Gut microbiota-mediated metabolism of green tea catechins and the biological consequences: An updated review.

Multiple beneficial effects have been attributed to green tea catechins (GTCs). However, the bioavailability of GTCs is generally low, with only a small portion directly absorbed in the small intestine. The majority of ingested GTCs reaches the large intestinal lumen, and are extensively degraded via biotransformation by gut microbiota, forming many low-molecular-weight metabolites such as phenyl-γ-valerolactones, phenolic acids, butyrate, and acetate. This process not only improves the overall bioavailability of GTC-derived metabolites but also enriches the biological activities of GTCs. Therefore, the intra- and inter-individual differences in human gut microbiota as well as the resulting biological contribution of microbial metabolites are crucial for the ultimate health benefits. In this review, the microbial degradation of major GTCs was characterized and an overview of the in vitro models used for GTC metabolism was summarized. The intra- and inter-individual differences of human gut microbiota composition and the resulting divergence in the metabolic patterns of GTCs were highlighted. Moreover, the potential beneficial effects of GTCs and their gut microbial metabolites were also discussed. Overall, the microbial metabolites of GTCs with higher bioavailability and bioactive potency are key factors for the observed beneficial effects of GTCs and green tea consumption.

Exploring the Relationship between Subcutaneous Fat Index and Neck Pain in Patients with Spinal Cervical Spondylosis: A Retrospective Cohort Study.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVES: This study measures the subcutaneous fat index (SFI) of the cervical spine in patients with spinal cervical spondylosis using cervical magnetic resonance imaging (MRI) and explores its relationship with neck pain in patients with spinal cervical spondylosis. METHODS: In this single-center retrospective study, 298 patients hospitalized for spinal cervical spondylosis between January and June 2021 were initially considered. After applying inclusion and exclusion criteria, 93 patients were enrolled. The cervical MRI data for these patients were analyzed using A-Site software. The SFI was measured at the median sagittal plane on T2-weighted images. Patients were categorized into two groups based on their admission complaints: those with cervical pain and those without it. Differences between these groups were then statistically analyzed. RESULTS: The mean SFIs with standard deviations for the neck and non-neck pain groups were 36.4%±7.7% and 27.0%±7.9%, respectively, with a significant difference (P<0.0001). The SFI was consistently higher across all neck segments in the neck pain group compared to the non-neck pain group (P<0.05). The two groups had no statistically significant difference in the body mass index (BMI). CONCLUSIONS: The SFI provides a more precise assessment of muscle and fat distribution in the posterior cervical region than BMI and is generally higher in patients with spinal cervical spondylosis who experience neck pain. These findings suggest the importance of early functional exercises post-surgery for potentially improving surgical outcomes in this patient population.

Scalable Deep Color Quantization: a Cluster Imitation Approach.

Color quantization reduces the number of colors used in an image while preserving its content, which is essential in pixel art and knitting art creation. Traditional methods primarily focus on visual fidelity and treat it as a clustering problem in the RGB space. While effective in large (5-6 bits) color spaces, these approaches cannot guarantee semantics in small (1-2 bits) color spaces. On the other hand, deep color quantization methods use network viewers such as AlexNet and ResNet for supervision, effectively preserving semantics in small color spaces. However, in large color spaces, they lag behind traditional methods in terms of visual fidelity. In this work, we propose ColorCNN+, a novel approach that combines the strengths of both. It uses network viewer signals for supervision in small color spaces and learns to cluster the colors in large color spaces. Noteworthily, it is non-trivial for neural networks to do clustering, where existing deep clustering methods often need K-means to cluster the features. In this work, through a newly introduced cluster imitation loss, ColorCNN+ learns to directly output the cluster assignment without any additional steps. Furthermore, ColorCNN+ supports multiple color space sizes and network viewers, offering scalability and easy deployment. Experimental results demonstrate competitive performance of ColorCNN+ across various settings. Code is available at link.

The correlation between serum levels of laminin, type IV collagen, type III procollagen N-terminal peptide and hyaluronic acid with the progression of post-COVID-19 pulmonary fibrosis.

COVID-19 patients often suffer from post-COVID-19 acute sequelae (PASC). Pulmonary fibrosis has the most significant long-term impact on the respiratory health of patients, known as post-COVID-19 pulmonary fibrosis (PC19-PF). PC19-PF can be caused by acute respiratory distress syndrome (ARDS) or COVID-19-induced pneumonia. Individuals who experience COVID-19 pneumonia symptoms (including cough, shortness of breath, dyspnea on exertion, and desaturation) for at least 12 weeks after diagnosis, almost all develop PC19-PF. Extracellular matrix molecules: laminin (LN), type IV collagen (IV Col), procollagen III N-terminal peptide (PIIINP), and hyaluronic acid (HA) are involved in the development and progression of PC19-PF. This study aimed to investigate the relationship between the progression of PC19-PF and serum levels of laminin, IV COL, PIIINP, and hyaluronic acid. This retrospective study included 162 PC19-PF patients treated and 160 healthy controls who received treatment at Shenzhen Longgang District Third People's Hospital, Hebei PetroChina Central Hospital and Changzhi People's Hospital from January 2021 to December 2023. Serum levels of LN, IV COL, PIIINP, and HA were detected by chemiluminescence immunoassay using commercial kits. Predicted forced vital capacity percentage (FVC% pred), predicted carbon monoxide lung diffusion capacity percentage (DLCO% pred), high-resolution computed tomography (HRCT) scores were assessed, and patient mortality was compared with healthy controls. Serum levels of LN, IV Col, PIIINP, and HA were significantly higher in PC19-PF or CTD-ILD patients than in healthy controls (all p < 0.05), and they were further elevated in acute exacerbation cases (all p < 0.01). In patients, HA was positively associated with HRCT scores and negatively associated with FVC% pred and DLCO% pred (all p < 0.05). Serum levels of LN, IV COL, PIIINP, and HA were significantly lower in surviving patients than in those who deceased (all p > 0.05). Serum levels of LN, IV C, PIIINP, and HA may affect the progression of PC19-PF and may serve as indicators of PC19-PF severity.

Preoperative pain sensitivity and its correlation with postoperative acute and chronic pain: a systematic review and meta-analysis.

BACKGROUND: Preoperative pain sensitivity (PPS) can be associated with postsurgical pain. However, estimates of this association are scarce. Confirming this correlation is essential to identifying patients at high risk for severe postoperative pain and for developing analgesic strategy. This systematic review and meta-analysis summarises PPS and assessed its correlation with postoperative pain. METHODS: PubMed, Scopus, Cochrane Library, and PsycINFO were searched up to October 1, 2023, for studies reporting the association between PPS and postsurgical pain. Two authors abstracted estimates of the effect of each method independently. A random-effects model was used to combine data. Subgroup analyses were performed to investigate the effect of pain types and surgical procedures on outcomes. RESULTS: A total of 70 prospective observational studies were included. A meta-analysis of 50 studies was performed. Postoperative pain was negatively associated with pressure pain threshold (PPT; r=-0.15, 95% confidence interval [CI] -0.23 to -0.07]) and electrical pain threshold (EPT; r=-0.28, 95% CI -0.42 to -0.14), but positively correlated with temporal summation of pain (TSP; r=0.21, 95% CI 0.12-0.30) and Pain Sensitivity Questionnaire (PSQ; r=0.25, 95% CI 0.13-0.37). Subgroup analysis showed that only TSP was associated with acute and chronic postoperative pain, whereas PPT, EPT, and PSQ were only associated with acute pain. A multilevel (three-level) meta-analysis showed that PSQ was not associated with postoperative pain. CONCLUSIONS: Lower PPT and EPT, and higher TSP are associated with acute postoperative pain while only TSP is associated with chronic postoperative pain. Patients with abnormal preoperative pain sensitivity should be identified by clinicians to adopt early interventions for effective analgesia. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023465727).

MiR-199a-5p Deficiency Promotes Artery Restenosis in Peripheral Artery Disease by Regulating ASMCs Function via Targeting HIF-1α and E2F3.

BACKGROUND: Restenosis (RS) poses a significant concern, leading to recurrent ischemia and the potential for amputation following intraluminal angioplasty in the treatment of Peripheral Artery Disease (PAD). Through microRNA microarray analysis, the study detected a significant downregulation of miR-199a-5p within arterial smooth muscle cells (ASMCs) associated with RS. OBJECTIVE: This research aims to explore the possible function and the underlying mechanisms of miR-199a-5p in the context of RS. METHODS: Primary ASMCs were extracted from the femoral arteries of both healthy individuals and patients with PAD or RS. The expression levels of miR-199a-5p were assessed using both qRT-PCR and in situ hybridization techniques. To examine the impacts of miR-199a-5p, a series of experiments were performed, including flow cytometry, TUNEL assay, EdU assay, CCK8 assay, Transwell assay, and wound closure assay. A rat carotid balloon injury model was employed to elucidate the mechanism through which miR-199a-5p mitigated neointimal hyperplasia. RESULTS: MiR-199a-5p exhibited downregulation in RS patients and was predominantly expressed within ASMCs. Elevated the expression of miR-199a-5p resulted in an inhibitory effect of proliferation and migration in ASMCs. Immunohistochemistry and a dual-luciferase reporter assay uncovered that RS exhibited elevated expression levels of both HIF-1α and E2F3, and they were identified as target genes regulated by miR-199a-5p. The co-transfection of lentiviruses carrying HIF-1α and E2F3 alongside miR-199a-5p further elucidated their role in the cellular responses mediated by miR-199a-5p. In vivo, the delivery of miR-199a-5p via lentivirus led to the mitigation of neointimal formation following angioplasty, achieved by targeting HIF-1α and E2F3. CONCLUSION: MiR-199a-5p exhibits promise as a prospective therapeutic target for RS since it alleviates the condition by inhibiting the proliferation and migration of ASMCs via its regulation of HIF-1α and E2F3.

A comparison of three-port and four-port Da Vinci robot-assisted thoracoscopic surgery for lung cancer: a retrospective study.

BACKGROUND: At present, research comparing the short-term postoperative outcomes of anatomical resection in lung cancer under different ports of da Vinci robot-assisted surgery is insufficient. This report aimed to compare the outcomes of three-port and four-port da Vinci robot-assisted thoracoscopic surgery for radical dissection of lung cancer. METHODS: 171 consecutive patients who presented to our hospital from January 2020 to October 2021 with non-small cell lung cancer and treated with da Vinci robot-assisted thoracoscopic surgery for radical resection of lung cancer were retrospectively collected and divided into the three-port group (n = 97) and the four-port group (n = 74). The general clinical data, perioperative data and life quality were individually compared between the two groups. RESULTS: All the 171 patients successfully underwent surgeries. Compared to the four-port group, the three-port group had comparable baseline characteristics in terms of age, sex, tumor location, tumor size, history of chronic disease, pathological type, and pathological staging. The three-port group also had shorter operation time, less intraoperative blood loss, lower chest tube drainage volume, shorter postoperative hospitalization stay durations, but showed no statistically significant difference (P > 0.05). Postoperative 24, 48 and 72 h visual analogue scale pain scores were lower in the three-port group (p < 0.001). No significant difference was observed between the two groups in the hospitalization costs (P = 0.664), number or stations of total lymph node dissected (p > 0.05) and postoperative respiratory complications (P > 0.05). CONCLUSIONS: The three-port robot-assisted thoracoscopic surgery is safe and effective and took better outcomes than the four-port robot-assisted thoracoscopic surgery in non-small cell lung cancer.

Effect of compressive and tensile forces on glucose concentration and cell viability within the intervertebral disc: A finite element study.

Understanding the role of mechanical force on tissue nutrient transport is essential, as sustained force may affect nutrient levels within the disc and initiate disc degeneration. This study aims to evaluate the time-dependent effects of different compressive force amplitudes as well as tensile force on glucose concentration and cell viability within the disc. Based on the mechano-electrochemical mixture theory, a multiphasic finite element model of the lumbar intervertebral disc was developed. The minimum glucose concentration and minimum cell density in both normal and degenerated discs were predicted for different compressive force amplitudes, tensile force, and corresponding creep time. Under high compressive force, the minimum glucose concentration exhibited an increasing and then decreasing trend with creep time in the normal disc, whereas that of the degenerated disc increased, then decreased, and finally increased again. At steady state, a higher compressive force was accompanied by a lower glucose concentration distribution. In the degenerated disc, the minimum cell density was negatively correlated with creep time, with a greater range of affected tissue under a higher compressive force. For tensile force, the minimum glucose concentration of the degenerated disc raised over time. This study highlighted the importance of creep time, force magnitude, and force type in affecting nutrient concentration and cell viability. Sustained weight-bearing activities could deteriorate the nutrient environment of the degenerated disc, while tensile force might have a nonnegligible role in effectively improving nutrient levels within the degenerated disc.

Proteomics-based identification of biomarkers reflecting endogenous and exogenous exposure to the advanced glycation end product precursor methylglyoxal in SH-SY5Y human neuroblastoma cells.

Methylglyoxal (MGO), a highly reactive precursor of advanced glycation end products, is endogenously produced and prevalent in various food products. This study aimed to characterize protein modifications in SH-SY5Y human neuroblastoma cells induced by MGO and identify potential biomarkers for its exposure and toxicity. A shot-gun proteomic analysis was applied to characterize protein modifications in cells incubated with and without exogenous MGO. Seventy-seven proteins were identified as highly susceptible to MGO modification, among which eight, including vimentin and histone H2B type 2-F, showing concentration-dependent modifications by externally added MGO, were defined as biomarkers for exogenous MGO exposure. Remarkably, up to 10 modification sites were identified on vimentin. Myosin light polypeptide 6 emerged as a biomarker for MGO toxicity, with modifications exclusively observed under cytotoxic MGO levels. Additionally, proteins like serine/threonine-protein kinase SIK2 and calcyphosin, exhibiting comparable or even higher modification levels in control compared to exogenous MGO-treated cells, were defined as biomarkers for endogenous exposure. Bioinformatics analysis revealed that motor proteins, cytoskeleton components, and glycolysis proteins were overrepresented among those highly susceptible to MGO modification. These results identify biomarkers for both endogenous and exogenous MGO exposure and provide insights into the cellular effects of endogenously formed versus externally added MGO.

Using empirical dynamic modeling to identify the impact of meteorological factors on hemorrhagic fever with renal syndrome in Weifang, Northeastern China, from 2011 to 2020.

BACKGROUND: Hemorrhagic Fever with Renal Syndrome (HFRS) continues to pose a significant public health threat to the well-being of the population. Given that the spread of HFRS is susceptible to meteorological factors, we aim to probe into the meteorological drivers of HFRS. Thus, novel techniques that can discern time-delayed non-linear relationships from nonlinear dynamical systems are compulsory. METHODS: We analyze the epidemiological features of HFRS in Weifang City, 2011-2020, via the employment of the Empirical Dynamic Modeling (EDM) method. Our analysis delves into the intricate web of time-delayed non-linear associations between meteorological factors and HFRS. Additionally, we investigate the repercussions of minor perturbations in meteorological variables on future HFRS incidence. RESULTS: A total of 2515 HFRS cases were reported in Weifang from 2011 to 2020. The number of cases per week was 4.81, and the average weekly incidence was 0.52 per 1,000,000. The propagation of HFRS is significantly impacted by the mean weekly temperature, relative humidity, cumulative rainfall, and wind speed, and the ρCCM converges to 0.55,0.48,0.38 and 0.39, respectively. The graphical representation of the relationship between temperature (lagged by 2 weeks) and the incidence of HFRS exhibits an inverted U-shaped curve, whereby the incidence of HFRS culminates as the temperature reaches 10 °C. Moreover, temperature, relative humidity, cumulative rainfall, and wind speed exhibit a positive correlation with HFRS incidence, with a time lag of 4-6 months. CONCLUSIONS: Our discoveries suggest that meteorological factors can drive the transmission of HFRS both at a macroscopic and microscopic scale. Prospective alterations in meteorological conditions, for instance, elevations in temperature, relative humidity, and precipitation will instigate an upsurge in the incidence of HFRS after 4-6 months, and thus, timely public health measures should be taken to mitigate these changes.

Azithromycin regulates Mettl3-mediated NF-κB pathway to enhance M2 polarization of RAW264.7 macrophages and attenuate LPS-triggered cytotoxicity of MLE-12 alveolar cells.

BACKGROUND: Azithromycin (AZM) has been proposed as a potential therapeutic drug in acute pulmonary injury due to its immunomodulatory and anti-inflammatory properties. However, its therapeutic mechanism remains not fully understood. METHODS: LPS was used to stimulate MLE-12 cells and RAW264.7 macrophages. Analyses of viability and apoptosis were performed by CCK-8 assay and flow cytometry, respectively. Protein analysis was performed by immunoblotting, and mRNA expression was tested by quantitative PCR. The secretion levels of TNF-α and IL-6 were detected by ELISA. MDA, GSH, ROS and Fe2+ contents were analyzed using assay kits. RESULTS: Administration of AZM or depletion of methyltransferase-like 3 (Mettl3) could attenuate LPS-triggered apoptosis, inflammation and ferroptosis in MLE-12 alveolar cells, as well as enhance M2 polarization of LPS-stimulated RAW264.7 macrophages. In LPS-exposed MLE-12 and RAW264.7 cells, AZM reduced Mettl3 protein expression and inactivated the NF-κB signaling through downregulation of Mettl3. Furthermore, Mettl3 restoration abated AZM-mediated anti-apoptosis, anti-inflammation and anti-ferroptosis effects in LPS-exposed MLE-12 cells and reversed AZM-mediated M2 polarization enhancement of LPS-exposed RAW264.7 macrophages. CONCLUSION: Our study indicates that AZM can promote M2 polarization of LPS-exposed RAW264.7 macrophages and attenuate LPS-triggered injury of MLE-12 alveolar cells by inactivating the Mettl3-mediated NF-κB pathway.

Microplastics footprint in nature reserves-a case study on the microplastics in the guano from Yancheng Wetland Rare Birds National Nature Reserve, China.

Bio-ingestion of microplastics poses a global threat to ecosystems, yet studies within nature reserves, crucial habitats for birds, remain scarce despite the well-documented ingestion of microplastics by avian species. Located in Jiangsu Province, China, the Yancheng Wetland Rare Birds Nature Reserve is home to diverse bird species, including many rare ones. This study aimed to assess the abundance and characteristics of microplastics in common bird species within the reserve, investigate microplastic enrichment across different species, and establish links between birds' habitat types and microplastic ingestion. Microplastics were extracted from the feces of 110 birds, with 84 particles identified from 37.27% of samples. Among 8 species studied, the average microplastic abundance ranged from 0.97 ± 0.47 to 43.43 ± 61.98 items per gram of feces, or 1.5 ± 0.87 to 3.4 ± 1.50 items per individual. The Swan goose (Anser cygnoides) exhibited the highest microplastic abundance per gram of feces, while the black-billed gull (Larus saundersi) had the highest abundance per individual. The predominant form of ingested microplastics among birds in the reserve was fibers, with polyethylene being the most common polymer type. Significant variations in plastic exposure were observed among species and between aquatic and terrestrial birds. This study represents the first quantitative assessment of microplastic concentrations in birds within the reserve, filling a crucial gap in research and providing insights for assessing microplastic pollution and guiding bird conservation efforts in aquatic and terrestrial environments.

Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation.

Several commonly used opioid analgesics, such as fentanyl, sufentanil, alfentanil, and hydrocodone, are by report primarily metabolized by the CYP3A4 enzyme. The concurrent use of ritonavir, a potent CYP3A4 inhibitor, can lead to significant drug interactions. Using physiologically based pharmacokinetic (PBPK) modeling and simulation, this study examines the effects of different dosing regimens of ritonavir on the pharmacokinetics of these opioids. The findings reveal that co-administration of ritonavir significantly increases the exposure of fentanyl analogs, with over a 10-fold increase in the exposure of alfentanil and sufentanil when given with ritonavir. Conversely, the effect of ritonavir on fentanyl exposure is modest, likely due to additional metabolism pathways. Additionally, the study demonstrates that the steady-state exposure of hydrocodone and its active metabolite hydromorphone can be increased by up to 87% and 95%, respectively, with concurrent use of ritonavir. The extended-release formulation of hydrocodone is particularly affected. These insights from PBPK modeling provide valuable guidance for optimizing opioid dosing and minimizing the risk of toxicity when used in combination with ritonavir-containing prescriptions.

Epidemiological characteristics of chronic non-communicable diseases in Dongfang, China, 2021: a cross-sectional survey.

