Exploring the heterogeneity of interstitial cells of Cajal and their properties in gastrointestinal mesenchymal tumors applying single-cell RNA sequencing analysis.

BACKGROUND: Gastrointestinal mesenchymal stromal tumors (GISTs) are a group of intramural tumors that exhibit a wide range of morphologies. Dysfunction or loss of interstitial cells of Cajal (ICCs) is correlated with the disorders of gastrointestinal motility. At present, the characterization and molecular mechanisms underlying the role of ICCs in GIST are still not clear. METHODS: The GSE162115 dataset from Gene Expression Omnibus database was processed using Seurat package for quality control, data normalization, and cell clustering. Differential expression and functional enrichment analyses were performed using the FindAllMarkers function and clusterProfiler package. Cellular heterogeneity was assessed by CytoTRACE and potential regulatory mechanisms of ICCs in GISTs were investigated using SCENIC. Cellular communication was inferred and analyzed applying the CellChat package. RESULTS: Eight clusters were identified based on 34,861 cells. Intra-tumor samples had a higher proportion of ICCs than peri-tumor. ICCs were related to cell cycle and glycolytic activity in intra-tumor samples, while those in peri-tumor samples were involved in immune response. Further analysis identified four ICC subgroups (subcluster 1-4), of which subcluster 3 showed the most typical stem cell properties and interacted with the rest of the cells through the MIF-CD74 (CD44) protein. CONCLUSION: This study analyzed the heterogeneity and stem cell properties of ICCs in GISTs, revealing the molecular mechanisms and potential therapeutic targets for GISTs.

Predicting potential microbe-disease associations based on dual branch graph convolutional network.

Studying the association between microbes and diseases not only aids in the prevention and diagnosis of diseases, but also provides crucial theoretical support for new drug development and personalized treatment. Due to the time-consuming and costly nature of laboratory-based biological tests to confirm the relationship between microbes and diseases, there is an urgent need for innovative computational frameworks to anticipate new associations between microbes and diseases. Here, we propose a novel computational approach based on a dual branch graph convolutional network (GCN) module, abbreviated as DBGCNMDA, for identifying microbe-disease associations. First, DBGCNMDA calculates the similarity matrix of diseases and microbes by integrating functional similarity and Gaussian association spectrum kernel (GAPK) similarity. Then, semantic information from different biological networks is extracted by two GCN modules from different perspectives. Finally, the scores of microbe-disease associations are predicted based on the extracted features. The main innovation of this method lies in the use of two types of information for microbe/disease similarity assessment. Additionally, we extend the disease nodes to address the issue of insufficient features due to low data dimensionality. We optimize the connectivity between the homogeneous entities using random walk with restart (RWR), and then use the optimized similarity matrix as the initial feature matrix. In terms of network understanding, we design a dual branch GCN module, namely GlobalGCN and LocalGCN, to fine-tune node representations by introducing side information, including homologous neighbour nodes. We evaluate the accuracy of the DBGCNMDA model using five-fold cross-validation (5-fold-CV) technique. The results show that the area under the receiver operating characteristic curve (AUC) and area under the precision versus recall curve (AUPR) of the DBGCNMDA model in the 5-fold-CV are 0.9559 and 0.9630, respectively. The results from the case studies using published experimental data confirm a significant number of predicted associations, indicating that DBGCNMDA is an effective tool for predicting potential microbe-disease associations.

Antibacterial activity of closantel against methicillin-resistant Staphylococcus aureus and itsbiofilm. / æ°¯æ°°ç¢˜æŸ³èƒºå¯¹è€ç”²æ°§è¥¿æž—é‡‘é»„è‰²è‘¡è„çƒèŒåŠå ¶ç”Ÿç‰©è†œçš„æŠ—èŒæ´»æ€§.

