Fabrication of biodegradable hollow microsphere composites made of polybutylene adipate co-terephthalate/polyvinylpyrrolidone for drug delivery and sustained release.

Sustained drug release has attracted increasing interest in targeted drug therapy. However, existing methods of drug therapy suffer drug action time, large fluctuations in the effective concentration of the drug, and the risk of side effects. Here, a biodegradable composite of polybutylene adipate co-terephthalate/polyvinylpyrrolidone (PBAT/PVP) consisting of electrospun hollow microspheres as sustained-released drug carriers is presented. The as-prepared PBAT/PVP composites show faster degradation rate and drug (Erlotinib) release than that of PBAT. Furthermore, PBAT/PVP composites loaded with Erlotinib provide sustained release effect, thus achieving a better efficacy than that after the direct injection of erlotinib due to the fact that the composites allow a high drug concentration in the tumor for a longer period. Hence, this work provides a potential effective solution for clinical drug therapy and tissue engineering using drug microspheres with a sustained release.

Feasibility and clinical benefits of the double-ProGlide technique for hemostasis after cryoballoon atrial fibrillation ablation with uninterrupted oral anticoagulants.

OBJECTIVE: To access the efficacy and safety of the double-ProGlide technique for the femoral vein access-site closure in cryoballoon ablation with uninterrupted oral anticoagulants (OAC), and its impact on the electrophysiology laboratory time as well as hospital stay after the procedure in this observational study. METHODS: Patients with atrial fibrillation undergoing cryoballoon ablation with uninterrupted OAC at Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China from May 2019 to May 2021 were enrolled in this study. From October 2020, double-ProGlide technique was consistently used for hemostasis (ProGlide group), and before that conventional manual compression was utilized (manual compression group). The occurrence of vascular and groin complications was accessed during the hospital stay and until the three-month follow-up. RESULTS: A total of 140 participants (69.30% of male, mean age: 59.21 ± 10.29 years) were evaluated, 70 participants being in each group. Immediate hemostasis was achieved in all the patients with ProGlide closure. No major vascular complications were found in the ProGlide group while two major vascular complications were occurred in the manual compression group. The incidence of any groin complication was obviously higher in subjects with manual compression than patients with ProGlide devices (15.71% vs. 2.86%, P = 0.009). In addition, compared with the manual compression group, the ProGlide group was associated with significantly shorter total time in the electrophysiology laboratory [112.0 (93.3-128.8) min vs. 123.5 (107.3-158.3) min, P = 0.006], time from sheath removal until venous site hemostasis [3.8 (3.4-4.2) min vs. 8.0 (7.6-8.5) min, P < 0.001], bed rest time [8.0 (7.6-8.0) h vs. 14.1 (12.0-17.6) h, P < 0.001] and hospital stay after the procedure [13.8 (12.5-17.8) h vs. 38.0 (21.5-41.0) h, P < 0.001]. CONCLUSIONS: Utilization of the double-ProGlide technique for hemostasis after cryoballoon ablation with uninterrupted OAC is feasible and safe, which has the clinical benefit in reducing the total electrophysiology laboratory time and the hospital stay length after the procedure.

Glomerular filtration rate estimated by differing measures and risk of all-cause mortality among Chinese individuals without or with diabetes: A nationwide prospective study.

BACKGROUND: Whether estimated glomerular filtration rates (eGFRs) by differing biomarkers are differentially associated with mortality or whether the associations differ by diabetes status remains unclear, especially in Chinese population. METHODS: We included 6995 participants without diabetes (mean age: 60.4 years) and 1543 with diabetes (mean age: 61.8 years). Each eGFR measure was divided into normal (≥90 mL/min/1.73 m2 ), modestly declined (60 to <90 mL/min/1.73 m2 ), and chronic kidney disease (CKD) (<60 mL/min/1.73 m2 ) groups. Cox proportional hazards models were used to estimate hazard ratio (HR) of all-cause mortality associated with each eGFR. RESULTS: Over a follow-up of 7 years, 677 and 215 deaths occurred among individuals without or with diabetes, respectively. Among those without diabetes, all measures of modestly declined eGFR were not associated with mortality, whereas CKD defined by eGFR cystatin C (eGFRcys) and eGFR creatinine (eGFRcr)-cys (HRs were 1.71 and 1.55, respectively) but not by eGFRcr were associated with higher risk of mortality. Among diabetes, all measures of modestly declined eGFR (HRs: 1.53, 1.56, and 2.09 for eGFRcr, eGFRcys, and eGFRcr-cys, respectively) and CKD (HRs: 2.57, 2.99, and 3.92 for eGFRcr, eGFRcys, and eGFRcr-cys, respectively) were associated with higher risk of mortality. Regardless of diabetes status, an addition of eGFRcys or eGFRcr-cys to traditional risk factors lead to a larger improvement in the prediction of all-cause mortality risk than adding eGFRcr. CONCLUSIONS: The association of eGFR with mortality risk appeared to be varied by its measures and by diabetes status among middle-aged and older Chinese, which needs to be considered in clinical practice.

