Diagnostic value and correlation analysis of serum cytokine levels in patients with multiple system atrophy.

Background: The association between cytokines in peripheral blood and clinical symptoms of multiple system atrophy (MSA) has been explored in only a few studies with small sample size, and the results were obviously controversial. Otherwise, no studies have explored the diagnostic value of serum cytokines in MSA. Methods: Serum cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-α), were measured in 125 MSA patients and 98 healthy controls (HCs). Correlations of these serum cytokines with clinical variables were analyzed in MSA patients. Diagnostic value of cytokines for MSA was plotted by receiver operating curves. Results: No significant differences were found in sex and age between the MSA group and the HCs. TNF-α in MSA patients were significantly higher than those in HCs (area under the curve (AUC) 0.768), while IL-6 and IL-8 were not. Only Hamilton Anxiety Scale (HAMA) has a positive correlation between with TNF-α in MSA patients with age and age at onset as covariates. Serum IL-6 was associated with HAMA, Hamilton Depression Scale (HAMD), the Unified MSA Rating Scale I (UMSARS I) scores, the UMSARS IV and the Instrumental Activity of Daily Living scores. However, IL-8 was not associated with all clinical variables in MSA patients. Regression analysis showed that HAMA and age at onset were significantly associated with TNF-α, and only HAMA was mild related with IL-6 levels in MSA patients. Conclusion: Serum TNF-α and IL-6 levels in MSA patients may be associated with anxiety symptom; however, only TNF-α was shown to be a useful tool in distinguishing between MSA and HCs.

A coordinated adaptive multiscale enhanced spatio-temporal fusion network for multi-lead electrocardiogram arrhythmia detection.

The multi-lead electrocardiogram (ECG) is widely utilized in clinical diagnosis and monitoring of cardiac conditions. The advancement of deep learning has led to the emergence of automated multi-lead ECG diagnostic networks, which have become essential in the fields of biomedical engineering and clinical cardiac disease diagnosis. Intelligent ECG diagnosis techniques encompass Recurrent Neural Networks (RNN), Transformers, and Convolutional Neural Networks (CNN). While CNN is capable of extracting local spatial information from images, it lacks the ability to learn global spatial features and temporal memory features. Conversely, RNN relies on time and can retain significant sequential features. However, they are not proficient in extracting lengthy dependencies of sequence data in practical scenarios. The self-attention mechanism in the Transformer model has the capability of global feature extraction, but it does not adequately prioritize local features and cannot extract spatial and channel features. This paper proposes STFAC-ECGNet, a model that incorporates CAMV-RNN block, CBMV-CNN block, and TSEF block to enhance the performance of the model by integrating the strengths of CNN, RNN, and Transformer. The CAMV-RNN block incorporates a coordinated adaptive simplified self-attention module that adaptively carries out global sequence feature retention and enhances spatial-temporal information. The CBMV-CNN block integrates spatial and channel attentional mechanism modules in a skip connection, enabling the fusion of spatial and channel information. The TSEF block implements enhanced multi-scale fusion of image spatial and sequence temporal features. In this study, comprehensive experiments were conducted using the PTB-XL large publicly available ECG dataset and the China Physiological Signal Challenge 2018 (CPSC2018) database. The results indicate that STFAC-ECGNet surpasses other cutting-edge techniques in multiple tasks, showcasing robustness and generalization.

The correlation between the thyroid function and urinary iodine/creatinine ratio of pregnant women attending a tertiary hospital in Beijing, China, during different trimesters.

OBJECTIVE: This study investigated the correlation between thyroid function and urinary iodine/creatinine ratio (UI/Cr) in pregnant women during different trimesters and explored potential influencing factors. METHODS: In this cross-sectional study, serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and UI/Cr were measured in 450 pregnant women. Correlations were analyzed using Pearson's correlation coefficient and multiple linear regression. Subgroup analyses were performed based on age, body mass index (BMI), parity, gestational age, education, occupation, and family history of thyroid disorders. RESULTS: UI/Cr was positively correlated with FT4 levels in the first and second trimesters, particularly in women with older age, higher BMI, multiparity, higher education, and employment. No significant correlations were found between UI/Cr and TSH or FT3 levels. CONCLUSION: UI/Cr is positively correlated with FT4 levels in early pregnancy, especially in women with certain risk factors. Regular monitoring of iodine status and thyroid function is recommended for pregnant women to ensure optimal maternal and fetal health.

A suitable and efficient optimization system for the culture of Chlamydia trachomatis in adult inclusion conjunctivitis.

The prevalence of Chlamydia trachomatis infection in the genitourinary tract is increasing, with an annual rise of 9 million cases. Individuals afflicted with these infections are at a heightened risk of developing adult inclusive conjunctivitis (AIC), which is commonly recognized as the ocular manifestation of this sexually transmitted infection. Despite its significant clinical implications, the lack of distinctive symptoms and the overlap with other ocular conditions often lead to underdiagnosis or misdiagnosis of AIC associated with C. trachomatis infection. Here, we established six distinct C. trachomatis culture cell lines, specifically highlighting the MA104 N*V cell line that exhibited diminished expression of interferon regulatory factor 3 (IRF3) and signal transducer and activator of transcription 1 (STAT1), resulting in reduced interferons. Infected MA104 N*V cells displayed the highest count of intracytoplasmic inclusions detected through immunofluorescence staining, peaking at 48 h postinfection. Subsequently, MA104 N*V cells were employed for clinical screening in adult patients diagnosed with AIC. Among the evaluated cohort of 20 patients, quantitative PCR (qPCR) testing revealed positive results in seven individuals, indicating the presence of C. trachomatis infection. Furthermore, the MA104 N*V cell cultures derived from these infected patients demonstrated successful cultivation and replication of the pathogen, confirming its viability and infectivity. Molecular genotyping identified four distinct urogenital serovars, with serovar D being the most prevalent (4/7), followed by E (1/7), F (1/7), and Ia (1/7). This novel cellular model contributes to studies on C. trachomatis pathogenesis, molecular mechanisms, and host-pathogen interactions both in vitro and in vivo. It also aids in acquiring clinically relevant strains critical for advancing diagnostics, treatments, and vaccines against C. trachomatis.

Development of a microbial dewaxing agent using three spore forming bacteria.

Microbial enhanced oil recovery (MEOR) is a cost effective and efficient method for recovering residual oil. However, the presence of wax (paraffin) in residual oil can substantially reduce the efficiency of MEOR. Therefore, microbial dewaxing is a critical process in MEOR. In this study, a bacterial dewaxing agent of three spore-forming bacteria was developed. Among these bacteria, Bacillus subtilis GZ6 produced the biosurfactant surfactin. Replacing the promoter of the surfactin synthase gene cluster (srfA), increased the titer of surfactin in this strain from 0.33 g/L to 2.32 g/L. The genetically modified strain produced oil spreading rings with diameters increasing from 3.5 ± 0.1 to 4.1 ± 0.2 cm. The LadA F10L/N133R mutant was created by engineering an alkane monooxygenase (LadA) using site-directed mutagenesis in the Escherichia coli host. Compared to the wild-type enzyme, the resulting mutant exhibited an 11.7-fold increase in catalytic efficiency toward the substrate octadecane. When the mutant (pIMPpladA2mu) was expressed in Geobacillus stearothermophilus GZ178 cells, it exhibited a 2.0-fold increase in octadecane-degrading activity. Cultures of the two modified strains (B. subtilis GZ6 (pg3srfA) and G. stearothermophilus GZ178 (pIMPpladA2mu)) were mixed with the culture of Geobacillus thermodenitrificans GZ156 at a ratio of 5:80:15. The resulting composition increased the rate of wax removal by 35% compared to the composition composed of three native strains. This study successfully developed a multi-strain bacterial agent with enhanced oil wax removal capabilities by genetically engineering two bacterial strains.

Prognostic value of morning blood pressure surge in chronic kidney disease.