OBJECTIVES: The antimicrobial resistance of Staphylococcus aureus (S. aureus) has become a challenge in the treatment of infectious diseases. It is of great clinical value to discovery effective antimicrobial agents against multi-drug resistant S. aureus and its biofilms. This study aims to explore the antibacterial activity of the antiparasitic drug closantel against methicillin-resistant S. aureus and its biofilms through drug repurposing. METHODS: The sensitivity of S. aureus to closantel was assessed using microbroth dilution and disk diffusion methods. The bacteriostatic and bactericidal activities of closantel were determined by time-kill curves and colony count. Scanning electron microscopy combined with SYTOX Green and DiSC3(5) fluorescence probes were used to study the bactericidal mechanism of closantel. The influence of resistance was assessed by continuous exposure to sub-inhibitory concentrations of closantel. The anti-biofilm activity was evaluated using 96-well plates and crystal violet staining, and cytotoxicity was measured using the CCK-8 assay. RESULTS: The minimal inhibitory concentration (MIC) of closantel for both methicillin-sensitive and methicillin-resistant S. aureus ranged from 0.125 to 1.000 µg/mL. Disk diffusion tests showed that 80 µg of closantel created an inhibition zone, which increased in diameter with higher drug amounts. Sub-inhibitory concentrations (0.031 µg/mL) of closantel significantly inhibited S. aureus proliferation, reducing bacterial turbidity from 0.26±0.00 to 0.11±0.01 (t=16.06, P<0.001), with stronger inhibition at higher concentrations. Closantel at 0.25×MIC inhibited S. aureus proliferation for 12 hours, while 1×MIC inhibited it for over 24 hours, with the number of viable bacteria decreasing as the drug concentration increased. Mechanistic studies indicated that closantel effectively disrupted the integrity of S. aureus cell membranes, significantly increasing SYTOX Green and DiSC3(5) fluorescence intensity. Even after 25 days of continuous exposure to sub-inhibitory concentrations of closantel, no resistance developed. Closantel at 0.0625 µg/mL significantly inhibited biofilm formation, reducing it from 1.29±0.16 to 0.62±0.04 (t=11.62, P<0.001), showing a clear dose-dependent effect. Closantel at 2 µg/mL also significantly eradicated established biofilms, reducing biofilm mass from 1.62±0.34 to 0.51±0.39 (t=4.84, P<0.01). Additionally, closantel exhibited extremely low cytotoxicity, with half-maximal lethal concentrations for HepG2 liver cancer cells and normal LO2 liver cells both exceeding 64 µg/mL. CONCLUSIONS: Closantel exhibits strong antibacterial activity against S. aureus and its biofilm with low cytotoxicity against human cells, making it a promising candidate for new therapeutic strategies against S. aureus-related infections.

Spatial preference behavior of robo-pigeons induced by electrical stimulus targeting fear nuclei.

BACKGROUND: Numerous studies have confirmed that stimulating the mid-brain motor nuclei can regulate movement forcibly for robo-pigeons, but research on behavior modulation using non-motor nuclei is scarce. OBJECTIVE: In this study, we constructed a spatial preference behavior by stimulating the stratum griseum periventriculare (SGP), a nucleus correlated with fear and escape, for robo-pigeons. METHODS: The study was carried out in a square-enclosed experimental field, with a designated box serving as the 'safe' area for the robo-pigeons. If the robo-pigeon exits this area, the SGP will be stimulated. After a brief training period, the robo-pigeons will have a clear spatial preference for the box. RESULTS: The result from five pigeons has shown that, after simple training, the animals develop a spatial preference for the box. They can quickly return to the box in any situation when the SGP is stimulated, with a success rate exceeding 80% (89.0 ± 6.5%). Moreover, this behavior is highly stable and remains consistent, unaffected by changes in the location of the box or the interference box. CONCLUSION: The results prove that using the electrical stimulus could enable animals to accomplish more complex tasks. It may offer a novel approach to regulating pigeon behavior and further advance the study of cyborg animals.

Pre-pubertal sublingual immunotherapy is more effective than immunotherapy during puberty in allergic rhinitis and asthma.

BACKGROUND: To evaluate the clinical efficacy of sublingual-specific immunotherapy (SLIT) and pulmonary function in children with allergic rhinitis and asthma before and after puberty. METHODS: This retrospective analysis included 136 patients aged 4-18 years with allergic asthma and rhinitis who received two years of SLIT treatment. Patients were divided into two groups based on age: the prepubertal group (4-10 years old) and the pubertal group (11-18 years old). After half a year, one year, and two years of SLIT, the total nasal symptom score (TNSS), total rhinitis medication score (TRMS), daytime asthma symptom score (DASS), nighttime asthma symptom score (NASS), total asthma medication score (TAMS), asthma control test (ACT), and peak expiratory flow rate (PEF%) were evaluated and compared with the baseline before treatment. RESULTS: In both groups, TNSS, TRMS, DASS, NASS, TAMS, ACT, and PEF% improved significantly after half a year, one year, and two years of SLIT treatment. After half a year of treatment, prepubertal patients showed better therapy for TNSS, DASS, NASS, and TAMS compared to the pubertal group. The TAMS of the pubertal group was higher than that of the prepubertal group after one year of treatment. Finally, the PEF% showed better therapy compared to the pubertal group. CONCLUSION: SLIT treatment with Dermatophagoides farinae drops can effectively control the symptoms of rhinitis and asthma in children with allergic rhinitis and asthma before and after puberty, reduce the use of symptomatic drugs, significantly improve the pulmonary function of patients, and have better effects on asthma in prepubertal children than in adolescents.

Metabolism score and machine learning models for the prediction of esophageal squamous cell carcinoma progression.

The incomplete prediction of prognosis in esophageal squamous cell carcinoma (ESCC) patients is attributed to various therapeutic interventions and complex prognostic factors. Consequently, there is a pressing demand for enhanced predictive biomarkers that can facilitate clinical management and treatment decisions. This study recruited 491 ESCC patients who underwent surgical treatment at Huashan Hospital, Fudan University. We incorporated 14 blood metabolic indicators and identified independent prognostic indicators for overall survival through univariate and multivariate analyses. Subsequently, a metabolism score formula was established based on the biochemical markers. We constructed a nomogram and machine learning models utilizing the metabolism score and clinically significant prognostic features, followed by an evaluation of their predictive accuracy and performance. We identified alkaline phosphatase, free fatty acids, homocysteine, lactate dehydrogenase, and triglycerides as independent prognostic indicators for ESCC. Subsequently, based on these five indicators, we established a metabolism score that serves as an independent prognostic factor in ESCC patients. By utilizing this metabolism score in conjunction with clinical features, a nomogram can precisely predict the prognosis of ESCC patients, achieving an area under the curve (AUC) of 0.89. The random forest (RF) model showed superior predictive ability (AUC = 0.90, accuracy = 86%, Matthews correlation coefficient = 0.55). Finally, we used an RF model with optimal performance to establish an online predictive tool. The metabolism score developed in this study serves as an independent prognostic indicator for ESCC patients.

Stalking Discourse on Reddit: A Comparative Analysis of Pre- and Post-COVID-19 Pandemic Using Big Data.

Stalking, a widespread and distressing phenomenon, has recently garnered considerable attention. The advent of digital platforms has revolutionized the landscape of stalking, presenting new avenues and challenges for research. However, the impact of the coronavirus disease (COVID)-19 pandemic on stalking remains underexplored, despite extensive studies on similar crimes such as intimate partner violence and domestic violence. To address this gap, our study focused on Reddit, a prominent online platform with a diverse user base and open discussion. Through an analysis of posts from the subreddit (https://www.reddit.com/r/Stalking/), we sought to compare the discourse on stalking before and after the COVID-19 pandemic. We found notable shifts in stalking-related posts before and after the COVID-19 pandemic, particularly with the emergence of new topics centered on cyberstalking. We also observed that the experiences of stalking victims have significantly changed following the COVID-19 pandemic. Based on our findings, we discussed the implications for policies to help stalking victims.

Understanding and comparing risk factors and subtypes in South Korean adult and adolescent women's suicidal ideation or suicide attempt using survey and social media data.

