The Application of Mendelian Randomization in Cardiovascular Disease Risk Prediction: Current Status and Future Prospects.

Cardiovascular disease (CVD), a leading cause of death and disability worldwide, and is associated with a wide range of risk factors, and genetically associated conditions. While many CVDs are preventable and early detection alongside treatment can significantly mitigate complication risks, current prediction models for CVDs need enhancements for better accuracy. Mendelian randomization (MR) offers a novel approach for estimating the causal relationship between exposure and outcome by using genetic variation in quasi-experimental data. This method minimizes the impact of confounding variables by leveraging the random allocation of genes during gamete formation, thereby facilitating the integration of new predictors into risk prediction models to refine the accuracy of prediction. In this review, we delve into the theory behind MR, as well as the strengths, applications, and limitations behind this emerging technology. A particular focus will be placed on MR application to CVD, and integration into CVD prediction frameworks. We conclude by discussing the inclusion of various populations and by offering insights into potential areas for future research and refinement.

Coixol mitigates Toxoplasma gondii infection-induced liver injury by inhibiting the Toxoplasma gondii HSP70/TLR4/NF-κB signaling pathway in hepatic macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Coix seed, the dry mature seed kernel of the gramineous plant coix (Coix lacryma-jobi L. var. ma-yuen Stapf), is widely consumed as a traditional Chinese medicine and functional food in China and South Korea. We have previously demonstrated the protective effect of coixol, a polyphenolic compound extracted from coix, against Toxoplasma gondii (T. gondii) infection-induced lung injury. However, the protective effect of coixol on hepatic injury induced by T. gondii infection have not yet been elucidated. AIM OF THE STUDY: This study explores the impact of coixol on T. gondii infection-induced liver injury and elucidates the underlying molecular mechanisms. MATERIALS AND METHODS: Female BALB/c mice and Kupffer cells (KCs) were employed to establish an acute T. gondii infection model in vivo and an inflammation model in vitro. The study examined coixol's influence on the T. gondii-derived heat shock protein 70 (T.g.HSP70)/toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway in T. gondii-infected liver macrophages. Furthermore, a co-culture system of KCs and NCTC-1469 hepatocytes was developed to observe the impact of liver macrophages infected with T. gondii on hepatocyte injury. RESULTS: Coixol notably inhibited the proliferation of tachyzoites and the expression of T.g.HSP70 in mouse liver and KCs, and attenuated pathological liver injury. Moreover, coixol decreased the production of high mobility group box 1, tumor necrosis factor-α, and inducible nitric oxide synthase by suppressing the TLR4/NF-κB signaling pathway in vitro and in vivo. Coixol also mitigated KCs-mediated hepatocyte injury. CONCLUSIONS: Coixol protects against liver injury caused by T. gondii infection, potentially by diminishing hepatocyte injury through the suppression of the inflammatory cascade mediated by the T.g.HSP70/TLR4/NF-κB signaling pathway in KCs. These findings offer new perspectives for developing coixol as a lead compound for anti-T. gondii drugs.

Metal fluorides-multi-functional tools for the study of phosphoryl transfer enzymes, a practical guide.

Enzymes facilitating the transfer of phosphate groups constitute the most extensive protein families across all kingdoms of life. They make up approximately 10% of the proteins found in the human genome. Understanding the mechanisms by which enzymes catalyze these reactions is essential in characterizing the processes they regulate. Metal fluorides can be used as multifunctional tools to study these enzymes. These ionic species bear the same charge as phosphate and the transferring phosphoryl group and, in addition, allow the enzyme to be trapped in catalytically important states with spectroscopically sensitive atoms interacting directly with active site residues. The ionic nature of these phosphate surrogates also allows their removal and replacement with other analogs. Here, we describe the best practices to obtain these complexes, their use in NMR, X-ray crystallography, cryo-EM, and SAXS and describe a new metal fluoride, scandium tetrafluoride, which has significant anomalous signal using soft X-rays.

Microbiological and molecular profile of furcation defects in a population with untreated periodontitis.

AIM: To describe the microbiological composition of subgingival dental plaque and molecular profile of gingival crevicular fluid (GCF) of periodontal furcation-involved defects. MATERIALS AND METHODS: Fifty-seven participants with periodontitis contributed with a degree II-III furcation involvement (FI), a non-furcation (NF) periodontal defect and a periodontally healthy site (HS). Subgingival plaque was analysed by sequencing the V3-V4 region of the 16S rRNA gene, and a multiplex bead immunoassay was carried out to estimate the GCF levels of 18 GCF biomarkers. Aiming to explore inherent patterns and the intrinsic structure of data, an AI-clustering method was also applied. RESULTS: In total, 171 subgingival plaque and 84 GCF samples were analysed. Four microbiome clusters were identified and associated with FI, NF and HS. A reduced aerobic microbiota (p = .01) was detected in FI compared with NF; IL-6, MMP-3, MMP-8, BMP-2, SOST, EGF and TIMP-1 levels were increased in the GCF of FI compared with NF. CONCLUSIONS: This is the first study to profile periodontal furcation defects from a microbiological and inflammatory standpoint using conventional and AI-based analyses. A reduced aerobic microbial biofilm and an increase of several inflammatory, connective tissue degradation and repair markers were detected compared with other periodontal defects.

Breaking Boundaries in Spinal Surgery: GPT-4's Quest to Revolutionize Surgical site Infection Management.

BACKGROUND: Surgical site infection (SSI) is a common and costly complication in spinal surgery. Identifying risk factors and preventive strategies is crucial for reducing SSIs. GPT-4 has evolved from a simple text-based tool to a sophisticated multimodal data expert, invaluable for clinicians. This study explored GPT-4's applications in SSI management across various clinical scenarios. METHODS: GPT-4 was employed in various clinical scenarios related to SSIs in spinal surgery. Researchers designed specific questions for GPT-4 to generate tailored responses. Six evaluators assessed these responses for logic and accuracy using a 5-point Likert scale. Inter-rater consistency was measured with Fleiss' kappa, and radar charts visualized GPT-4's performance. RESULTS: The inter-rater consistency, measured by Fleiss' kappa, ranged from 0.62 to 0.83. The overall average scores for logic and accuracy were 24.27±0.4 and 24.46±0.25 on 5-point Likert scale. Radar charts showed GPT-4's consistently high performance across various criteria. GPT-4 demonstrated high proficiency in creating personalized treatment plans tailored to diverse clinical patient records and offered interactive patient education. It significantly improved SSI management strategies, infection prediction models, and identified emerging research trends. However, it had limitations in fine-tuning antibiotic treatments and customizing patient education materials. CONCLUSIONS: GPT-4 represents a significant advancement in managing SSIs in spinal surgery, promoting patient-centered care and precision medicine. Despite some limitations in antibiotic customization and patient education, GPT-4's continuous learning, attention to data privacy and security, collaboration with healthcare professionals, and patient acceptance of AI recommendations suggest its potential to revolutionize SSI management, requiring further development and clinical integration.

The Impact of a Twice-daily vs Once-daily Proton Pump Inhibitor Dosing Regimen on Laryngopharyngeal Reflux Symptoms: A Prospective Randomized Controlled Trial.

Background/Aims: Proton pump inhibitors (PPIs) play a crucial role in managing laryngopharyngeal reflux (LPR), but the optimal dosing regimen remains unclear. We aim to compare the effectiveness of the same total PPI dose administered twice daily versus once daily in LPR patients. Methods: We conducted a prospective randomized controlled trial at a tertiary referral hospital, enrolling a total of 132 patients aged 19-79 with LPR. These patients were randomly assigned to receive either a 10 mg twice daily (BID) or a 20 mg once daily (QD) dose of ilaprazole for 12 weeks. The Reflux Symptom Index (RSI) and Reflux Finding Score (RFS) were assessed at 8 weeks and 16 weeks. The primary endpoint was the RSI response, defined as a reduction of 50% or more in the total RSI score from the baseline. We also analyzed the efficacy of the dosing regimens and the impact of dosing and duration on treatment outcomes. Results: The BID group did not display a higher response rate for RSI than the QD group. The changes in total RSI scores at the 8-week and 16-week visits showed no significant differences between the 2 groups. Total RFS alterations were also comparable between both groups. Each dosing regimen demonstrated significant decreases in RSI and RFS. Conclusions: Both BID and QD PPI dosing regimens improved subjective symptom scores and objective laryngoscopic findings. There was no significant difference in RSI improvement between the 2 dosing regimens, indicating that either dosing regimen could be considered a viable treatment option.

Identification of oxidative stress-related diagnostic markers and immune infiltration features for idiopathic pulmonary fibrosis by bibliometrics and bioinformatics.

Idiopathic pulmonary fibrosis (IPF) garners considerable attention due to its high fatality rate and profound impact on quality of life. Our study conducts a comprehensive literature review on IPF using bibliometric analysis to explore existing hot research topics, and identifies novel diagnostic and therapeutic targets for IPF using bioinformatics analysis. Publications related to IPF from 2013 to 2023 were searched on the Web of Science Core Collection (WoSCC) database. Data analysis and visualization were conducted using CiteSpace and VOSviewer software primarily. The gene expression profiles GSE24206 and GSE53845 were employed as the training dataset. The GSE110147 dataset was employed as the validation dataset. We identified differentially expressed genes (DEGs) and differentially expressed genes related to oxidative stress (DEOSGs) between IPF and normal samples. Then, we conducted Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The hub genes were screened by protein-protein interaction (PPI) networks and machine learning algorithms. The CIBERSORT was used to analyze the immune infiltration of 22 kinds of immune cells. Finally, we conducted the expression and validation of hub genes. The diagnostic efficacy of hub genes was evaluated by employing Receiver Operating Characteristic (ROC) curves and the associations between hub genes and immune cells were analyzed. A total of 6,500 articles were identified, and the annual number of articles exhibited an upward trend. The United States emerged as the leading contributor in terms of publication count, institutional affiliations, highly cited articles, and prolific authorship. According to co-occurrence analysis, oxidative stress and inflammation are hot topics in IPF research. A total of 1,140 DEGs were identified, and 72 genes were classified as DEOSGs. By employing PPI network analysis and machine learning algorithms, PON2 and TLR4 were identified as hub genes. A total of 10 immune cells exhibited significant differences between IPF and normal samples. PON2 and TLR4, as oxidative stress-related genes, not only exhibit high diagnostic efficacy but also show close associations with immune cells. In summary, our study highlights oxidative stress and inflammation are hot topics in IPF research. Oxidative stress and immune cells play a vital role in the pathogenesis of IPF. Our findings suggest the potential of PON2 and TLR4 as novel diagnostic and therapeutic targets for IPF.

Chronic Wound Caused by Lymphorrhea after Skin Abscess Drainage on Lower Extremity: A Case Report.

ABSTRACT: Surgical operations such as lymph node dissection may inadvertently damage the lymphatic system and lead to lymphorrhea. Excessive lymphatic exudation can cause a chronic wound. However, for surgery that does not involve the lymphatic system, lymphorrhea is a rare postoperative complication. This case report describes a 38-year-old patient who presented with lymphatic cutaneous leakage after incision and drainage of a skin abscess on the lower extremity. Persistent lymphorrhea increased the amount of wound exudation, which affected wound healing. After treatment of the lymphorrhea, the lower extremity wound healed completely within 4 weeks and did not result in lymphedema. Ligation of lymphatic vessels is a simple and easily performed treatment method for lymphatic leakage.

Durable and programmable ultrafast nanophotonic matrix of spectral pixels.

