Sequential CD7 CAR T-Cell Therapy and Allogeneic HSCT without GVHD Prophylaxis.

BACKGROUND: Patients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear. METHODS: We tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored. RESULTS: After CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease-negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100). CONCLUSIONS: Our findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.).

CatLearning: highly accurate gene expression prediction from histone mark.

Histone modifications, known as histone marks, are pivotal in regulating gene expression within cells. The vast array of potential combinations of histone marks presents a considerable challenge in decoding the regulatory mechanisms solely through biological experimental approaches. To overcome this challenge, we have developed a method called CatLearning. It utilizes a modified convolutional neural network architecture with a specialized adaptation Residual Network to quantitatively interpret histone marks and predict gene expression. This architecture integrates long-range histone information up to 500Kb and learns chromatin interaction features without 3D information. By using only one histone mark, CatLearning achieves a high level of accuracy. Furthermore, CatLearning predicts gene expression by simulating changes in histone modifications at enhancers and throughout the genome. These findings help comprehend the architecture of histone marks and develop diagnostic and therapeutic targets for diseases with epigenetic changes.

Prenatal diagnosis and genetic analysis of small supernumerary marker chromosomes in the eastern chinese han population: A retrospective study of 36 cases.

BACKGROUND: Small supernumerary marker chromosomes (sSMCs) are additional chromosomes with unclear structures and origins, and their correlations with clinical fetal phenotypes remain incompletely understood, which reduces the accuracy of genetic counseling. METHODS: We conducted a retrospective analysis of a cohort of 36 cases of sSMCs diagnosed in our center. We performed G-banding and chromosomal microarray analysis (CMA). The resulting karyotypes were compared with case reports in the literature and various databases including OMIM, DECIPHER, ClinVar, ClinGen, ISCA, DGV, and PubMed. RESULTS: Karyotype analysis data revealed that 19 out of 36 fetuses were mosaic. Copy number variants (CNVs) analysis results showed that 27 out of 36 fetuses harbored pathogenic/likely pathogenic variants. Among these 27 cases, 11 fetuses carried sex chromosome-related CNVs, including 4 female cases exhibiting Turner syndrome phenotypes and 7 cases showing Y chromosome deletions. In the remaining 16 fetuses with autosomal CNVs, 9 fetuses carried variants associated with Cat eye syndrome, Emanuel syndrome, Tetrasomy 18p, and 15q11-q13 duplication syndrome. Among these, 22 fetuses were terminated, and the remaining 5 fetuses were delivered and developed normally. Additionally, we identified a few variants with unclear pathogenicity. CONCLUSION: Cytogenetic analysis is essential for identifying the pathogenicity of sSMCs and increasing the accuracy of genetic counseling.

Detecting Cellular Microstructural Changes of Liver Fibrosis with Time-Dependent Diffusion MRI.

Background The potential of time-dependent diffusion MRI in imaging the progression from liver fibrosis to cirrhosis has not been established. Purpose To assess the effectiveness of time-dependent diffusion MRI in mapping the microstructure and characterizing cellular attributes during the progression of liver fibrosis to cirrhosis and to investigate its potential in grading liver fibrosis. Materials and Methods This prospective study, performed between December 2022 and October 2023, used 60 rats to establish a liver fibrosis model by means of diethylnitrosamine administration, with five additional rats serving as control animals. Time-dependent diffusion MRI was performed with equivalent diffusion time of 5.4, 10.7, and 69.3 msec on a 3.0-T scanner. Time-dependent diffusion MRI-based microstructural parameters, including cell diameter, intracellular volume fraction (ICVF), cellularity, and extracellular diffusivity, were estimated with use of the imaging microstructural parameters using limited spectrally edited diffusion, or IMPULSED, model. The fitted microstructural parameters were validated with histopathologic measurements. Results All 60 rats developed liver fibrosis, with a noticeable decrease in cell diameter and an increase in ICVF and cellularity observed as liver fibrosis progressed. The diameter measured at pathologic examination ranged from 11.4 µm to 35.4 µm, aligning with the range of 12.4-33.4 µm observed in time-dependent diffusion MRI, which indicated a strong correlation (r = 0.84; P < .001). The quantified ICVF at pathologic examination ranged from 0.28 to 0.89 and varied from 0.23 to 0.85 at time-dependent diffusion MRI, showing a high correlation (r = 0.62; P < .001). The cellularity observed at pathologic examination increased from 0.74 to 5.85, while the cellularity measured at time-dependent diffusion MRI ranged from 0.77 to 3.70, showing a correlation (r = 0.44; P < .001). Conclusion This study revealed the changes in quantitative microstructural mapping across the spectrum from liver fibrosis to cirrhosis. Cell diameter, ICVF, and cellularity are reliable markers for liver fibrosis, with diameter and ICVF presenting good discrimination ability. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Matos and Metens in this issue.