Objective: This study aimed to investigate the similarities and differences in risk factors for suicide among adult and adolescent women in South Korea and identify subtypes of suicidal ideation or suicide attempt in each group. Methods: Multifaceted data were collected and analyzed by linking survey and social media data. Interpretable machine learning models were constructed to predict suicide risk and major risk factors were extracted by investigating their feature importance. Additionally, subtypes of suicidal adult and adolescent women were identified and explained using risk factors. Results: The risk factors for adult women were primarily related to mental disorders, while those for adolescent women were primarily related to interpersonal experiences and needs. Two subtypes of suicidal adult women were one with high psychiatric symptoms and mental disorders of them and/or their families and the other with excessive social media use and high online victimization. Two subtypes of suicidal adolescent women were one with high psychiatric symptoms, high ACEs, and high social connectedness, and the other with frequent social media use, high online sexual victimization, and high social assurance. Conclusions: These findings enable a stratified and targeted understanding of suicide in women and help develop customized suicide prevention plans in South Korea.

Nur77-IRF1 axis inhibits esophageal squamous cell carcinoma growth and improves anti-PD-1 treatment efficacy.

The nuclear receptor Nur77 plays paradoxical roles in numerous cancers. However, whether Nur77 inhibits esophageal squamous cell carcinoma (ESCC) growth and affects immunological responses against ESCC has not been determined. The functional role of Nur77 in ESCC was investigated in this study using human ESCC cell lines, quantitative real-time polymerase chain reaction (PCR), cell proliferation and colony formation assays, flow cytometry analysis, western blotting and animal models. The target gene controlled by Nur77 was verified using dual-luciferase reporter assays, chromatin immunoprecipitation analysis and functional rescue experiments. To examine the clinical importance of Nur77, 72 human primary ESCC tissues were subjected to immunohistochemistry. Taken together, these findings showed that, both in vitro and in vivo, Nur77 dramatically reduced ESCC cell growth and triggered apoptosis. Nur77 directly interacts with the interferon regulatory factor 1 (IRF1) promoter to inhibit its activity in ESCC. Pharmacological induction of Nur77 using cytosporone B (CsnB) inhibited ESCC cell proliferation and promoted apoptosis both in vitro and in vivo. Furthermore, CsnB increased CD8+ T-cell infiltration and cytotoxicity to inhibit the formation of ESCC tumors in an immunocompetent mouse model. In ESCC tissues, Nur77 expression was downregulated, and IRF1 expression was increased; moreover, their expression levels were negatively related. IRF1 and Nur77 were strongly correlated with overall survival. These findings suggested that Nur77 targets and regulates the IRF1/PD-L1 axis to serve as a tumor suppressor in ESCC. Graphical abstract of the regulatory mechanism of Nur77 overexpression downregulates IRF1 in the inhibition of ESCC progression and enhance anti-PD-1 therapy efficacy.

TNF-α promotes osteocyte necroptosis by upregulating TLR4 in postmenopausal osteoporosis.

Postmenopausal osteoporosis (PMOP) is a common kind of osteoporosis that is associated with excessive osteocyte death and bone loss. Previous studies have shown that TNF-α-induced osteocyte necroptosis might exert a stronger effect on PMOP than apoptosis, and TLR4 can also induce cell necroptosis, as confirmed by recent studies. However, little is known about the relationship between TNF-α-induced osteocyte necroptosis and TLR4. In the present study, we showed that TNF-α increased the expression of TLR4, which promoted osteocyte necroptosis in PMOP. In patients with PMOP, TLR4 was highly expressed at skeletal sites where exists osteocyte necroptosis, and high TLR4 expression is correlated with enhanced TNF-α expression. Osteocytes exhibited robust TLR4 expression upon exposure to necroptotic osteocytes in vivo and in vitro. Western blotting and immunofluorescence analyses demonstrated that TNF-α upregulated TLR4 expression in vitro, which might further promote osteocyte necroptosis. Furthermore, inhibition of TLR4 by TAK-242 in vitro effectively blocked osteocyte necroptosis induced by TNF-α. Collectively, these results suggest a novel TLR4-mediated process of osteocyte necroptosis, which might increase osteocyte death and bone loss in the process of PMOP.