Locally addressable nanophotonic devices are essential for modern applications such as light detection, optical imaging, beam steering and displays. Despite recent advances, a versatile solution with a high-speed tuning rate, long-life durability and programmability across multiple pixels remains elusive. Here we introduce a programmable nanophotonic matrix consisting of vanadium dioxide (VO2) cavities on pixelated microheaters that meets all these requirements. The indirect Joule heating of these VO2 cavities can result in pronounced spectral modulation with colour changes and ensures exceptional endurance even after a million switching cycles. Precise control over the thermal dissipation power through a SiO2 layer of an optimized thickness on Si facilitates an ultrafast modulation rate exceeding 70 kHz. We demonstrated a video-rate nanophotonic colour display by electrically addressing a matrix of 12 × 12 pixels. Furthermore, inspired by the unique pixel-level programmability with multiple intermediate states of the spectral pixels, a spatiotemporal modulation concept is introduced for spectrum detection.

Discovering Potential Mechanisms of Intervertebral Disc Disease Using Systematic Mendelian Randomization of Human Circulating Immunocytomics.

BACKGROUND: Although intervertebral disc degeneration (IVDD) is a critical factor in many spine-related diseases and has an extremely high prevalence in the aging population, the potential pathogenesis remains to be clarified entirely. Immune cells have been found to perform an essential function during the onset and progression of IVDD in recent years. Therefore, we explored the association between immune cell characteristics and IVDD through Mendelian randomization (MR) analysis and further delved into the mediating role of potential metabolites. METHODS: Based on the MR analysis, the association of 731 immune cell phenotypes and 1400 metabolites on IVDD were assessed. Single nucleotide polymorphisms were closely associated the expression levels of immune cell characteristics and the concentrations of metabolites and have been used as instrumental variables for deducing them as risk factors or protective factors for IVDD. In addition, mediation analyses have been performed to identify potential metabolite mediators between immune cell characteristics and IVDD. RESULTS: MR analysis identified 27 immune cell phenotypes and 79 metabolites significantly associated with IVDD. In addition, mediation analysis was performed by selecting the immune cell phenotype that most significantly increased the risk of IVDD - CD86 on monocytes. A total of 4 metabolite-mediated mediation relationships were revealed (3 b-hydroxy-5-cholenoic acid, X-22509, N-acetyl-L-glutamine, and N2-acetyl, N6, N6-dimethyllysine). CONCLUSIONS: The findings of this analysis identified underlying association between immune cell phenotypes, metabolite, and IVDD that may serve as predictive and prognostic clinical biomarkers and benefit IVDD pathogenesis research.

Feasibility of a modified hybrid glubran-supported single-proglide technique for access closure during endovascular aneurysm repair.

Objective: This study aimed to evaluate the feasibility of a hybrid Glubran-supported single-Proglide technique for large bore femoral access closure during percutaneous access endovascular aneurysm repair (EVAR). Methods: A retrospective cohort study was performed for all percutaneous EVARs at our center from January 2023 to June 2023. All patients received the hybrid Glubran-supported single-Proglide technique involving a mixture of surgical glue and Lipiodol injection after single suture placement for femoral access closure. Technical success was defined as achieving complete hemostasis without a bailout strategy. Vascular complications and bleeding were defined by Valve Academic Research Consortium-3 (VARC-3) criteria. Vascular access changes and 30-day mortality were recorded. Results: The technique success rate for the entire study population was 100% (55 femoral access in 37 patients; median age: 72; 78% males). The mean sheath size was 20.4 ± 2.3F. The mean manual compression time was 3.5 ± 1.4 min, the mean hemostasis time was 9.0 ± 2.5 min, and the mean procedural time was 103.9 ± 34.7 min. One patient (1.6%) developed an access site infection and recovered conservatively. No VARC-3 vascular complications and access changes were observed. No 30-day mortality happened. Conclusions: The hybrid Glubran-supported single-Proglide technique is feasible for large bore access closure during EVAR and may be a viable alternative; however, larger prospective studies are required to confirm its efficacy.