Multifunctional Injectable Hydrogel Microparticles Loaded with miR-29a Abundant BMSCs Derived Exosomes Enhanced Bone Regeneration by Regulating Osteogenesis and Angiogenesis.

The study investigated whether both the osteogenic and angiogenic potential of Exos (Exosomes) can be enhanced by overexpression of exosomal miRNA (microRNA) and to confirm whether Exos loaded in HMPs (Hydrogel microparticles) exert long-term effects during new bone formation. BMSCs and Exos are successfully obtained. In vitro and in vivo experiments confirmed that HDAC4 (Histone deacetylase 4) is inhibited by miR-29a overexpression accompanied by the upregulation of RUNX2 (Runt-related transcription factor 2) and VEGF (Vascular Endothelial Growth Factor), thereby enhancing osteogenic and angiogenic capabilities. The HMP@Exo system is synthesized from HB-PEGDA (Hyperbranched Poly Ethylene Glycol Diacrylate)- and SH-HA (Sulfhydryl-Modified Hyaluronic Acid)-containing Exos using a microfluidic technique. The HMP surface is modified with RGD (Arg-Gly-Asp) peptides to enhance cell adhesion. The system demonstrated good injectability, remarkable compatibility, outstanding cell adhesion properties, and slow degradation capacity, and the sustained release of Agomir-29a-Exos (Exosomes derived from Agomir-29a transfected BMSCs) from HMPs enhanced the proliferation and migration of BMSCs and HUVECs (Human Umbilical Vein Endothelial Cells) while promoting osteogenesis and angiogenesis. Overall, the findings demonstrate that the HMP@Exo system can effectively maintain the activity and half-life of Exos, accompanied by overexpression of miR-29a (microRNA-29a). The injectable system provides an innovative approach for accelerating fracture healing by coupling osteogenesis and angiogenesis.

Multidimensional engineering of Saccharomyces cerevisiae for the efficient production of heme by exploring the cytotoxicity and tolerance of heme.

Heme has attracted considerable attention due to its indispensable biological roles and applications in healthcare and artificial foods. The development and utilization of edible microorganisms instead of animals to produce heme is the most promising method to promote the large-scale industrial production and safe application of heme. However, the cytotoxicity of heme severely restricts its efficient synthesis by microorganisms, and the cytotoxic mechanism is not fully understood. In this study, the effect of heme toxicity on Saccharomyces cerevisiae was evaluated by enhancing its synthesis using metabolic engineering. The results showed that the accumulation of heme after the disruption of heme homeostasis caused serious impairments in cell growth and metabolism, as demonstrated by significantly poor growth, mitochondrial damage, cell deformations, and chapped cell surfaces, and these features which were further associated with substantially elevated reactive oxygen species (ROS) levels within the cell (mainly H2O2 and superoxide anion radicals). To improve cellular tolerance to heme, 5 rounds of laboratory evolution were performed, increasing heme production by 7.3-fold and 4.2-fold in terms of the titer (38.9 mg/L) and specific production capacity (1.4 mg/L/OD600), respectively. Based on comparative transcriptomic analyses, 32 genes were identified as candidates that can be modified to enhance heme production by more than 20% in S. cerevisiae. The combined overexpression of 5 genes (SPS22, REE1, PHO84, HEM4 and CLB2) was shown to be an optimal method to enhance heme production. Therefore, a strain with enhanced heme tolerance and ROS quenching ability (R5-M) was developed that could generate 380.5 mg/L heme with a productivity of 4.2 mg/L/h in fed-batch fermentation, with S. cerevisiae strains being the highest producers reported to date. These findings highlight the importance of improving heme tolerance for the microbial production of heme and provide a solution for efficient heme production by engineered yeasts.

Effects of biomass burning on CO, HCN, C2H6, C2H2 and H2CO during long-term FTIR measurements in Hefei, China.

High-resolution solar absorption spectra were continuously collected by a ground-based Fourier transform infrared (FTIR) spectrometer to retrieve the total column of carbon monoxide (CO), hydrogen cyanide (HCN), ethane (C2H6), acetylene (C2H2), and formaldehyde (H2CO). The time series and variation characteristics of these gases were analyzed. The biomass combustion process is identified by using the correlations between the monthly mean deviations of HCN, C2H6, C2H2 and H2CO versus CO and satellite fire point data. The months with high correlation coefficients (R > 0.8) and peaks of fire point number are considered to be with biomass combustion occurrence. The emissions of HCN, C2H6, C2H2 and H2CO in Anhui were estimated using the enhancement ratios of gases to CO in these months when biomass combustion was the main driving factor of gas concentration change. The study proved the ability of FTIR system in inferring the period during biomass combustion and estimating emissions of the trace gases concerning biomass combustion.

Terahertz fan-beam computed tomography.

A terahertz (THz) fan-beam computed tomography (CT) system using a 0.3 THz continuous-wave sheet beam is proposed. The diffraction-free sheet beam expands in a fan shape in only one direction and provides propagation-invariant focal lines and extended the depth-of-field. The fan-beam CT based on this beam is the second-generation THz CT. It breaks the conventional 4-f symmetric structure of THz CT using the parallel beam. The fan-beam THz CT allows for use with a linear array detector, which reduces the time required to collect data. To demonstrate its feasibility for three-dimensional (3D) imaging, the 3D structure of a metal rod packed in a carton is reconstructed with the support of the system. The results show that the object's internal structure can be obtained by this new THz CT system while retaining the geometrically magnified features of the cross-sectional structure. The results of our research provide a template for the second-generation THz CT system, which provides an additional method for nondestructive testing.

Machine learning for accurate detection of small airway dysfunction-related respiratory changes: an observational study.

BACKGROUND: The use of machine learning(ML) methods would improve the diagnosis of small airway dysfunction(SAD) in subjects with chronic respiratory symptoms and preserved pulmonary function(PPF). This paper evaluated the performance of several ML algorithms associated with the impulse oscillometry(IOS) analysis to aid in the diagnostic of respiratory changes in SAD. We also find out the best configuration for this task. METHODS: IOS and spirometry were measured in 280 subjects, including a healthy control group (n = 78), a group with normal spirometry (n = 158) and a group with abnormal spirometry (n = 44). Various supervised machine learning (ML) algorithms and feature selection strategies were examined, such as Support Vector Machines (SVM), Random Forests (RF), Adaptive Boosting (ADABOOST), Navie Bayesian (BAYES), and K-Nearest Neighbors (KNN). RESULTS: The first experiment of this study demonstrated that the best oscillometric parameter (BOP) was R5, with an AUC value of 0.642, when comparing a healthy control group(CG) with patients in the group without lung volume-defined SAD(PPFN). The AUC value of BOP in the control group was 0.769 compared with patients with spirometry defined SAD(PPFA) in the PPF population. In the second experiment, the ML technique was used. In CGvsPPFN, RF and ADABOOST had the best diagnostic results (AUC = 0.914, 0.915), with significantly higher accuracy compared to BOP (p < 0.01). In CGvsPPFA, RF and ADABOOST had the best diagnostic results (AUC = 0.951, 0.971) and significantly higher diagnostic accuracy (p < 0.01). In the third, fourth and fifth experiments, different feature selection techniques allowed us to find the best IOS parameters (R5, (R5-R20)/R5 and Fres). The results demonstrate that the performance of ADABOOST remained essentially unaltered following the application of the feature selector, whereas the diagnostic accuracy of the remaining four classifiers (RF, SVM, BAYES, and KNN) is marginally enhanced. CONCLUSIONS: IOS combined with ML algorithms provide a new method for diagnosing SAD in subjects with chronic respiratory symptoms and PPF. The present study's findings provide evidence that this combination may help in the early diagnosis of respiratory changes in these patients.

Predictors and risk factors of bile duct injury after transcatheter arterial chemoembolization for hepatocellular carcinoma.

PURPOSE: Bile duct injury is a serious complication after transcatheter arterial chemoembolization (TACE). If it is not detected early and treated actively, it will not only affect the subsequent tumor-related treatment of hepatocellular carcinoma (HCC) patients, but also may lead to serious consequences such as infection, liver failure and even death. To analyze the risk factors of bile duct injury after TACE in patients with HCC and explore the predictive indicators of bile duct injury after TACE, which is helpful for doctors to detect and intervene early and avoid the occurrence of serious complications. METHOD: We retrospectively analyzed the clinical data of 847 patients with primary hepatocellular carcinoma who underwent TACE for the first time in our interventional department. Patients were divided into two groups according to whether bile duct injury occurred after TACE: (1) bile duct injury group, N = 55; (2) no bile duct injury group, N = 792. The basic data, intraoperative conditions and the outcome of bile duct injury were analyzed. The chi-square test was used for comparison of enumeration data. The Mann-Whitney U test was used for comparison of measurement data. Risk factor analysis was performed using binary logistic regression analysis. RESULTS: Basic data and intraoperative conditions were compared between the bile duct injury group and the group without bile duct injury: preoperative alkaline phosphatase (ALP) (103.24 ± 32.77U/L vs. 89.17 ± 37.35U/L, P = 0.003); history of hepatobiliary surgery (36.4% vs. 20.8%, P = 0.011); intraoperative lipiodol volume (P = 0.007); combined use of gelatin sponge particles (65.5% vs. 35.0%, P < 0.001); hypovascularity (58.2% vs. 24.5%, P < 0.001); and embolization site (P < 0.001). Comparison of postoperative liver function between bile duct injury group and non-bile duct injury group: postoperative total bilirubin (43.34 ± 25.18umol/L vs. 21.94 ± 9.82umol/L, P < 0.001); postoperative γ-glutamyltransferase(GGT) (188.09 ± 55.62U/L vs. 84.04 ± 36.47U/L, P < 0.001); postoperative ALP(251.51 ± 61.51U/L vs. 99.92 ± 45.98U/L, P < 0.001). CONCLUSION: The dosage of lipiodol in TACE, supplementation of gelatin sponge particles, embolization site, and hypovascularity of the tumor are risk factors for biliary duct injury after TACE. After TACE, GGT and ALP increased ≥ 2 times compared with preoperative indicators as predictors of bile duct injury. Bile duct injury occurring after TACE can achieve good outcomes with aggressive management.

Utility and predictive value of the CRAFITY score in advanced hepatocellular carcinoma treated with transarterial chemoembolization plus tyrosine kinase inhibitors and PD-1 inhibitor.

BACKGROUND: The prognostic significance of the CRAFITY score (CRP and AFP in ImmunoTherapY) has been demonstrated in hepatocellular carcinoma (HCC) patients receiving immunotherapy. The purpose of this study was to investigate the utility and the predictive value of CRAFITY score in HCC after transarterial chemoembolization (TACE) in combination with tyrosine kinase inhibitors (TKIs) and immunotherapy. MATERIALS AND METHODS: Data from patients with advanced HCC treated with TACE plus TKIs and PD-1 inhibitor from January 2019 to June 2022 were collected and analyzed retrospectively. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point. Patients were divided into three groups according to their CRAFITY score (CRAFITY-low, 0 points; CRAFITY-intermediate, 1 point; and CRAFITY-high, 2 points). The differences in overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were compared among the three groups. Tumor response was evaluated at 3, 6 and 12 months after the first combination treatment. Risk factors for OS and PFS were assessed. RESULTS: A total of 70 patients were included. The patients were assigned CRAFITY scores of 0 points (CRAFITY-low, n = 25 [35.71%]), 1 point (CRAFITY-intermediate, n = 29 [41.42%]), and 2 points (CRAFITY-high, n = 16 [22.81%]). Multivariate analysis showed that lower CRAFITY score was an independent factor for the improved OS (P =.045) and PFS (P <.001). TACE session was also associated with the OS (P =.048) in the multivariate analysis. The CRAFITY-low cohort achieved a higher objective response rate (ORR) at the 3-month evaluation of tumor response. However, there was no significant difference in ORR and disease control rate (DCR) observed at the 6-month follow-up. DCR showed a statistically significant difference among three groups during the 12-month follow-up period. The percentage of patients with protein urea was highest in the CRAFITY-high group. No significance differences were observed in grade ≥ 3 AEs in three groups. CONCLUSION: The CRAFITY score is simple and could be useful for predicting treatment outcomes, tumor response and AEs of the HCC patients receiving TACE plus TKIs and PD-1 inhibitor therapy.

Increased Ordering of Potassium Stearate/Stearic Acid/Glyceryl Stearate Confined between Swollen Cross-Linked Poly(acrylic acid).

In this paper, we investigate the phase behavior of a surfactant mixture comprising glyceryl stearate, potassium stearate, and stearic acid, in the presence of Carbopol, a commonly used thickener in personal care products. At low Carbopol concentrations (<0.03%), the surfactant mixture interacted with Carbopol electrostatically, increasing the degree of Carbopol swelling and, consequently, the overall viscosity. However, such an effect diminished as the Carbopol concentration was further increased. At a Carbopol concentration of 0.2%, two types of liquid crystalline surfactant structures, namely, multilamellar vesicles and lamellae, were observed between the swollen Carbopol domains. Although similar types of surfactant structures were present in a much more concentrated surfactant solution having a similar viscosity but without Carbopol, the lamellae in the presence of Carbopol were more ordered and with a larger d spacing. The increased ordering was probably induced by the interactions between the surfactants and Carbopol as the surfactants were confined between the swollen Carbopol domains.

PHLDA1 is a P53 target gene involved in P53-mediated cell apoptosis.

Pleckstrin homeolike domain, family A, member 1 (PHLDA1) is a multifunctional protein that plays diverse roles in A variety of biological processes, including cell death, and hence its altered expression has been found in different types of cancer. Although studies have shown a regulatory relationship between p53 and PHLDA1, the molecular mechanism is still unclear. Especially, the role of PHLDA1 in the process of apoptosis is still controversial. In this study, we found that the expression of PHLDA1 in human cervical cancer cell lines was correlated with the up-expression of p53 after treatment with apoptosis-inducing factors. Subsequently, the binding site and the binding effect of p53 on the promoter region of PHLDA1 were verified by our bioinformatics data analysis and luciferase reporter assay. Indeed, we used CRISPR-Cas9 to knockout the p53 gene in HeLa cells and further confirmed that p53 can bind to the promoter region of PHLDA1 gene, and then directly regulate the expression of PHLDA1 by recruiting P300 and CBP to change the acetylation and methylation levels in the promoter region. Finally, a series of gain-of-function experiments further confirmed that p53 re-expression in HeLap53-/- cell can up-regulate the reduction of PHLDA1 caused by p53 knockout, and affect cell apoptosis and proliferation. Our study is the first to explore the regulatory mechanism of p53 on PHLDA1 by using the p53 gene knockout cell model, which further proves that PHLDA1 is a target-gene in p53-mediated apoptosis, and reveals the important role of PHLDA1 in cell fate determination.

Synergistic Control of Trimethoprim and the Antimicrobial Resistome in Electrogenic Microbial Communities.

Synergistic control of the risks posed by emerging antimicrobials and antibiotic resistance genes (ARGs) is crucial for ensuring ecological safety. Although electrogenic respiration can enhance the biodegradation of several antimicrobials and reduce ARGs accumulation, the association mechanisms of antimicrobial biodegradation (trimethoprim, TMP) with the fate of the antimicrobial resistome remain unclear. Here, the biotransformation pathway of TMP, microbial associations, and functional gene profiles (e.g., degradation, antimicrobial resistance, and electron transfer) were analyzed. The results showed that the microbial electrogenic respiration significantly enhanced the biodegradation of TMP, especially with a cosubstrate sodium acetate supply. Electroactive bacteria enriched in the electrode biofilm positively correlated with potential TMP degraders dominated in the planktonic communities. These cross-niche microbial associations may contribute to the accelerated catabolism of TMP and extracellular electron transfer. Importantly, the evolution and dissemination of overall ARGs and mobile genetic elements (MGEs) were significantly weakened due to the enhanced cometabolic biodegradation of TMP. This study provides a promising strategy for the synergistic control of the water ecological risks of antimicrobials and their resistome, while also highlighting new insights into the association of antimicrobial biodegradation with the evolution of the resistome in an electrically integrated biological process.