OBJECTIVES: The study aimed to understand the composition, epidemiological characteristics and disease burden of chronic non-communicable diseases and to evaluate the association between sociodemographic factors and chronic non-communicable diseases. DESIGN: A cross-sectional study. SETTING AND PARTICIPANTS: Medical records of 196 761 residents were collected from Dongfang disease surveillance system from January to December 2021. PRIMARY OUTCOME: Prevalence and disability burden were recorded. Logistic regression was used to investigate the relationship between sociodemography factors and diseases. RESULTS: Cardiovascular diseases, chronic lower respiratory diseases and other upper respiratory tract diseases were the main chronic non-communicable diseases. In multivariable analysis, men were associated with increased risk of cardiovascular diseases (OR=1.210, 95% CI 1.162 to 1.261) and chronic lower respiratory diseases (OR=1.128, 95% CI 1.079 to 1.180). Older age was associated with increased risk of cardiovascular diseases (OR=83.952, 95% CI 58.954 to 119.550), whereas was associated with decreased risk of chronic lower respiratory diseases (OR=0.442, 95% CI 0.415 to 0.471) and other upper respiratory tract diseases (OR=0.450, 95% CI 0.411 to 0.493). The unemployed and poor household were associated with decreased risk of cardiovascular diseases (OR=0.463, 95% CI 0.412 to 0.521 and OR=0.390, 95% CI 0.342 to 0.444, respectively), whereas were associated with increased risk of chronic lower respiratory diseases (OR=12.219, 95% CI 6.343 to 23.539 and OR=10.954, 95% CI 5.666 to 21.177, respectively) and other upper respiratory tract diseases (OR=2.246, 95% CI 1.719 to 2.936 and OR=3.035, 95% CI 2.308 to 3.991, respectively). Gender and age moderated the association between personnel category and major diseases. CONCLUSIONS: The spectrum and epidemiological characteristics of chronic diseases observed in Dongfang is good evidence for developing prevention guides and health policies for region.

Physiologically based pharmacokinetic modeling to predict the pharmacokinetics of codeine in different CYP2D6 phenotypes.

Objectives: Codeine, a prodrug used as an opioid agonist, is metabolized to the active product morphine by CYP2D6. This study aimed to establish physiologically based pharmacokinetic (PBPK) models of codeine and morphine and explore the influence of CYP2D6 genetic polymorphisms on the pharmacokinetics of codeine and morphine. Methods: An initial PBPK modeling of codeine in healthy adults was established using PK-Sim® software and subsequently extrapolated to CYP2D6 phenotype-related PBPK modeling based on the turnover frequency (Kcat) of CYP2D6 for different phenotype populations (UM, EM, IM, and PM). The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between the predicted and observed values of the pharmacokinetic parameters to evaluate the accuracy of PBPK modeling. The validated models were then used to support dose safety for different CYP2D6 phenotypes. Results: The developed and validated CYP2D6 phenotype-related PBPK model successfully predicted codeine and morphine dispositions in different CYP2D6 phenotypes. Compared with EMs, the predicted AUC0-∞ value of morphine was 98.6% lower in PMs, 60.84% lower in IMs, and 73.43% higher in UMs. Morphine plasma exposure in IMs administered 80 mg of codeine was roughly comparable to that in EMs administered 30 mg of codeine. CYP2D6 UMs may start dose titration to achieve an optimal individual regimen and avoid a single dose of over 20 mg. Codeine should not be used in PMs for pain relief, considering its insufficient efficacy. Conclusion: PBPK modeling can be applied to explore the dosing safety of codeine and can be helpful in predicting the effect of CYP2D6 genetic polymorphisms on drug-drug interactions (DDIs) with codeine in the future.

Safety and efficacy of umbilical cord tissue-derived mesenchymal stem cells in the treatment of patients with aging frailty: a phase I/II randomized, double-blind, placebo-controlled study.