Impact of stakeholder pressure on digital process innovation: An empirical analysis.

Digital technologies can bring about fundamental changes in corporate processes, which may result in a shift from process innovation to digital process innovation. However, owing to resource constraints and various stakeholders, digital process implementation is extremely challenging for firms. Based on stakeholder theory, this study explores whether and how stakeholder pressure for digitalization can facilitate corporate digital process innovation and unravels the mediating effect of routine reconfiguration and the moderating effect of strategic flexibility. The findings from a survey of 351 firms prove that stakeholder pressure for digitalization can facilitate corporate digital process innovation via routine reconfiguration. Moreover, this study finds that increased strategic flexibility can strengthen the positive mediating effect of routine reconfiguration. The findings contribute to the deep understanding of digital process innovation and offer a boundary condition for the effectiveness of stakeholder pressure.

Integrative analysis of aging-related genes reveals CEBPA as a novel therapeutic target in non-small cell lung cancer.

BACKGROUND: To explore the impact of ARGs on the prognosis of NSCLC, and its correlation with clinicopathological parameters and immune microenvironment. Preliminary research on the biological functions of CEBPA in NSCLC. METHODS: Using consensus clustering analysis to identify molecular subtypes of ARGs in NSCLC patients; employing LASSO regression and multivariate Cox analysis to select 7 prognostic risk genes and construct a prognostic risk model; validating independent prognostic factors of NSCLC using forest plot analysis; analyzing immune microenvironment correlations using ESTIMATE and ssGSEA; assessing correlations between prognostic risk genes via qPCR and Western blot in NSCLC; measuring mRNA and protein expression levels of knocked down and overexpressed CEBPA in NSCLC using CCK-8 and EdU assays; evaluating the effects of knocked down and overexpressed CEBPA on cell proliferation using Transwell experiments; examining the correlation of CEBPA with T cells and B cells using mIHC analysis. RESULTS: Consensus clustering analysis identified three molecular subtypes, suggesting significant differential expression of these ARGs in NSCLC prognosis and clinical pathological parameters. There was significant differential expression between the two risk groups in the prognostic risk model, with P < 0.001. The risk score of the prognostic risk model was also P < 0.001. CEBPA exhibited higher mRNA and protein expression levels in NSCLC cell lines. Knockdown of CEBPA significantly reduced mRNA and protein expression levels of CEBPB, YWHAZ, ABL1, and CDK1 in H1650 and A549 cells. siRNA-mediated knockdown of CEBPA markedly inhibited proliferation, migration, and invasion of NSCLC cells, whereas overexpression of CEBPA showed the opposite trend. mIHC results indicated a significant increase in CD3 + CD4+, CD3 + CD8+, and CD20 + cell counts in the high CEBPA expression group. CONCLUSIONS: The risk score of the prognostic risk model can serve as an independent prognostic factor, guiding the diagnosis and treatment of NSCLC. CEBPA may serve as a potential tumor biomarker and immune target, facilitating further exploration of the biological functions and immunological relevance in NSCLC.

Knowledge, attitude, and practice of Chinese parents with infants (aged 0-3 years) toward immunity, gut microbiota and biotics: a comprehensive study.