Design, synthesis and biological evaluation of 4,6-diarylquinoxaline-based KDM4D inhibitors.

Histone lysine demethylase 4D (KDM4D) is a critical player in the regulation of tumorigenesis, emerging as a potential target for developing anti-tumor agents. In this study, a series of KDM4D inhibitors containing the 4,6-diarylquinoxaline scaffold were prepared based on the previously discovered hit compound QD-1. Among these inhibitors, 33a was the most potent compound, with an IC50 value of 0.62 µM. In an in vitro assay, 33a showed a superior ability to inhibit the viability of liver cancer Huh-7 cells with IC50 = 5.23 µM. 33a exhibits significant effects in inhibiting cell cycle progression and proliferation of liver cancer cells, as well as suppressing cell migration. This work provided a promising scaffold for developing KDM4D inhibitors, as well as a lead compound for the development of anti-tumor drugs targeting KDM4D.

Theoretical study on the surface poisoning of high-entropy alloys during hydrogen storage cycles: the effect of metal elements and phases.

High-entropy alloys offer promising hydrogen storage properties and design versatility but suffer from compromised capacity and stability in practical industrial applications owing to surface poisoning caused by trace impurities or unexpected contact with air. Theoretical simulations provide a rapid and efficient platform for estimating anti-poisoning performance, particularly concerning alloys versus metal elements in various phases. This work explores the surface poisoning behavior of two typical high entropy materials: BCC-phase V35Ti30Cr25Fe10 and Laves-phase ZrTiVNiCrFe, along with pure metals V, Ti, Cr, and Fe as well as single AB2 (A = Zr, Ti, B = V, Ni, Cr, and Fe) compounds, at various phase stages during hydrogen storage cycles using density functional theory (DFT) simulations. Results show that surfaces of V35Ti30Cr25Fe10 and ZrTiVNiCrFe with a hydrogen uptake of 100% can facilitate O2 adsorption over dissociation, especially when O2 adsorbs on Fe sites, and formation of hydroxyl. The O2 poisoning behavior of high-entropy alloys was roughly estimated using the molar ratio weighted sum of constituent components, with the maximum deviation of 15.92% between predicted values and calculated values. This study sheds light on anti-poisoning mechanisms and aids in designing resilient high-entropy alloys.

Combining occlusion of the right hepatic vein with the Pringle maneuver in laparoscopic anatomic right posterior liver resection.

BACKGROUND: Laparoscopic right posterior anatomic resection (LRPAR) presents challenges due to uncontrollable hemorrhage from the inferior vena cava and the risk of carbon dioxide (CO2) gas embolism. However, there is a lack of research specifically addressing the safe exposure of right hepatic vein (RHV). Herein, we introduced a novel technique of combining occlusion of the RHV with the Pringle maneuver and presented the outcomes of our initial series. PATIENT AND METHOD: All consecutive patients who underwent LRPAR using this novel technique were enrolled in this study from March 2021 to January 2024. The demographic characteristics, perioperative outcomes and follow-up data were collected and analyzed. RESULTS: A total of 12 patients underwent LRPAR using the technique of double occlusion during study period. All the procedures were performed laparoscopically, with no conversions to open surgery. The median operative time was 203 min (range of 172-279 min) and the median blood loss was 200 ml (range of 50-280 ml). No patient received a blood transfusion during the perioperative period. Of note, the main trunk of the RHV was fully exposed on the cutting surface in all cases, and no evidence of CO2 gas embolism was observed following double occlusion. None of the patients suffered from Clavien-Dindo grade II or higher postoperative complications, and the perioperative mortality was nil. The median postoperative stay was 5 days (range of 5-7 days). The median hospitalization cost was 43,048.5 RMB (40,240.35-57,921.53 RMB). At a median follow-up period of 24 months (range of 4-35 months), all patients were alive with normal daily living and no disease recurrence was observed. CONCLUSIONS: Combining occlusion of the right hepatic vein with the Pringle maneuver appears to be a feasible and expected technique for securing the exposure of RHV in LRPAR. Further follow-up and well-designed prospective comparative studies are needed to validate the feasibility and efficacy of this technique.

Caudo-dorsal approach combined with the occlusion of right hepatic vein and Pringle maneuver in laparoscopic anatomical resection of segment 7.

BACKGROUND: Laparoscopic anatomical resection of segment 7 (LARS7) remains a technically challenging procedure due to the deep anatomical location and the potential risk of injury to the right hepatic vein (RHV). Herein, we initiated an innovative technique of caudo-dorsal approach combined with the occlusion of the RHV and Pringle maneuver for LARS7 and presented the outcomes of our initial series. METHOD: Since January 2021, the patients who underwent LARS7 by using this novel technique were enrolled in this study. The critical aspect of this technique was the interruption of communication between the RHV and the inferior vena cava. Meanwhile, the Pringle maneuver was adopted to control the hepatic inflow. RESULT: A total of 11 patients underwent LARS7 by using this novel technique, which included 8 hepatocellular carcinoma, 2 bile duct adenocarcinoma and one focal nodular hyperplasia. The median operative time was 199 min (range of 151-318 min) and the median blood loss was 150 ml (range of 50-200 ml). The main trunk of the RHV was fully exposed on the cutting surface in all cases and no patient received perioperative blood transfusion. No procedure was converted to open surgery. Of note, no indications of CO2 gas embolism were observed in these cases after the introduction of double occlusion. Only one patient suffered from postoperative complications and healed after treatment. The median postoperative stay was 5 days (range of 4-7 days). The 90-day mortality was nil. At a median follow-up period of 19 months, all of the patients were alive without any evidence of tumor recurrence. CONCLUSION: The caudo-dorsal approach combined with the occlusion of RHV and the Pringle maneuver may be a feasible and expected technique for safe exposure of RHV in LARS7. Further validation of the feasibility and efficacy of this technique is needed.

Novel kinase 1 regulates CD8+T cells as a potential therapeutic mechanism for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic and progressively worsening lung disease that poses a significant threat to patient prognosis, with a mortality rate exceeding that of some common malignancies. Effective methods for early diagnosis and treatment remain for this condition are elusive. In our study, we used the GEO database to access second-generation sequencing data and associated clinical information from IPF patients. By utilizing bioinformatics techniques, we identified crucial disease-related genes and their biological functions, and characterized their expression patterns. Furthermore, we mapped out the immune landscape of IPF, which revealed potential roles for novel kinase 1 and CD8+T cells in disease progression and outcome. These findings can aid the development of new strategies for the clinical diagnosis and treatment of IPF.

C1q/Tumor Necrosis Factor-Related Protein-9 Enhances Macrophage Cholesterol Efflux and Improves Reverse Cholesterol Transport via AMPK Activation.

Cholesterol efflux from foam cells in atherosclerotic plaques is crucial for reverse cholesterol transport (RCT), an important antiatherogenic event. ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1, are key receptors in the cholesterol efflux pathway. C1q/tumor necrosis factor-related protein-9 (CTRP9) is a newly discovered adipokine and exhibits an atheroprotective activity. However, the role of CTRP9 in RCT still remains unknown. In this work, we investigated the effect of subcutaneous administration of CTRP9 protein on RCT and atherosclerotic lesion formation in ApoE-/- mice fed with a high-fat diet. CTRP9-dependent regulation of cholesterol efflux and ABC transporters in RAW 264.7 foam cells was determined. Our results showed that CTRP9 protein decreased atherosclerotic lesions, increased cholesterol efflux, and upregulated liver ABCA1 and ABCG1 expression in ApoE-/- mice. CTRP9 treatment dose-dependently increased mRNA and protein expression of ABCA1, ABCG1, and LXR-α in RAW 264.7 foam cells. Moreover, the expression and phosphorylation of AMPK was potentiated upon CTRP9 treatment. Notably, CTRP9-induced cholesterol efflux and upregulation of ABCA, ABCG1, and LXR-α were impaired when AMPK was knocked down. AMPK depletion restored cholesterol accumulation in CTRP9-treated RAW 264.7 cells. Taken together, subcutaneous injection is an effective novel delivery route for CTRP9 protein, and exogenous CTRP9 can facilitate cholesterol efflux and promote RCT in an animal model of atherosclerosis. The atheroprotective activity of CTRP9 is mediated through the activation of AMPK signaling.