This was a retrospective study. This study investigated the occurrence of a composite endpoints (cardiovascular and cerebrovascular events, end-stage renal disease, and death) in 153 patients (aged ≥ 18 years) with a diagnosis of in chronic kidney disease (CKD). Based on morning blood pressure surge (MBPS) defined as ≥35 mm Hg, patients were divided into two groups: with MBPS (n = 50) and without MBPS (n = 103). All patients were followed up for at least 1 year. Baseline demographic, laboratory and follow-up data were collected. The clinical characteristics of the two groups were compared. The relationships between MBPS and endpoint events were analyzed using the Kaplan-Meier method and Cox regression model. In total, 153 patients (mean age 41.8 years; 56.86% males) were included in this study. During the follow-up period (mean 4.3 years), 34 endpoint events occurred. After adjustment for the covariates, the risk of cardiovascular and cerebrovascular events, end-stage renal disease and death remained significantly higher in patients with MBPS (hazard ratio [HR] and 95% confidence interval [CI] 3.124 [1.096-9.130]]) Among the other variables, systolic blood pressure, and night-time and daytime pulse pressures remained significantly associated with outcome in patients of CKD (1.789 [1.205-2.654], 1.710 [1.200-2.437], and 1.318 [1.096-1.586], respectively]. In conclusions, MBPS was identified as an independent prognostic factor for composite endpoint events (cardiovascular and cerebrovascular events, end-stage renal disease and death) patients with chronic kidney disease patients.

Drug-induced liver injury in children: A nationwide cohort study from China.

Background & Aims: Currently, there is limited knowledge on the clinical profile of drug-induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China. Methods: This nationwide, multicenter, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf causality assessment method score, only patients with scores ≥6 or diagnosed with DILI by three experts after scoring <6 were included in the analysis. Among them, 460 cases met the EASL biochemical criteria. The study categorized children into three age groups: toddlers (≥30 days to <6 years old), school-age children (6 to <12 years old), and adolescents (12 to <18 years old). Results: Hepatocellular injury was the predominant clinical classification, accounting for 63% of cases, with 34% of these cases meeting Hy's law criteria. Adolescents comprised the majority of children with moderate/severe DILI (65%). Similarly, adolescents faced a significantly higher risk of severe liver injury compared to younger children (adjusted odd ratios 4.75, p = 0.002). The top three most frequently prescribed drug classes across all age groups were antineoplastic agents (25.9%), antimicrobials (21.5%), and traditional Chinese medicine (13.7%). For adolescents, the most commonly suspected drugs were antitubercular drugs (22%) and traditional Chinese medicine (23%). Conclusion: Adolescents are at a greater risk of severe and potentially fatal liver injury compared to younger children. Recognizing the risk of pediatric DILI is crucial for ensuring safe medical practices. Impact and implications: Drug-induced liver injury, a poorly understood yet serious cause of pediatric liver disease, encompasses a spectrum of clinical presentations, ranging from asymptomatic liver enzyme elevation to acute liver failure. This retrospective study, utilizing a large Chinese cohort of pediatric liver injury cases from 308 centers nationwide, characterized the major clinical patterns and suspected drugs in detail, revealing that adolescents are at a greater risk of severe liver injury compared to younger children. Vigilant care and careful surveillance of at-risk pediatric patients are crucial for physicians, researchers, patients, caregivers, and policymakers. Additional multicenter prospective studies are needed to evaluate the risk of hepatotoxicity in outpatients and hospitalized pediatric patients.

Constructing CoP/Ni2P Heterostructure Confined Ru Sub-Nanoclusters for Enhanced Water Splitting in Wide pH Conditions.

Developing efficient electrocatalysts for water splitting is of great significance for realizing sustainable energy conversion. In this work, Ru sub-nanoclusters anchored on cobalt-nickel bimetallic phosphides (Ru-CoP/Ni2P) are constructed by an interfacial confinement strategy. Remarkably, Ru-CoP/Ni2P with low noble metal loading (33.1 µg cm-2) shows superior activity for hydrogen evolution reaction (HER) in all pH values, whose turnover frequency (TOF) is 8.7, 15.3, and 124.7 times higher than that of Pt/C in acidic, alkaline, and neutral conditions, respectively. Meanwhile, it only requires the overpotential of 171 mV@10 mA cm-2 for oxygen evolution reaction (OER) and corresponding TOF is 20.3 times higher than that of RuO2. More importantly, the Ru-CoP/Ni2P||Ru-CoP/Ni2P displays superior mass activity of 4017 mA mgnoble metal -1 at 2.0 V in flowing alkaline water electrolyzer, which is 105.1 times higher than that of Pt/C||IrO2. In situ Raman spectroscopy demonstrates that the Ru sites in Ru-CoP/Ni2P play a key role for water splitting and follow the adsorption evolution mechanism toward OER. Further mechanism studies disclose the confined Ru atom contributes to the desorption of H2 during HER and the formation of O-O bond during OER, leading to fast reaction kinetics. This study emphasizes the importance of interface confinement for enhancing electrocatalytic activity.

Metagenomic analysis reveals altered gut virome and diagnostic potential in pancreatic cancer.

Pancreatic cancer (PC) is a highly aggressive malignancy with a poor prognosis, making early diagnosis crucial for improving patient outcomes. While the gut microbiome, including bacteria and viruses, is believed to be essential in cancer pathogenicity, the potential contribution of the gut virome to PC remains largely unexplored. In this study, we conducted a comparative analysis of the gut viral compositional and functional profiles between PC patients and healthy controls, based on fecal metagenomes from two publicly available data sets comprising a total of 101 patients and 82 healthy controls. Our results revealed a decreasing trend in the gut virome diversity of PC patients with disease severity. We identified significant alterations in the overall viral structure of PC patients, with a meta-analysis revealing 219 viral operational taxonomic units (vOTUs) showing significant differences in relative abundance between patients and healthy controls. Among these, 65 vOTUs were enriched in PC patients, and 154 were reduced. Host prediction revealed that PC-enriched vOTUs preferentially infected bacterial members of Veillonellaceae, Enterobacteriaceae, Fusobacteriaceae, and Streptococcaceae, while PC-reduced vOTUs were more likely to infect Ruminococcaceae, Lachnospiraceae, Clostridiaceae, Oscillospiraceae, and Peptostreptococcaceae. Furthermore, we constructed random forest models based on the PC-associated vOTUs, achieving an optimal average area under the curve (AUC) of up to 0.879 for distinguishing patients from controls. Through additional 10 public cohorts, we demonstrated the reproducibility and high specificity of these viral signatures. Our study suggests that the gut virome may play a role in PC development and could serve as a promising target for PC diagnosis and therapeutic intervention. Future studies should further explore the underlying mechanisms of gut virus-bacteria interactions and validate the diagnostic models in larger and more diverse populations.

Metagenomic analysis of the gut virome in patients with irritable bowel syndrome.

Irritable bowel syndrome (IBS), a chronic functional gastrointestinal disorder, is recognized for its association with alterations in the gut microbiome and metabolome. This study delves into the largely unexplored domain of the gut virome in IBS patients. We conducted a comprehensive analysis of the fecal metagenomic data set from 277 IBS patients and 84 healthy controls to characterize the gut viral community. Our findings revealed a distinct gut virome in IBS patients compared to healthy individuals, marked by significant variances in between-sample diversity and altered abundances of 127 viral operational taxonomic units (vOTUs). Specifically, 111 vOTUs, predominantly belonging to crAss-like, Siphoviridae, Myoviridae, and Quimbyviridae families, were more abundant in IBS patients, whereas the healthy control group exhibited enrichment of 16 vOTUs from multiple families. We also investigated the interplay between the gut virome and bacteriome, identifying a correlation between IBS-enriched bacteria like Klebsiella pneumoniae, Fusobacterium varium, and Ruminococcus gnavus, and the IBS-associated vOTUs. Furthermore, we assessed the potential of gut viral signatures in predicting IBS, achieving a notable area under the receiver operator characteristic curve (AUC) of 0.834. These findings highlight significant shifts in the viral diversity, taxonomic distribution, and functional composition of the gut virome in IBS patients, suggesting the potential role of the gut virome in IBS pathogenesis and opening new avenues for diagnostic and therapeutic strategies targeting the gut virome in IBS management.

Sanguinarine Induces Necroptosis of HCC by Targeting PKM2 Mediated Energy Metabolism.