Urinary phthalate metabolites and heart rate variability: A panel study.

Phthalates exposure is linked with cardiovascular disease. Decreased heart rate variability (HRV) is an early indicator of cardiac autonomic imbalance. We conducted a longitudinal panel study in 127 Chinese adults with 3 repeated visits to explore the associations of individual and mixtures of phthalates exposure with HRV. We quantified 10 urinary phthalate metabolites by gas chromatograph-tandem mass spectrometer (GC-MS/MS) and 6 HRV indices by 3-channel digital Holter monitors. Linear mixed-effect (LME) models and Bayesian kernel machine regression (BKMR) models were separately implemented to evaluate the associations. After multivariate adjustments, we found that urinary mono-ethyl phthalate (MEP), mono-iso-butyl phthalate (MiBP), and mono-n-butyl phthalate (MBP) at lag 0 day were inversely associated with low-frequency power (LF) or total power (TP) (all P-FDR <0.05). In mixture analysis, we observed negative overall associations of phthalate mixtures at lag 0 day with LF or TP, and MiBP was the major contributor. Moreover, stratified analysis suggested that the inverse relationships of MiBP at lag 0 day with LF and TP were more prominent in subjects aged >50 years (all Pinteraction < 0.01). Our findings revealed that exposure to individual and mixtures of phthalates, especially MiBP, were related to decreased HRV.

Dietary ferulic acid supplementation improves antioxidant capacity and lipid metabolism in liver of piglets with intrauterine growth retardation.

Intrauterine growth retardation (IUGR) can result in early liver oxidative damage and abnormal lipid metabolism in neonatal piglets. Ferulic acid (FA), a phenolic compound widely found in plants, has many biological functions, such as anti-inflammation and anti-oxidation. Thus, we explored the effects of dietary FA supplementation on antioxidant capacity and lipid metabolism in newborn piglets with IUGR. In the study, 24 7-day-old piglets were divided into three groups: normal birth weight (NBW), IUGR, and IUGR + FA. The NBW and IUGR groups were fed formula milk as a basal diet, while the IUGR + FA group was fed a basal diet supplemented with 100 mg/kg FA. The trial lasted 21 days. The results showed that IUGR decreased absolute liver weight, increased transaminase activity, reduced antioxidant capacity, and disrupted lipid metabolism in piglets. Dietary FA supplementation enhanced absolute liver weight, reduced serum MDA level and ROS concentrations in serum and liver, markedly increased serum and liver GSH-PX and T-SOD activities, decreased serum HDL-C and LDL-C and liver NEFA, and increased TG content and HL activity in the liver. The mRNA expression related to the Nrf2-Keap1 signaling pathway and lipid metabolism in liver were affected by IUGR. Supplementing FA improved the antioxidant capacity of liver by down-regulating Keap1 and up-regulating the mRNA expression of SOD1 and CAT, and regulated lipid metabolism by increasing the mRNA expression level of Fasn, Pparα, LPL, and CD36. In conclusion, the study suggests that FA supplementation can improve antioxidant capacity and alleviate lipid metabolism disorders in IUGR piglets.

Assembly of the Complete Mitochondrial Genome of Pereskia aculeata Revealed That Two Pairs of Repetitive Elements Mediated the Recombination of the Genome.