Global research on sinonasal inverted papilloma over the past two decades: a bibliometric analysis.

Objective: This study aimed to investigate the global research status, hot topics, and prospects in the field of sinonasal inverted papilloma (SNIP) through bibliometric analysis. Methods: The literature on SNIP was retrieved and downloaded from the Web of Science Core Collection from 2002 to 2021. The bibliometric and visualisation networks of SNIP were constructed using VOSviewer 1.6.18, CiteSpace 6.1. R2, and a bibliometric online analysis platform. Results: A total of 560 original articles about SNIP research were included, involving 2,457 authors from 610 institutions in 45 countries. The number of SNIP publications showed an overall rising trend, with an average annual output of 28 articles and almost 3 times as many articles published in 2020 as in 2002. The analysis of keyword burst detection indicated that EGFR mutation, malignant transformation and infection are emerging research hotspots. Moreover, EGFR mutation, KRAS mutation, malignant tumour, metallothionein 2a gene, pre-operative diagnosis, HPV-negative tumour, and expression were among the 11 key clusters of co-cited references. Conclusions: This study provided a comprehensive, systematic, and objective analysis and visualised knowledge map of SNIP over the past 2 decades. In particular, current hotspots and prospective trends in the field of SNIP have been identified. These results highlight the future direction of SNIP research for rhinologists.

Rad51 and Systemic Inflammatory Indicators as Novel Prognostic Markers in Esophageal Squamous Cell Carcinoma.

BACKGROUND: RAD51 is a central protein involved in homologous recombination, which has been linked to cancer development and progression. systemic inflammatory indicator markers such as neutrophil-to-lymphocyte ratio and lymphocyte-to-monocyte ratio have also been implicated in cancer. However, the relationship between Rad51 and these inflammatory markers in esophageal cancer patients undergoing esophagectomy is not yet understood. METHODS: We retrospectively observed 320 esophageal cancer patients who underwent esophagectomy. We collected clinical characteristics, postoperative complications, and survival analysis data and analyzed the relationship between Rad51 expression, inflammatory markers, and prognosis. RESULTS: We found significant linear relationships among the inflammatory markers. There were also close relationships between Rad51 expression and neutrophil-to-lymphocyte ratio or C-reactive protein. Patients with low lymphocyte percentage were more likely to have low Rad51 expression (P = .026), high C-reactive protein (P = .007), and high neutrophil-to-lymphocyte ratio (P = .006). Low lymphocyte-to-monocyte ratio was associated with poor overall survival and was an independent prognostic factor (HR = 2.214; 95% confidence interval: 1.044-4.695, P = .038). In patients without lymph node metastases, low albumin (HR= 0.131; 95% confidence interval: 0.025-0.687, P = .016), high neutrophil-to-lymphocyte ratio (HR = 0.002; 95% confidence interval: 0.000-0.221, P = .009), and high Rad51 expression (HR = 14.394; 95% confidence interval: 2.217-97.402, P = .006) were associated with poor overall survival. CONCLUSIONS: Our study found a close correlation between elevated Rad51 expression and inflammatory markers. High Rad51 expression, high neutrophil-to-lymphocyte ratio, and low lymphocyte-to-monocyte ratio are associated with lower survival rates. The combined assessment of Rad51 and inflammatory markers can be useful for preoperative assessment and prognostic evaluation in esophageal squamous cell carcinoma patients.

Carfilzomib suppressed LDHA-mediated metabolic reprogramming by targeting ATF3 in esophageal squamous cell carcinoma.