BACKGROUNDS: Abnormal metabolism is the hallmark of hepatocellular carcinoma. Targeting energy metabolism has become the major focus of cancer therapy. The natural product, sanguinarine, displays remarkable anti-tumor properties by disturbing energy homeostasis; however, the underlying mechanism has not yet been elucidated. METHODS: The anticancer activity of sanguinarine was determined using CCK-8 and colony formation assay. Morphological changes of induced cell death were observed under electron microscopy. Necroptosis and apoptosis related markers were detected using western blotting. PKM2 was identified as the target by transcriptome sequencing. Molecular docking assay was used to evaluate the binding affinity of sanguinarine to the PKM2 molecule. Furthermore, Alb-CreERT2; PKM2loxp/loxp; Rosa26RFP mice was used to construct the model of HCC-through the intervention of sanguinarine in vitro and in vivo-to accurately explore the regulation effect of sanguinarine on cancer energy metabolism. RESULTS: Sanguinarine inhibited tumor proliferation, metastasis and induced two modes of cell death. Molecular docking of sanguinarine with PKM2 showed appreciable binding affinity. PKM2 kinase activity and aerobic glycolysis rate declined, and mitochondrial oxidative phosphorylation was inhibited by sanguinarine application; these changes result in energy deficits and lead to necroptosis. Additionally, sanguinarine treatment prevents the translocation of PKM2 into the nucleus and suppresses the interaction of PKM2 with ß-catenin; the transcriptional activity of PKM2/ß-catenin signaling and its downstream genes were decreased. CONCLUSIONS: Sanguinarine showed remarkable anti-HCC activity via regulating energy metabolism by PKM2/ß-catenin signaling. On the basis of these investigations, we propose that sanguinarine might be considered as a promising compound for discovery of anti-HCC drugs.

Pregnant patient with Xp11.2/transcription factor E3 translocation renal cell carcinoma: a case report and literature review.

MiT family translocation renal cell carcinomas (tRCCs) primarily include Xp11.2/transcription factor E3 (TFE3) gene fusion-associated renal cell carcinoma (Xp11.2 tRCC) and t(6;11)/TFEB gene fusion-associated RCC. Clinical cases of these carcinomas are rare. Fluorescence in situ hybridization can be used to identify the type, but there are no standard diagnostic and treatment methods available, and the prognosis remains controversial. Herein, we present a case of a patient with Xp11.2 tRCC at 29 weeks of gestation. The baby was successfully delivered, and radical surgery was performed for renal cancer at the same time. This is a unique and extremely rare case. We have described the case and performed a literature review to report the progress of current research on the treatment and prognosis of pregnant patients with Xp11.2/TFE3 translocation renal cell carcinoma. This study aims to contribute to improving the diagnosis and treatment of Xp11.2 tRCC in pregnant patients.

Milk Fat Globule-EGF Factor 8 (MFGE8) Mitigates Cognitive Impairment in Rats with Sepsis-Associated Encephalopathy: An fMRI Study.