Pereskia aculeata is a potential new crop species that has both food and medicinal (antinociceptive activity) properties. However, comprehensive genomic research on P. aculeata is still lacking, particularly concerning its organelle genome. In this study, P. aculeata was studied to sequence the mitochondrial genome (mitogenome) and to ascertain the assembly, informational content, and developmental expression of the mitogenome. The findings revealed that the mitogenome of P. aculeata is circular and measures 515,187 bp in length with a GC content of 44.05%. It contains 52 unique genes, including 33 protein-coding genes, 19 tRNA genes, and three rRNA genes. Additionally, the mitogenome analysis identified 165 SSRs, primarily consisting of tetra-nucleotides, and 421 pairs of dispersed repeats with lengths greater than or equal to 30, which were mainly forward repeats. Based on long reads and PCR experiments, we confirmed that two pairs of long-fragment repetitive elements were highly involved with the mitogenome recombination process. Furthermore, there were 38 homologous fragments detected between the mitogenome and chloroplast genome, and the longest fragment was 3962 bp. This is the first report on the mitogenome in the family Cactaceae. The decoding of the mitogenome of P. aculeata will provide important genetic materials for phylogenetic studies of Cactaceae and promote the utilization of species germplasm resources.

Identification, Characterization, and Cytological Analysis of Several Unexpected Hybrids Derived from Reciprocal Crosses between Raphanobrassica and Its Diploid Parents.

Interspecific hybridization and accompanying backcross between crops and relatives have been recognized as a powerful method to broaden genetic diversity and transfer desirable adaptive traits. Crosses between radish (Raphanus sativus, RR, 2n = 18) and Brassica oleracea (CC, 2n = 18), which formed allotetraploid Raphanobrassica (RRCC, 2n = 36), initiated the construction of resynthetic allopolyploids. However, these progenies from the backcrosses between Raphanobrassica and the two diploid parents have not been well deciphered. Herein, thousands of backcrosses using both Raphanobrassica and the two diploid parents as pollen donors were employed. Several hybrids with expected (2n = 27) and unexpected chromosome numbers (2n = 26 and 2n = 36) were obtained. Fluorescence in situ hybridization (FISH) analysis with R-genome-specific sequences as probes demonstrated that the genome structures of the two expected hybrids were RRC and CCR, and the genome structures of the three unexpected hybrids were RRRC, CCCR, and RRC' (harbouring an incomplete C genome). The unexpected hybrids with extra R or C genomes showed similar phenotypic characteristics to their expected hybrids. FISH analysis with C-genome-specific sequences as probes demonstrated that the unexpected allotetraploid hybrids exhibited significantly more intergenomic chromosome pairings than the expected hybrids. The expected and unexpected hybrids provide not only novel germplasm resources for the breeding of radish and B. oleracea but also very important genetic material for genome dosage analysis.

Cholangioscopy-assisted extraction through novel papillary support for small-calibre and sediment-like common bile duct stones.

BACKGROUND: To date, endoscopic retrograde cholangiopancreatography has become a well-established treatment for common bile duct (CBD) stones. However, it is not suitable for some special patients, such as pregnant women, children or those who cannot stop taking anti-coagulation/anti-platelet agents because of radiation injury and the risk of postoperative bleeding resulting from endoscopic sphincterotomy. To overcome these two problems, this study introduced cholangioscopy-assisted extraction through a novel papillary support for small-calibre and sediment-like CBD stones. AIM: To assess the feasibility and safety of cholangioscopy-assisted extraction through a novel papillary support (CEPTS) for small-calibre and sediment-like common bile duct (CBD) stones. METHODS: This Retrospective study was approved by the Ethics Committee of the Chinese PLA General Hospital. We designed a covered single dumbbell-style papillary support between 2021 and 2022. Between July 2022 and September 2022, 7 consecutive patients with small-calibre (cross diameter ≤ 1.0 cm) or sediment-like CBD stones underwent CETPS procedures in our center. The clinical characteristics and treatment outcomes of these 7 patients were extracted from a prospectively collected database. And the related data were analyzed. Informed consent was obtained from all participating patients. RESULTS: A total of 2 patients had yellow sediment-like CBD stones, and aspiration extraction was performed after the insertion of papillary support. Of the 5 patients with clumpy CBD stones (0.4-1.0 cm), 2 underwent basket extraction under direct vision for a single stone (0.5-1.0 cm, black and black grey), 1 underwent balloon plus aspiration extraction under direct vision for 5 stones (0.4-0.6 cm, brown), and 2 underwent aspiration extraction only for a single stone (0.5-0.6 cm, yellow, none). Technical success, namely, no residual stones in the CBD or left and right hepatic ducts, was achieved in all 7 cases (100%). The median operating time was 45.0 minutes (range 13.0-87.0 minutes). Postoperative pancreatitis (PEP) occurred in one case (14.3%). Hyperamylasaemia without abdominal pain was noted in 2 of 7 patients. No residual stones or cholangitis were found during the follow-up. CONCLUSION: CETPS appeared to be feasible to treat patients with small-calibre or sediment-like CBD stones. Patients, especially pregnant women and those who cannot stop anticoagulation/anti-platelet agents, could benefit from this technique.

Low Total Testosterone Levels in Men with Newly Diagnosed Early-Onset Type 2 Diabetes: A Cross-Sectional Study in China.

Objective: There is a bidirectional interaction between circulating testosterone and blood glucose levels. We aim to investigate the testosterone levels in men with early-onset type 2 diabetes (T2DM). Methods: A total of 153 drug naive men with T2DM were enrolled in the study. Early- (n = 63) and late-onset (n = 90) T2DM was classified according to age 40 years old. Clinical characteristics and plasma for biochemical criterions were collected. Gonadal hormones were measured using chemiluminescent immunometric assay. The concentrations of 3ß- and 17ß-HSD were determined using ELISA. Results: Compared with men with late-onset T2DM, those with early-onset T2DM had lower serum total testosterone (TT), sex hormone-binding globulin (SHBG), and FSH, but higher dehydroepiandrosterone sulfate (DHEA-S) level (p < 0.05). The mediating effect analysis showed that the decreased TT levels in patients with early-onset T2DM were associated with the higher HbA1c, BMI, and triglyceride in these patients (both p < 0.05). The early-onset of T2DM directly correlated with increased DHEA-S (both p < 0.01). The 3ß-HSD concentration in the early-onset T2DM group was lower than that in the late-onset T2DM group (11.07 ± 3.05 vs. 12.40 ± 2.72 pg/mL, p = 0.048) and was positively correlated with fasting C-peptide, while negatively correlated with HbA1c and fasting glucagon (p all < 0.05). Conclusions: Patients with early-onset T2DM showed inhibition of conversion from DHEA to testosterone, which may attribute to the low level of 3ß-HSD and high blood glucose in these patients.

Construction of predictive model for prognosis of patients after radical resection of colon cancer based on nomogram.

OBJECTIVE: To construct a predictive model for 3-year survival of patients after curative resection of colon cancer by nomogram. METHOD: A retrospective analysis was conducted to analyze the clinicopathologic data of 102 patients who underwent radical resection of colon cancer in Baoji Central Hospital from April 2015 to April 2017. The optimal cutoff values of preoperative CEA, CA125, and NLR for predicting overall survival were analyzed by receiver operating characteristic (ROC) curves. To observe the relationship between NLR, CEA and CA125 and clinicopathologic data, we performed multivariate Cox regression to analyze the independent factors affecting the prognosis of patients, and Kaplan-Meier test to identify the relationship between NLR, CEA and CA125 and patient survival. A nomogram prediction model was drawn for patients' 1-, 2-, and 3-year survival after radical resection of colon cancer, and the efficacy of the prediction model was evaluated. RESULTS: The area under the curve (AUC) of NLR, CEA and CA125 in predicting patient death was 0.784, 0.790 and 0.771, respectively. NLR was correlated with clinical stage, tumor diameter and differentiation (all P < 0.05); CEA was associated with clinical stage, tumor diameter, differentiation and lymph node metastasis (all P < 0.05); CA125 was only associated with tumor diameter in patients (P < 0.05). Differentiation, NLR, CEA and CA125 were independent risk factors affecting the prognosis of patients (all P < 0.05). The nomogram predicted a model C-index of 0.918 (95% CI 0.885-0.952), and the risk model score was found to have a high clinical value in the 3-year survival of preexisting patients. CONCLUSION: Preoperative NLR, CEA, CA125 and clinical stage are correlated with the prognosis of patients with colon cancer. The nomogram model constructed based on NLR, CEA, CA125 and clinical stage has good accuracy.

Blue LED light promoting the growth, accumulation of high-value isoflavonoids and astragalosides, antioxidant response, and biosynthesis gene expression in Astragalus membranaceus (Fisch.) Bunge hairy root cultures.

The root of Astragalus membranaceus (Fisch.) Bunge is one of the most frequently used herbs in traditional Chinese medicine (TCM) formulae for fighting COVID-19 infections, due to the presence of isoflavonoids and astragalosides associated with antiviral and immune-enhancing activities. For the first time, the exposure of A. membranaceus hairy root cultures (AMHRCs) to different colors of LED lights i.e., red, green, blue, red/green/blue (1/1/1, RGB), and white, was conducted to promote the root growth and accumulation of isoflavonoids and astragalosides. LED light treatment regardless of colors was found beneficial for root growth, which might be a result of the formation of more root hairs upon light stimulation. Blue LED light was found most effective for enhancing phytochemical accumulation. Results showed that the productivity of root biomass in blue-light grown AMHRCs with an initial inoculum size of 0.6% for 55 days was 1.40-fold higher than that in dark (control), and yields of high-value isoflavonoids and astragalosides including calycosin, formononetin, astragaloside IV, and astragaloside I increased by 3.17-fold, 2.66-fold, 1.78-fold, and 1.52-fold relative to control, respectively. Moreover, the photooxidative stress together with transcriptional activation of biosynthesis genes might contribute to the enhanced accumulation of isoflavonoids and astragalosides in blue-light grown AMHRCs. Overall, this work offered a feasible approach for obtaining higher yields of root biomass and medicinally important compounds in AMHRCs via the simple supplementation of blue LED light, which made blue-light grown AMHRCs industrially attractive as plant factory in controlled growing systems. Supplementary Information: The online version contains supplementary material available at 10.1007/s11240-023-02486-7.

In vivo pharmacodynamic study of contezolid acefosamil, a prodrug of contezolid for oral and intravenous administration.

OBJECTIVES: Contezolid acefosamil is a novel O-acyl phosphoramidate prodrug of contezolid. In the current study, we aimed to systemically evaluate the efficacy of contezolid acefosamil against infections caused by multiple Gram-positive pathogens, and compare the efficacy of the prodrug by oral and intravenous administrations. METHODS: The in vivo pharmacodynamic efficacy of contezolid acefosamil was evaluated in mouse models of systemic (with five S. aureus, three S. pneumoniae and two S. pyogenes bacterial isolates) and thigh (with two S. aureus isolates) infections using linezolid as the reference agent. RESULTS: In both models, contezolid acefosamil administrated either orally or intravenously, demonstrated high antibacterial efficacy similar to linezolid, and the antibacterial efficacy of oral and intravenous contezolid acefosamil were comparable. CONCLUSIONS: The high aqueous solubility and great efficacy of contezolid acefosamil support its clinical development as an injectable and oral antibiotic suitable for serious Gram-positive infections.

Effects and mechanism of perinatal nonylphenol exposure on cardiac function and myocardial mitochondria in neonatal rats.

BACKGROUND: Nonylphenol (NP) is a common environmental endocrine disruptor that is associated with the development of cardiovascular disease. However, the toxic effect of NP on mitochondria in the heart of offspring to exposed individuals remains exclusive. OBJECTIVE: To investigate whether perinatal NP exposure causes mitochondrial damage in the hearts of offspring of exposed individuals and determine its mechanism of action through both animal and cell experiments. METHODS AND RESULTS: For the in vivo experiment, pregnant rats were randomly divided into four groups: the control group (corn oil, C), low dose group (2.5 mg/kg/day, L-NP group), medium dose group (50 mg/kg/day, M-NP group), and high dose group (100 mg/kg/day, H-NP group), with 12 rats in each group. The NP concentration in the hearts of offspring at PND21 and PND90 increased with the increase of the NP dose. Perinatal NP exposure induced a gradual increase in systolic blood pressure in offspring at PND90. In the H-NP group, there was a high degree of inflammatory cell infiltration, myofibril breaks, inconspicuous or absent nuclei, and pink collagen deposition. At PND90, the membrane integrity of mitochondria in the H-NP group was disrupted, the cristae disorder was aggravated, and there was internal lysis with vacuolation. Compared to the control group, the mitochondrial membrane potential of offspring at PND21 and PND90 was decreased in each of the NP exposure groups. NP exposure decreased the activity of mitochondrial respiratory enzyme complex I (CI) and increased the activity of mitochondrial respiratory enzyme complex IV (CIV) in the offspring. At PND21 and PND90, the mRNA and protein expression levels of cardiac mitochondrial PGC-1α, NRF-1, and TFAM decreased with increasing NP dose in a dose-dependent manner. In the in vitro experiment, H9C2 cells were divided into the following four groups: the blank group, RSV group (15 µg/ml), RSV + NP group (15 µg/ml RSV + 120 mmol/L NP), and NP group (120 mmol/L). With increasing NP concentration, the cell survival rate gradually decreased. Compared to the control, the membrane potential was significantly decreased in the NP group; the protein expression levels of SIRT1, PGC-1α, NRF-1, and TFAM in the NP group were significantly lower. CONCLUSION: Perinatal NP exposure caused mitochondrial damage and dysfunction in the offspring of exposed individuals in a dose-dependent manner. This toxic effect may be related to NP-induced mitochondrial pathology in the offspring and the inhibition of both gene and protein expression involved in the PGC-1α/NRF-1/TFAM mitochondrial biogenesis signaling pathway following NP exposure.

High-Efficiency ZnS: Cu+, Al3+ Scintillator for X-ray Detection in a Non-Darkroom Environment.

Scintillator is a key component in X-ray detectors that determine the performance of the devices. Nevertheless, due to the interference of the ambient light sources, scintillators are only operated in a darkroom environment currently. In this study, we designed a Cu+ and Al3+ co-doped ZnS scintillator (ZnS: Cu+, Al3+) that introduces donor-acceptor (D-A) pairs for X-ray detection. The prepared scintillator displayed an extremely high steady-state light yield (53,000 photons per MeV) upon X-ray irradiation, which is 5.3 times higher than that of the commercial Bi4Ge3O12 (BGO) scintillator, making it possible in X-ray detection with the interference of ambient light. Furthermore, the prepared material was employed as a scintillator to construct an indirect X-ray detector, which performed a superior spatial resolution (≈10.0 lp/mm) as well as persistent stability under visible light interference, demonstrating the feasibility of the scintillator in practical applications. Therefore, this research presented a convenient and useful strategy to realize X-ray detection in a non-darkroom environment.

Revealing platelet-related subtypes and prognostic signature in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) is a malignant tumor with high heterogeneity and poor prognosis. In this study, we sought to identify the value of platelet-related genes in prognosis and heterogeneity of PDAC through multiple transcriptomic methods. METHODS: Based on datasets from Gene Expression Omnibus and The Cancer Genome Atlas (TCGA), platelet-related genes were screened out, and the TCGA cohort (n = 171) was identified into two subtypes by unsupervised clustering. The platelet-related risk score model (PLRScore) was constructed by univariate Cox and LASSO regression, and the predictive ability was evaluated by Kaplan-Meier test and time-dependent receiver operating characteristic (ROC) curves. The results were validated in two other external validation sets, ICGC-CA (n = 140) and GSE62452 (n = 66). Furthermore, predictive nomogram containing clinical characteristics and PLRScore was established. In addition, we determined the possible correlation between PLRScore and immune infiltration and response of immunotherapy. Finally, we analyzed the heterogeneity of our signature in various types of cells using single-cell analysis. RESULTS: Platelet-related subtypes that have significant difference of overall survival and immune states (p < 0.05) were identified. PLRScore model based on four-gene signature (CEP55, LAMA3, CA12, SCN8A) was constructed to predict patient prognosis. The AUCs of training cohort were 0.697, 0.687 and 0.675 for 1-, 3-and 5-year, respectively. Further evaluation of the validation cohorts yielded similar results. In addition, PLRScore was associated with immune cell infiltration and immune checkpoint expression, and had promising ability to predict response to immunotherapy of PDAC. CONCLUSIONS: In this study, the platelet-related subtypes were identified and the four-gene signature was constructed and validated. It may provide new insights into the therapeutic decision-making and molecular targets of PDAC.