Carfilzomib, a second-generation proteasome inhibitor, has been approved as a treatment for relapsed and/or refractory multiple myeloma. Nevertheless, the molecular mechanism by which Carfilzomib inhibits esophageal squamous cell carcinoma (ESCC) progression largely remains to be determined. In the present study, we found that Carfilzomib demonstrated potent anti-tumor activity against esophageal squamous cell carcinoma both in vitro and in vivo. Mechanistically, carfilzomib triggers mitochondrial apoptosis and reprograms cellular metabolism in ESCC cells. Moreover, it has been identified that activating transcription factor 3 (ATF3) plays a crucial cellular target role in ESCC cells treated with Carfilzomib. Overexpression of ATF3 effectively antagonized the effects of carfilzomib on ESCC cell proliferation, apoptosis, and metabolic reprogramming. Furthermore, the ATF3 protein is specifically bound to lactate dehydrogenase A (LDHA) to effectively suppress LDHA-mediated metabolic reprogramming in response to carfilzomib treatment. Research conducted in xenograft models demonstrates that ATF3 mediates the anti-tumor activity of Carfilzomib. The examination of human esophageal squamous cell carcinoma indicated that ATF3 and LDHA have the potential to function as innovative targets for therapeutic intervention in the treatment of ESCC. Our findings demonstrate the novel function of Carfilzomib in modulating ESCC metabolism and progression, highlighting the potential of Carfilzomib as a promising therapeutic agent for the treatment of ESCC.

Large vestibular schwannomas presenting in the late state of pregnancy: a case report and literature review.

Vestibular schwannomas in pregnancy have rarely been reported, and there is a lack of in-depth discussion on the experience of management of massive acoustic neuromas in pregnancy. Herein, we present a pregnant woman with a giant vestibular schwannoma and obstructive hydrocephalus who presented at 30 weeks of gestation. She was initially misdiagnosed as having a pregnancy-related reaction of headache, dizziness, and vomiting that had occurred 2 months earlier. After observation at home, her symptoms progressed at 30 weeks of gestation, and imaging findings revealed a brain tumor in the CPA region with secondary cerebella tonsil herniation and obstructive hydrocephalus, and she was transferred to our center for treatment. Consequently, we relieved her hydrocephalus with a ventriculoperitoneal shunt (V-P shunt) and used corticosteroids to simulate fetal maturation. After 10 days, her mental condition deteriorated, and her right limb muscle strength gradually decreased until grade 0 (MMT Grading). Finally, under a joint consultation with the Department of Neurosurgery, Obstetrics, and Anesthesiology, she underwent a cesarean section under general anesthesia and first-stage tumor removal at 31 weeks of gestation. Upon discharge, the previously observed neurological deficits, which were reversible and had manifested during her gestational period, had been successfully resolved, and the fetus had been conserved. The neuroimaging confirmed the complete tumor removal, while the neuropathologic examination revealed a vestibular schwannoma. Therefore, we recommend early diagnosis and treatment for these patients, especially people with headaches, vomiting, and sudden hearing loss during pregnancy. Herein, we concluded that our cases provide a valuable experience in the latest acceptable time frame for the operation to prevent irreversible neurological impairment and premature delivery in late pregnancy.

ESRRG-PKM2 axis reprograms metabolism to suppress esophageal squamous carcinoma progression and enhance anti-PD-1 therapy efficacy.

BACKGROUND: Glycolysis under normoxic conditions, known as the Warburg effect, confers a selective advantage for the survival and proliferation of many tumors. In this study, we investigated the role of estrogen-related receptor gamma (ESRRG) in metabolic reprogramming in esophageal squamous cell carcinoma (ESCC). METHODS: Bioinformatics analysis indicated that ESRRG expression was decreased in ESCC tissue and associated with poor clinical outcomes. We also examined the effects of altered ESRRG expression on the proliferation and metabolic reprogramming of ESCC cells. We explored the impact of ESRRG on Pyruvate kinase M2 (PKM2) expression and malignant behavior in ESCC. RESULTS: Our study revealed the inhibitory effects of ESRRG on the growth, tumorigenesis, and glycolysis activity of ESCC cells, which were mediated by the downregulation of PKM2 expression. We further demonstrated that ESRRG directly interacts with the PKM2 promoter to inhibit its activity in ESCC. Notably, the ESRRG-specific agonist, DY131, inhibited ESCC cell proliferation and glycolysis activity by modulating genes in the glycolysis pathway. Moreover, we verified that DY131 exhibits enhanced activity as an immune checkpoint inhibitor, considering the significance of the ESRRG-PKM2 axis in the lactate regulation of ESCC cells. CONCLUSION: Our findings provide novel insights into the role of ESRRG-PKM2 signaling in regulating ESCC cell metabolism and immune checkpoint regulation. Additionally, we suggest that DY131 holds promise as a promising therapeutic agent for ESCC treatment.