BACKGROUND: Sepsis-associated encephalopathy (SAE) impairs hippocampal microglial efferocytosis, causing cognitive deficits. Previous research found that milk fat globule epidermal growth factor 8 protein (MFGE8) stimulates efferocytosis, reducing hippocampal inflammation in SAE rats. In this study, we explore MFGE8's role in alleviating cognitive impairment and its impact on neural activity using functional magnetic resonance imaging (fMRI). METHODS: Sixty male Sprague Dawley rats were divided into four groups: Sham, cecal ligation and puncture (CLP), CLP+MFGE8, and CLP+MFGE8+CGT (Cilengitide). After CLP, CLP+MFGE8 rats received intracerebroventricular MFGE8 (3.3 µg), while CLP+MFGE8+CGT rats received intraperitoneal Cilengitide (10 mg/kg). We assessed cognitive function with the Morris water maze and open field test over five days. Eight days post-surgery, rats underwent T2-weighted magnetic resonance imaging (MRI) and resting state (rs)-fMRI scans. Brain tissues were collected for western blot, hematoxylin-eosin (HE) staining, and immunofluorescence. Statistical analysis employed one-way analysis of variance (ANOVA) followed by Tukey's post-test for multiple comparisons. RESULTS: MFGE8 improved neurobehavioral performance in open field task (OFT) and morris water maze (MWM) tests. fMRI indicated a significant reduction in abnormal neural activity in the right hippocampal CA1, CA3, and dentate gyrus of SAE rats following MFGE8 treatment. Voxel-based morphometry (VBM) analysis revealed decreased high-signal areas in the hippocampus, along with reduced hippocampal volume due to alleviated neural edema. Western blot analysis demonstrated that MFGE8 enhanced ras-related C3 botulinum toxin substrate 1 (Rac1) and microtubule-associated protein 1A/1B-light chain 3 (LC3) expression in the rat hippocampus, while CGT reduced these protein levels. Behavioral experiments and fMRI results confirmed that CGT reversed the cognitive effects of MFGE8 by inhibiting microglial αVß3/αVß5 integrin receptors. CONCLUSIONS: Our findings show that MFGE8 reduced amplitude of low-frequency fluctuations (ALFF) values in the right hippocampal CA1, CA3, and the dentate gyrus, mitigating abnormal neural activity and decreasing hippocampal volume. This led to an improvement in cognitive dysfunction in SAE rats. These results suggest that MFGE8 enhances microglial efferocytosis by activating αVß3 and αVß5 integrin receptors on microglial surfaces, ultimately improving cognitive function in SAE rats.

Varied cellular abnormalities in thin vs. normal endometrium in recurrent implantation failure by single-cell transcriptomics.

BACKGROUND: Reduced endometrium thickness and receptivity are two important reasons for recurrent implantation failure (RIF). In order to elucidate differences between these two types of endometrial defects in terms of molecular signatures, cellular interactions, and structural changes, we systematically investigated the single-cell transcriptomic atlas across three distinct groups: RIF patients with thin endometrium (≤ 6 mm, TE-RIF), RIF patients with normal endometrium thickness (≥ 8 mm, NE-RIF), and fertile individuals (Control). METHODS: The late proliferative and mid-secretory phases of the endometrium were collected from three individuals in the TE-RIF group, two in the NE-RIF group, and three in the control group. The study employed a combination of advanced techniques. Single-cell RNA sequencing (scRNA-seq) was utilized to capture comprehensive transcriptomic profiles at the single-cell level, providing insights into gene expression patterns within specific cell types. Scanning and transmission electron microscopy were employed to visualize ultrastructural details of the endometrial tissue, while hematoxylin and eosin staining facilitated the examination of tissue morphology and cellular composition. Immunohistochemistry techniques were also applied to detect and localize specific protein markers relevant to endometrial receptivity and function. RESULTS: Through comparative analysis of differentially expressed genes among these groups and KEGG pathway analysis, the TE-RIF group exhibited notable dysregulations in the TNF and MAPK signaling pathways, which are pivotal in stromal cell growth and endometrial receptivity. Conversely, in the NE-RIF group, disturbances in energy metabolism emerged as a primary contributor to reduced endometrial receptivity. Additionally, using CellPhoneDB for intercellular communication analysis revealed aberrant interactions between epithelial and stromal cells, impacting endometrial receptivity specifically in the TE-RIF group. CONCLUSION: Overall, our findings provide valuable insights into the heterogeneous molecular pathways and cellular interactions associated with RIF in different endometrial conditions. These insights may pave the way for targeted therapeutic interventions aimed at improving endometrial receptivity and enhancing reproductive outcomes in patients undergoing ART. Further research is warranted to validate these findings and translate them into clinical applications for personalized fertility treatments. TRIAL REGISTRATION: Not applicable.

Differential prognostic impact and potential molecular mechanisms of PCDHGA12 expression in lung adenocarcinoma and squamous cell carcinoma.

Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), subtypes of non-small cell lung cancer (NSCLC), exhibit distinct characteristics. The expression and prognostic significance of Protocadherin Gamma Subfamily A, 12 (PCDHGA12) in NSCLC remain unexplored. This study analyzed transcriptomic and genomic datasets from TCGA to investigate PCDHGA12 expression and its prognostic relevance in LUAD and LUSC. We found PCDHGA12 mRNA and protein levels were downregulated in both LUAD and LUSC tissues compared to adjacent non-cancerous tissues, with high PCDHGA12 expression correlating with lower overall survival in LUSC but not in LUAD. GSEA revealed a unique enrichment pattern associated with PCDHGA12 low expression in LUSC, especially in the DNA repair pathway. Co-expression analysis showed associations of PCDHGA12 with focal adhesion and the PI3K-AKT pathway in LUAD, and additionally with ECM-receptor interaction in LUSC. Hub gene prognosis analysis identified genes correlated with prognosis only in LUSC, reflecting PCDHGA12's influence. Mutation analysis linked with PCDHGA12 identified differential mutations in SPTA1, KEAP1, and TNR in LUAD, and a notable NAV3 mutation in LUSC. Additionally, immuno-infiltration analysis reveals a positive correlation between PCDHGA12 expression and immune cell infiltration. Specifically, lower PCDHGA12 expression in LUSC is associated with higher levels of CD8 T cells and DCs, lower levels of Tregs and M0 macrophages, and increased expression of HMGB1 and TNFRSF18. These genetic and immunological differences may account for the significant prognostic disparity of PCDHGA12 levels between LUAD and LUSC. Further experimental studies are essential to validate these associations and investigate potential targeted and immunotherapeutic strategies.

Treatment of Tislelizumab-Induced Toxic Epidermal Necrolysis and Agranulocytosis: A Case Report and Literature Review.

BACKGROUND: Non-small Cell Lung Cancer (NSCLC) makes up about 85% of lung cancer cases, mainly adenocarcinoma and squamous cell carcinoma. Recently, PD-1 inhibitors have become crucial in NSCLC treatment, significantly enhancing survival for some. However, side effects, like skin reactions and hematotoxicity, limit their use, with drug-induced TEN and immunotherapy-induced agranulocytosis as severe adverse effects. CASE PRESENTATION: Herein, we have reported the case of a 75-year-old male diagnosed with metastatic Lung Squamous cell Carcinoma (LUSC) in the left lung. He received first-line treatment with one cycle of tislelizumab in combination with nab-paclitaxel and carboplatin, after which he developed Toxic Epidermal Necrolysis (TEN) and granulocytopenia. To address these two serious immune-related Adverse Events (irAEs), the patient was administered methylprednisolone in combination with gamma globulin for TEN and dexamethasone in combination with G-CSF for agranulocytosis. Antibiotics were also administered according to the patient's medication regimen. After treatment, the patient recovered and was discharged from the hospital. It was also noted that the lung tumor condition improved. CONCLUSION: Effective management of severe immune-related side effects from tislelizumab, including TEN and agranulocytosis, can be partly achieved through steroids, gamma globulin, GCSF, and antibiotics. This strategy not only alleviates these adverse effects, but also potentially improves tumor conditions, highlighting the crucial role of vigilant monitoring and management in immunotherapy.

De novo biosynthesis of ß-arbutin in Corynebacterium glutamicum via pathway engineering and process optimization.

BACKGROUND: ß-Arbutin, a hydroquinone glucoside found in pears, bearberry leaves, and various plants, exhibits antioxidant, anti-inflammatory, antimicrobial, and anticancer effects. ß-Arbutin has wide applications in the pharmaceutical and cosmetic industries. However, the limited availability of high-performance strains limits the biobased production of ß-arbutin. RESULTS: This study established the ß-arbutin biosynthetic pathway in C. glutamicum ATCC13032 by introducing codon-optimized ubiC, MNX1, and AS. Additionally, the production titer of ß-arbutin was increased by further inactivation of csm and trpE to impede the competitive metabolic pathway. Further modification of the upstream metabolic pathway and supplementation of UDP-glucose resulted in the final engineered strain, C. glutamicum AR11, which achieved a ß-arbutin production titer of 7.94 g/L in the optimized fermentation medium. CONCLUSIONS: This study represents the first successful instance of de novo ß-arbutin production in C. glutamicum, offering a chassis cell for ß-arbutin biosynthesis.