Machine Learning-Based Prognostic Model for Patients After Lung Transplantation.

Importance: Although numerous prognostic factors have been found for patients after lung transplantation (LTx) over the years, an accurate prognostic tool for LTx recipients remains unavailable. Objective: To develop and validate a prognostic model for predicting overall survival in patients after LTx using random survival forests (RSF), a machine learning algorithm. Design, Setting, and Participants: This retrospective prognostic study included patients who underwent LTx between January 2017 and December 2020. The LTx recipients were randomly assigned to training and test sets in accordance with a ratio of 7:3. Feature selection was performed using variable importance with bootstrapping resampling. The prognostic model was fitted using the RSF algorithm, and a Cox regression model was set as a benchmark. The integrated area under the curve (iAUC) and integrated Brier score (iBS) were applied to assess model performance in the test set. Data were analyzed from January 2017 to December 2019. Main Outcomes And Measures: Overall survival in patients after LTx. Results: A total of 504 patients were eligible for this study, consisting of 353 patients in the training set (mean [SD] age, 55.03 [12.78] years; 235 [66.6%] male patients) and 151 patients in the test set (mean [SD] age, 56.79 [10.95] years; 99 [65.6%] male patients). According to the variable importance of each factor, 16 were selected for the final RSF model, and postoperative extracorporeal membrane oxygenation time was identified as the most valuable factor. The RSF model had excellent performance with an iAUC of 0.879 (95% CI, 0.832-0.921) and an iBS of 0.130 (95% CI, 0.106-0.154). The Cox regression model fitted by the same modeling factors to the RSF model was significantly inferior to the RSF model with an iAUC of 0.658 (95% CI, 0.572-0.747; P < .001) and an iBS of 0.205 (95% CI, 0.176-0.233; P < .001). According to the RSF model predictions, the patients after LTx were stratified into 2 prognostic groups displaying significant difference, with mean overall survival of 52.91 months (95% CI, 48.51-57.32) and 14.83 months (95% CI, 9.44-20.22; log-rank P < .001), respectively. Conclusions and relevance: In this prognostic study, the findings first demonstrated that RSF could provide more accurate overall survival prediction and remarkable prognostic stratification than the Cox regression model for patients after LTx.

Osteogenesis promotion by injectable methacryloylated gelatin containing psoralen and its bacteriostatic properties.

The treatment of periodontitis focuses on controlling the progression of inflammation, reducing plaque accumulation, and promoting bone tissue reconstruction. Among them, the reconstruction of irregular bone resorption caused by periodontitis is a long-standing challenge. At present, the local drug treatment of periodontitis is mainly anti-inflammatory and antibacterial drugs. In this study, psoralen (Pso), a Chinese herbal medicine with anti-inflammatory, antibacterial, and osteogenic effects, was selected for the local treatment of periodontitis. Meanwhile, an injectable methacrylate gelatin (GelMA) platform loading with Pso was constructed. Pso-GelMA had the properties of fluidity, light cohesion, self-healing, and slow release, which could be better used in the deep and narrow structure of the periodontal pocket, and greatly increased the effectiveness of local drug delivery. The pore size of Gelma hydrogel did not change after loading Pso by SEM. In vitro, Pso-GelMA effectively upregulated the expression of osteogenic genes and proteins, increased alkaline phosphatase activity, promoted the mineralisation of rat bone marrow mesenchymal stem cells (BMSCs) extracellular matrix, and had significant antibacterial effects on Staphylococcus aureus and Fusobacterium nucleatum. Therefore, Pso-GelMA has immense promise in the adjuvant treatment of periodontitis.

Clinical feasibility and oncological safety of non-radioactive targeted axillary dissection after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: a prospective diagnostic and prognostic study.