BACKGROUND: Mesenchymal stem cells (MSCs) hold a great promise for cell-based therapy in the field of regenerative medicine. In this study, we aimed to evaluate the safety and efficacy of intravenous infusion of human umbilical cord-derived MSCs (HUC-MSCs) in patients with aging frailty. METHODS: In this randomized, double-blind, placebo-controlled trial, participants diagnosed with aging frailty were randomly assigned to receive intravenous administrations of HUC-MSCs or placebo. All of serious adverse events and AEs were monitored to evaluate the safety of treatment during the 6-month follow-up. The primary efficacy endpoint was alteration of physical component scores (PCS) of SF-36 qualities of life at 6 months. The secondary outcomes including physical performance tests and pro-inflammatory cytokines, were also observed and compared at each follow-up visits. All evaluations were performed at 1 week, 1, 2, 3 and 6 months following the first intravenous infusion of HUC-MSCs. RESULTS: In the MSCs group, significant improvements in PCS of SF-36 were observed from first post-treatment visit and sustained throughout the follow-up period, with greater changes compared to the placebo group (p = 0.042). EQ-VAS scores of MSCs group improved significantly at 2 month (p = 0.023) and continued until the end of the 6-month visit (p = 0.002) in comparison to the placebo group. The timed up and go (TUG) physical performance test revealed significant group difference and showed continual enhancements over 6 months (p < 0.05). MSC transplantation improved the function of 4-m walking test (4MWT) compared with the placebo group with a decrease of 2.05 s at 6 months of follow-up (p = 0.21). The measurement of grip strength revealed group difference with MSCs group demonstrating better performance, particularly at 6 months (p = 0.002). Inflammatory cytokines (TNF-α, IL-17) exhibited declines in MSCs group at 6 months compared to the placebo group (p = 0.034 and 0.033, respectively). There was no difference of incidence of AEs between the two groups. CONCLUSION: Intravenous transplantation of HUC-MSCs is a safe and effective therapeutic approach on aging frailty. The positive outcomes observed in improving quality of life, physical performance, and reducing chronic inflammation, suggest that HUC-MSC therapy may be a promising potential treatment option for aging frailty. TRIAL REGISTRATION: Clinicaltrial.gov; NCT04314011; https://clinicaltrials.gov/ct2/show/NCT04314011 .

Porcine epidemic diarrhea virus E protein induces formation of stress granules and attenuates protein translation through activation of the PERK/eIF2α signaling pathway.

Porcine epidemic diarrhea virus (PEDV) envelope protein (E) has been characterized as an important structural protein that plays critical roles in the interplay with its host to affect the virus life cycle. Stress granules (SGs) are host translationally silent ribonucleoproteins, which are mainly induced by the phosphorylation of eIF2α in the PERK/eIF2α signaling pathway. Our previous study found that PEDV E protein caused endoplasmic reticulum stress response (ERS)-mediated suppression of antiviral proteins' translation. However, the link and the underlying mechanism by which PEDV induces SGs formation and suppresses host translation remain elusive. In this study, our results showed that PEDV E protein significantly elevated the expression of GRP78, CANX, and phosphorylation of PERK and eIF2α, indicating that the PERK/eIF2α branch of ERS was activated. PEDV E protein localized to the ER and aggregated into puncta to reconstruct ER structure, and further induced SGs formation, which has been caused through upregulating the G3BP1 expression level. In addition, a significant global translational stall and endogenous protein translation attenuation were detected in the presence of E protein overexpression, but the global mRNA transcriptional level remained unchanged, suggesting that the shutoff of protein translation was associated with the translation, not with the transcription process. Collectively, this study demonstrates that PERK/eIF2α activation is required for SGs formation and protein translation stall. This study is beneficial for us to better understand the mechanism by which PEDV E suppresses host protein synthesis, and provides us a new insight into the host translation regulation during virus infection.

[Preliminary application of indocyanine green fluorescence imaging technology in nasal endoscopic tumor surgery].

Objective:To preliminarily study the practical value of Indocyanine green（ICG） molecular fluorescence imaging technology in nasal endoscopic tumor surgery. Methods:Five patients with tumors related to nasal sinuses, orbital wall and skull base in the Department of Otolaryngology head and Neck Surgery, General Hospital of Xinjiang Military Command from December 2022 to April 2023 were enrolled. Among them, 3 were benign tumors and 2 were malignant tumors. All patients underwent surgery under the guidance of ICG molecular fluorescence imaging. ICG was administered intravenously through cubital vein at a dose of 0.5 mg/kg 12 to 24 h before surgery. Tumors were labeled by fluorescence imaging during the operation. surgeons cleared the tumor tissue strictly according to the labeled range and depth, malignant tumors were further expanded and cleaned according to pathology results. Results:All 5 patients achieved accurate tumor localization with the aid of fluorescence imaging technology. Resections were performed with reference to fluorescent labeling boundaries, all patients achieved complete tumor cleanup or negative margins. Conclusion:For tumor-related surgery under nasal endoscopy, ICG molecular fluorescence imaging technology can not only achieve accurate real-time positioning, but also provide evidence for surgeons to judge tumor boundaries. Therefore, we believe that the technology should have certain practical value in nasal endoscopic tumor surgery.

Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer.