In the wake of the COVID-19 pandemic, there has been an increasing focus towards infant immunity. The development and maintenance of the immune system are significantly influenced from birth, and is shaped by early-life infant feeding behavior. Hence, the knowledge, attitude, and practice (KAP) of parents play a crucial role in shaping the immune system of infants. A total of 2369 parents across 19 cities in China were surveyed using a self-designed online questionnaire. The KAP questionnaire assessed three domains: immunity, gut microbiota, and biotics (prebiotics, probiotics, and synbiotics). The questionnaire also included questions on infant health. An overwhelming majority of parents (97.90%) placed high value on their children's immunity, and 40.40% of them reported an increased level of concern following the COVID-19 pandemic. Diarrhea (78.80%), colds (75.70%), nighttime crying (73.80%), regurgitation (71.70%) and food retention (66.50%) were the major health issues reported. Knowledge scores toward immunity and gut microbiota were positively correlated to attitude and practice scores, respectively. Attitude scores toward immunity, gut microbiota and biotics were positively correlated to their respective practice scores. Parental knowledge score on immunity was negatively correlated with diarrhea, colds, regurgitation and food retention. On the other hand, parental practice scores toward immunity were negatively correlated with food retention. In regards to gut microbiota, parental knowledge score was negatively correlated with diarrhea, regurgitation and food retention; parental attitude score was negatively correlated with nighttime crying whereas practice score was negatively correlated with diarrhea, regurgitation, food retention and nighttime crying. Attitude score toward biotics was negatively correlated with nighttime crying and practice scores toward biotics was negatively correlated with colds, food retention and nighttime crying. This study demonstrated that significant gaps and misunderstandings exist among parents regarding immunity, gut microbiota health, and biotics. Both public education and interventions are crucial to enhance parental knowledge and practices, thereby improving infant immunity.

The Essential Role of Traditional Chinese Medicine Compounds in Regulating Recurrent Spontaneous Abortion by Inhibiting Oxidative Stress.

Due to the lack of accurate registration of RSA and miscarriages, many early miscarriages are overlooked and not diagnosed or treated promptly in hospitals. This uncertainty in pathogenesis prevents clinicians from taking targeted therapeutic measures, leading to unsatisfactory treatment outcomes and placing a heavy burden on the patient's family and the healthcare system. Oxidative stress is present in embryonic development and affects the regulation of oxidative stress in pregnancy and the reproductive endocrine system. Oxidative stress injury is a significant pathogenesis of RSA, so improving the body's ability to resist oxidative stress injury is crucial in treating RSA. For patients with RSA, there is an urgent need for safe, efficient, and cost-effective anti-oxidative stress drugs, and there is growing evidence that treatment with Traditional Chinese medicine (TCM) can improve pregnancy success with fewer adverse effects. Many active ingredients for treating RSA are mainly derived from certain components of TCM, including flavonoids, phenols, and other compounds, which have been shown to treat RSA directly or indirectly by targeting anti-oxidative stress-related pathways. This article summarizes the experimental and clinical evidence of several common TCM compounds for treating RSA. It provides ideas and perspectives for further exploring the pathogenesis of RSA and TCM compounds for treating RSA.

Construction of porous Cu/CeO2 catalyst with abundant interfacial sites for effective methanol steam reforming.

Methanol is a promising hydrogen carrier for fuel cell vehicles (FCVs) via methanol steam reforming (MSR) reaction. Ceria supported copper catalyst has attracted extensive attentions due to the extraordinary oxygen storage capacity and abundant oxygen vacancies. Herein, we developed a colloidal solution combustion (CSC) method to synthesize a porous Cu/CeO2(CSC) catalyst. Compared with Cu/CeO2 catalysts prepared by other methods, the Cu/CeO2(CSC) catalyst possesses highly dispersed copper species and abundant Cu+-Ov-Ce3+ sites at the copper-ceria interface, contributing to methanol conversion of 66.3 %, CO2 selectivity of 99.2 %, and outstanding hydrogen production rate of 490 mmol gcat-1 h-1 under 250 °C. The linear correlation between TOF values and Cu+-Ov-Ce3+ sites amount indicates the vital role of Cu+-Ov-Ce3+ sites in MSR reaction, presenting efficient ability in activation of water. Subsequently, a deep understanding of CSC method is further presented. In addition to serving as a hard template, the colloidal silica also acts as disperser between nanoparticles, enhancing the copper-ceria interactions and facilitating the generation of Cu+-Ov-Ce3+ sites. This study offers an alternative approach to synthesize highly dispersed supported copper catalysts.