Stem cells as potential therapeutics for hearing loss.

Hearing impairment is a global health problem. Stem cell therapy has become a cutting-edge approach to tissue regeneration. In this review, the recent advances in stem cell therapy for hearing loss have been discussed. Nanomaterials can modulate the stem cell microenvironment to augment the therapeutic effects further. The potential of combining nanomaterials with stem cells for repairing and regenerating damaged inner ear hair cells (HCs) and spiral ganglion neurons (SGNs) has also been discussed. Stem cell-derived exosomes can contribute to the repair and regeneration of damaged tissue, and the research progress on exosome-based hearing loss treatment has been summarized as well. Despite stem cell therapy's technical and practical limitations, the findings reported so far are promising and warrant further investigation for eventual clinical translation.

A Modified 14-Day Dual Therapy with Vonoprazan and Amoxicillin Amplified the Advantages Over Conventional Therapies for Eradication of Helicobacter pylori: A Non-Inferiority Clinical Trial.

Purpose: The emergence of resistant strains has greatly reduced the eradication rate of H. pylori (HP) in conventional bismuth-containing quadruple therapy. Meanwhile, the new 7-day dual therapy with vonoprazan (VPZ) and amoxicillin (AMO) failed to achieve the expected therapeutic effect in China. Patients and Methods: A total of 256 untreated HP-infected patients are included in this non-inferiority clinical trial. The patients were randomly divided into three groups: 14-day dual therapy group (VPZ 20mg b.i.d + AMO 750mg t.i.d for 14 days, VA14), 14-day modified triple therapy group (VA14 + Jinghua Weikang Capsule 160mg t.i.d, VAC), and conventional bismuth-containing quadruple therapy group for 14 days (BCQ). Eradication rates, drug-related adverse events (AEs), patient compliance, and drug costs were compared among the three groups. Results: The eradication rates in the BCQ, VA14, and VAC were 78.67, 77.33%, and 86.49% by intention-to-treat analysis, respectively, and 96.72%, 90.63%, and 92.75% by pre-protocol or modified intention-to-treat analysis, respectively. VA14 therapy indicated a non-inferiority eradication rate and advanced safety and economics to BCQ therapy. JWC further improved the eradication rate and reduced the incidence of AEs. Conclusion: A modified 14-day dual therapy with VPZ and AMO provides satisfied efficacy as the first-line treatment for HP infection in China.

The characteristics and clinical relevance of tumor fusion burden in non-EBV (+) gastric cancer with MSS.

BACKGROUND: Next-generation sequencing (NGS) is maturely applied for gene fusion detection. Although tumor fusion burden (TFB) has been identified as an immune marker for cancer, the relationship between these fusions and the immunogenicity and molecular characteristics of gastric cancer (GC) patients remains unclear. GCs have different clinical significance depending on their subtypes, and thus, this study aimed to investigate the characteristics and clinical relevance of TFB in non-Epstein-Barr-virus-positive (EBV+) GC with microsatellite stability (MSS). METHODS: A total of 319 GC patients from The Cancer Genome Atlas stomach adenocarcinoma (TCGA-STAD) and a cohort of 45-case from ENA (PRJEB25780) were included. The cohort characteristics and distribution of TFB among the patients were analyzed. Additionally, the correlations of TFB with mutation characteristics, pathway differences, relative abundance of immune cells, and prognosis were examined in the TCGA-STAD cohort of MSS and non-EBV (+) patients. RESULTS: We observed that in the MSS and non-EBV (+) cohort, the TFB-low group exhibited significantly lower gene mutation frequency, gene copy number, loss of heterozygosity score, and tumor mutation burden than in the TFB-high group. Additionally, the TFB-low group exhibited a higher abundance of immune cells. Furthermore, the immune gene signatures were significantly upregulated in the TFB-low group, 2-year disease-specific survival was markedly increased in the TFB-low group compared with to the TFB-high group. The rates of TFB-low cases were significantly higher TFB-than high cases in durable clinical benefit (DCB) and response groups with pembrolizumab treatment. Low TFB may serve as a predictor of GC prognosis, and the TFB-low group exhibits higher immunogenicity. CONCLUSION: In conclusion, this study reveals that the TFB-based classification of GC patient may be instructive for individualized immunotherapy regimens.