BACKGROUND: Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting treatment outcomes. Emerging evidence from various cancers suggests that early assessment of serum metabolites could serve as valuable biomarkers for predicting outcomes. This study aims to identify metabolites linked to treatment outcomes in patients with advanced NSCLC undergoing first-line or second-line therapy with programmed cell death 1 (PD-1) inhibitors plus chemotherapy. METHOD: 200 patients with advanced NSCLC receiving either first-line or second-line PD-1 inhibitor plus chemotherapy, and 50 patients undergoing first-line chemotherapy were enrolled in this study. The 200 patients receiving combination therapy were divided into a Discovery set (n=50) and a Validation set (n=150). These sets were further categorized into respond and non-respond groups based on progression-free survival PFS criteria (PFS≥12 and PFS<12 months). Serum samples were collected from all patients before treatment initiation for untargeted metabolomics analysis, with the goal of identifying and validating biomarkers that can predict the efficacy of immunotherapy plus chemotherapy. Additionally, the validated metabolites were grouped into high and low categories based on their medians, and their relationship with PFS was analyzed using Cox regression models in patients receiving combination therapy. RESULTS: After the impact of chemotherapy was accounted for, two significant differential metabolites were identified in both the Discovery and Validation sets: N-(3-Indolylacetyl)-L-alanine and methomyl (VIP>1 and p<0.05). Notably, upregulation of both metabolites was observed in the group with a poorer prognosis. In the univariate analysis of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were associated with longer PFS (HR=0.59, 95% CI, 0.41 to 0.84, p=0.003), and a prolonged PFS was also indicated by lower levels of methomyl (HR=0.67, 95% CI, 0.47 to 0.96, p=0.029). In multivariate analyses of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were significantly associated with a longer PFS (HR=0.60, 95% CI, 0.37 to 0.98, p=0.041). CONCLUSION: Improved outcomes were associated with lower levels of N-(3-Indolylacetyl)-L-alanine in patients with stage IIIB-IV NSCLC lacking driver gene mutations, who underwent first-line or second-line therapy with PD-1 inhibitors combined with chemotherapy. Further exploration of the potential predictive value of pretreatment detection of N-(3-Indolylacetyl)-L-alanine in peripheral blood for the efficacy of combination therapy is warranted. STATEMENT: The combination of ICIs and chemotherapy has established itself as the new standard of care for first-line or second-line treatment in patients with advanced NSCLC lacking oncogenic driver alterations. Therefore, identifying biomarkers that can predict the efficacy and prognosis of immunotherapy plus chemotherapy is of paramount importance. Currently, the only validated predictive biomarker is programmed cell death ligand-1 (PD-L1), but its predictive value is not absolute. Our study suggests that the detection of N-(3-Indolylacetyl)-L-alanine in patient serum with untargeted metabolomics prior to combined therapy may predict the efficacy of treatment. Compared with detecting PD-L1 expression, the advantage of our biomarker is that it is more convenient, more dynamic, and seems to work synergistically with PD-L1 expression.

Real-world impact of chemotherapy on overall survival in craniomaxillofacial osteosarcoma.

OBJECTIVES: The goal of this study was to identify the survival benefit of chemotherapy in craniomaxillofacial osteosarcoma (CMFO) patients based on a US population. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to select patients with CMFO from 1988 to 2016. Age and tumor size were grouped by X-tail. Cox analysis were used to estimate hazards ratios (HR) among patients. All of patients were divided into two cohorts by using Propensity Score Matching (PSM) method to evaluate the effect of chemotherapy. All prognostic factors were included in the nomograms which predict the median survival time. RESULTS: 410 patients were included in our study. The results of survival rate, Kaplan-Meier and Cox regression were showed no significant difference between the group of chemotherapy performed and the group without chemotherapy. PSM analysis also demonstrated the limited survival advantage of chemotherapy. Moreover, all factors were further incorporated to construct the novel nomograms and its concordance indices (C-index) for internal validation of OS prediction were 0.749 (95 %CI:0.731-0.767). CONCLUSIONS: Our study did not show the advantage of chemotherapy on the overall survival outcome of CMFO. Although neoadjuvant chemotherapy was currently recommended in clinical treatment, more rigorous randomized controlled trials are still needed. Nomograms would assist clinicians in making more accurate survival evaluation and choosing the optimal medical treatment.