BACKGROUND: Targeted axillary dissection (TAD) includes biopsy of clipped lymph node and sentinel lymph nodes. However, clinical evidence regarding clinical feasibility and oncological safety of non-radioactive TAD in a real-world cohort remains limited. METHODS: In this prospective registry study, patients routinely underwent clip insertion into biopsy-confirmed lymph node. Eligible patients received neoadjuvant chemotherapy (NACT) followed by axillary surgery. Main endpoints included the false-negative rate (FNR) of TAD and nodal recurrence rate. RESULTS: Data from 353 eligible patients were analyzed. After completion of NACT, 85 patients directly proceeded to axillary lymph node dissection (ALND), furthermore, TAD with or without ALND was performed in 152 and 85 patients, respectively. Overall detection rate of clipped node was 94.9% (95%CI, 91.3%-97.4%) and FNR of TAD was 12.2% (95%CI, 6.0%-21.3%) in our study, with FNR decreasing to 6.0% (95%CI, 1.7%-14.6%) in initially cN1 patients. During a median follow-up of 36.6 months, 3 nodal recurrences occurred (3/237 with ALND; 0/85 with TAD alone), with a three-year freedom-from-nodal-recurrence rate of 100.0% among the TAD-only patients and 98.7% among the ALND patients with axillary pathologic complete response (P=0.29). CONCLUSIONS: TAD is feasible in initially cN1 breast cancer patients with biopsy-confirmed nodal metastases. ALND can safely be foregone in patients with negativity or a low volume of nodal positivity on TAD, with a low nodal failure rate and no compromise of three-year recurrence-free survival.

Dietary glutathione supplementation attenuates oxidative stress and improves intestinal barrier in diquat-treated weaned piglets.

The aim of this study was to investigate the protective effects of glutathione (GSH) against oxidative stress and intestinal barrier disruption caused by diquat (an oxidative stress inducer) in weaned piglets. Twenty-four piglets were randomly assigned to four treatments with six pigs per treatment for an 18-d trial. Treatments were basal diet, basal diet + diquat challenge, 50 mg/kg GSH diets + diquat challenge and 100 mg/kg GSH diets + diquat challenge. On day 15, piglets in basal diet group and diquat-challenged groups were intraperitoneally injected with sterile saline and diquat at 10 mg/kg body weight, respectively. The results showed that GSH supplementation improved growth performance of diquat-injected piglets from days 15 to 18 (p < 0.05), especially at a dose of 100 mg/kg GSH. Meanwhile, diquat also caused oxidative stress and intestinal barrier damage in piglets. However, GSH supplementation enhanced the antioxidant capacity of serum and jejunum, as evidenced by the increase in GSH content and total superoxide dismutase activities and the decrease in 8-hydroxy-2'-deoxyguanosine concentrations (p < 0.05). GSH also up-regulated the mRNA expressions of intestinal tight junction protein (zonula occludens 1, ZO1; occludin, OCLN; claudin-1, CLDN1) and mitochondrial biogenesis and function (peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, PGC1α; mitochondrial transcription factor A, TFAM; cytochrome c, CYCS), compared with diquat-challenged piglets in basal diet (p < 0.05). Thus, the study demonstrates that GSH protects piglets from oxidative stress caused by diquat and 100 mg/kg GSH has a better protective role.

Inhibition of ACSL4 Alleviates Parkinsonism Phenotypes by Reduction of Lipid Reactive Oxygen Species.

Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be defined. Acyl-CoA synthetase long-chain family member 4 (ACSL4) esterifies polyunsaturated fatty acids (PUFAs) which is essential to trigger ferroptosis, and is suggested as a key gene in the pathogenesis of several neurological diseases including ischemic stroke and multiple sclerosis. Here, we report that ACSL4 expression in the substantia nigra (SN) was increased in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated model of PD and in dopaminergic neurons in PD patients. Knockdown of ACSL4 in the SN protected against dopaminergic neuronal death and motor deficits in the MPTP mice, while inhibition of ACSL4 activity with Triacsin C similarly ameliorated the parkinsonism phenotypes. Similar effects of ACSL4 reduction were observed in cells treated with 1-methyl-4-phenylpyridinium (MPP+) and it specifically prevented the lipid ROS elevation without affecting the mitochondrial ROS changes. These data support ACSL4 as a therapeutic target associated with lipid peroxidation in PD.