A Prognostic Model Incorporating Relevant Peripheral Blood Inflammation Indicator to Predict Postherpetic Neuralgia in Patients with Acute Herpes Zoster.

Objective: To determine the risk of postherpetic neuralgia (PHN) in patients with acute herpes zoster (HZ), this study developed and validated a novel clinical prediction model by incorporating a relevant peripheral blood inflammation indicator. Methods: Between January 2019 and June 2023, 209 patients with acute HZ were categorized into the PHN group (n = 62) and the non-PHN group (n = 147). Univariate and multivariate logistic regression analyses were conducted to identify risk factors serving as independent predictors of PHN development. Subsequently, a nomogram prediction model was established, and the discriminative ability and calibration were evaluated using the receiver operating characteristic curve, calibration plots, and decision curve analysis (DCA). The nomogram model was internally verified through the bootstrap test method. Results: According to univariate logistic regression analyses, five variables, namely age, hypertension, acute phase Numeric Rating Scale (NRS-11) score, platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index, were significantly associated with PHN development. Multifactorial analysis further unveiled that age (odds ratio (OR) [95% confidence interval (CI)]: 2.309 [1.163-4.660]), acute phase NRS-11 score (OR [95% CI]: 2.837 [1.294-6.275]), and PLR (OR [95% CI]: 1.015 [1.010-1.022]) were independent risk factors for PHN. These three predictors were integrated to establish the prediction model and construct the nomogram. The area under the receiver operating characteristic curve (AUC) for predicting the PHN risk was 0.787, and the AUC of internal validation determined using the bootstrap method was 0.776. The DCA and calibration curve also indicated that the predictive performance of the nomogram model was commendable. Conclusion: In this study, a risk prediction model was developed and validated to accurately forecast the probability of PHN after HZ, thereby demonstrating favorable discrimination, calibration, and clinical applicability.

Advanced Lung Adenocarcinoma with EGFR 19-del Mutation Transformed into SCC after EGFR-tyrosine Kinase inhibitors Treatment: A Case report.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improve the survival of patients with Epidermal growth factor receptor (EGFR) sensitive mutations in non-small cell lung cancer (NSCLC). CASE SUMMARY: A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment. Secondary pathological tissue biopsy confirmed squamous cell carcinoma (SCC) transformation. Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time, while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC. Notably, EGFR-TKIs resistance includes primary and acquired. Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs, with SCC transformation being relatively rare. Our results provide more detailed results of the patient's diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma. CONCLUSION: Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.

Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

Alterations of resting-state network dynamics in Alzheimer's disease based on leading eigenvector dynamics analysis.

Alzheimer's disease (AD) is a neurodegenerative disease, and mild cognitive impairment (MCI) is considered a transitional stage between healthy aging and dementia. Early detection of MCI can help slow down the progression of AD. At present, there are few studies exploring the characteristics of abnormal dynamic brain activity in AD. This article uses a method called Leading Eigenvector Dynamics Analysis (LEiDA) to study resting-state functional magnetic resonance imaging (rs-fMRI) data of AD, MCI, and cognitively normal (CN) participants. By identifying repetitive states of phase coherence, inter group differences in brain dynamic activity indicators are examined. And the neurobehavioral scales were used to assess the relationship between abnormal dynamic activities and cognitive function. The results showed that in the indicators of occurrence probability and lifetime, the globally synchronized state of the patient group decreased. The activity state of the limbic regions significantly detected the difference between AD and the other two groups. Compared to CN, AD and MCI have varying degrees of increase in default and visual regions activity states. In addition, in the analysis related to the cognitive scales, it was found that individuals with poorer cognitive abilities were less active in the globally synchronized state, and more active in limbic regions activity state and visual regions activity state. Taken together, these findings reveal abnormal dynamic activity of resting-state networks in patients with AD and MCI, provide new insights into the dynamic analysis of brain networks, and contribute to a deeper understanding of abnormal spatial dynamic patterns in AD patients.