Protective effect of additional cathelicidin antimicrobial peptide PR-39 on prosthetic-joint infections.

BACKGROUND: Prosthetic-joint infection (PJI) is one of the severest complications after arthroplasty. However, antibiotics are not effective in the bacteria in biofilm outside the prosthetic-joint. Antimicrobial peptides have an efficient antimicrobial activity in staphylococcus aureus compared with conventional antibiotics. METHODS: Bone marrow stem cells (BMSCs) were isolated, cultured and transfected with cathelicidins antimicrobial peptides proline-arginine-rich 39 amino acid peptide (PR-39) lentivirus. The expression of PR-39 gene in BMSCs was detected by RT-PCR, and the antibacterial activity of PR-39 was measured by agar diffusion method. The transfection efficiency was detected by fluorescence microscopy. The infection model of artificial knee joint in rabbits were established. Kirschner wire was used as the knee joint implant to implant the distal femur through the femoral intercondylar fossa of rabbits. 24 rabbits were randomly divided into 2 groups for the above operations: group A was inoculated 0.5 mL into the joint cavity immediately after the incision was sutured 1 × 107 Staphylococcus aureus of colony forming unit (CFU), group B was inoculated with Staphylococcus aureus and PR-39. After operation, the wound conditions and histological changes were observed by X-ray and optical microscope respectively, CRP and erythrocyte sedimentation rate were measured by test assay. RESULTS: The transfection efficiency of lentivirus vectortransfected BMSCs was 74.09%. The supernatant of lentivirus vector had obvious inhibitory effect on Staphylococcus aureus, and the antibacterial rate was 98.43%. 100% infection observed in group A while few infection observed in group B; serum CRP and ESR at a high level in group A while decreased in group B after operation. There were no significant difference in CRP and ESR between the pLV/PR-39 group and pLV/EGFP group at day 1 and 3 respectively after surgery. However, CRP and ESR in the pLV/PR-39 groupwere significantly lower than the pLV/EGFP group at day 7 and 14 respectively after operation. CONCLUSIONS: Rabbits planted BMSCs expressing PR-39 were significantly increased resistance to Staphylococcus aureus in PJI than control group thus showing great potential for preventing implant-associated infection. It will provide a potential new therapeutic agent for implant-associated infection.

Interpretable machine learning-based approaches for understanding suicide risk and protective factors among South Korean females using survey and social media data.

OBJECTIVE: We aimed to identify and understand risk and protective factors for suicide among South Korean females by linking survey and social media data and using interpretable machine learning approaches. MATERIALS AND METHODS: We collected a wide range of potential factors including the material, psychosocial, and behavioral data from a detailed survey, which we then linked to data from social media. In addition, we adopted interpretable machine learning approaches to (1) predict the suicide risk, (2) explain the relative importance of factors and their interactions regarding suicide, and (3) understand individual differences affecting suicide risk. RESULTS: The best-performing machine learning model achieved an AUC of 0.737. Adverse childhood experiences, social connectedness, and mean positive sentiment score of social media posts were the three risk factors that had a monotonic or unimodal relationship with suicide, and satisfaction with life, narcissistic self-presentation, and number of close friends on social media were the three protective factors that had a monotonic or unimodal relationship with suicide. We also found several meaningful interactions between specific psychiatric symptoms and narcissistic self-presentation. CONCLUSIONS: Our findings can help governmental organizations to better assess female suicide risk in South Korea and develop more informed and customized suicide prevention strategies.