Ralf-Thorsten , Bozzi Elena , Sciuto Rosa , Lam Marnix , Deportós Moreno Jordi , Debrus Roxane , Zech Christoph J.
Published: June 2024

Purpose

Holmium-166 has emerged as a promising option for selective internal radiotherapy (SIRT) for hepatic malignancies, but data on routine clinical use are lacking. The purpose of this study was to describe the safety and effectiveness of Holmium-166 SIRT in real-world practice through retrospective analysis of a multicenter registry.

Methods

Retrospective analysis was conducted on Holmium-166 SIRT procedures performed between July 15, 2019, and July 15, 2021, across seven European centers. Treatment planning, treatment realization and post-treatment follow-up were conducted according to routine local practice. Safety and effectiveness data were extracted from the patients’ health records. Primary endpoint analysis was assessed for the entire study population with separate analysis for subgroups with hepatocellular carcinoma, metastatic colorectal cancer and intrahepatic cholangiocarcinoma.

Results

A total of 167 SIRT procedures in 146 patients (mean age 66 ± 11 years, 68% male) were retrospectively evaluated. Most common tumor entities were hepatocellular carcinoma (n=55), metastatic colorectal cancer (n=35), intrahepatic cholangiocarcinoma (n=19) and metastatic neuroendocrine tumors (n=10). Nine adverse events grade ≥ 3 according to Common Terminology Criteria for Adverse Events were recorded, including one fatal case of radioembolization-induced liver disease. Response rates and median overall survival for the above mentioned subgroups were comparable to results from previous Holmium-166 trials as well as to results from Yttrium-90 registries.

Conclusion

This study confirms that the safety and effectiveness of Holmium-166 SIRT derived from prospective trials also applies in routine clinical practice, reinforcing its potential as a viable treatment option for primary and secondary liver cancer.
Performance of MYC, BCL2, and BCL6 break-apart FISH in small biopsies with large B-cell lymphoma: a retrospective Cytopathology Hematopathology Interinstitutional Consortium study
Authors: Menke Joshua R. , Aypar Umut , Bangs Charles D. , Cook Stephen L. , Gupta Srishti , Hasserjian Robert P. , Kong Christina S. , Lin Oscar , Long Steven R. , Ly Amy , Menke Jacob A. S. , Natkunam Yasodha , Ruiz-Cordero Roberto , Spiteri Elizabeth , Ye Julia , Zadeh Sara L. , Gratzinger Dita A.
Published: June 2024

Introduction

Fluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2, or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies.

Methods

We describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens.

Results

FISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement.

Discussion

FISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2, or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing.