Endothelial YAP/TEAD1-CXCL17 signaling recruits myeloid-derived suppressor cells against liver ischemia-reperfusion injury.

BACKGROUND AND AIMS: Liver ischemia-reperfusion injury (IRI) is a common complication of liver transplantation and hepatectomy and causes acute liver dysfunction and even organ failure. Myeloid-derived suppressor cells (MDSCs) accumulate and play immunosuppressive function in cancers and inflammation. However, the role of MDSCs in liver IRI has not been defined. APPROACH AND RESULTS: We enrolled recipients receiving OLT and obtained the pre-OLT/post-OLT blood and liver samples. The proportions of MDSCs were significantly elevated after OLT and negatively associated with liver damage. In single-cell RNA-sequencing analysis of liver samples during OLT, 2 cell clusters with MDSC-like phenotypes were identified and showed maturation and infiltration in post-OLT livers. In the mouse model, liver IRI mobilized MDSCs and promoted their infiltration in the damaged liver, and intrahepatic MDSCs were possessed with enhanced immunosuppressive function by upregulation of STAT3 signaling. Under treatment with αGr-1 antibody or adoptive transfer MDSCs to change the proportion of MDSCs in vivo, we found that intrahepatic MDSCs alleviated liver IRI-induced inflammation and damage by inhibiting M1 macrophage polarization. Mechanistically, bulk RNA-sequencing analysis and in vivo experiments verified that C-X-C motif chemokine ligand 17 (CXCL17) was upregulated by YAP/TEAD1 signaling and subsequently recruited MDSCs through binding with GPR35 during liver IRI. Moreover, hepatic endothelial cells were the major cells responsible for CXCL17 expression in injured livers, among which hypoxia-reoxygenation stimulation activated the YAP/TEAD1 complex to promote CXCL17 transcription. CONCLUSIONS: Endothelial YAP/TEAD1-CXCL17 signaling recruited MDSCs to attenuate liver IRI, providing evidence of therapeutic potential for managing IRI in liver surgery.

Proxalutamide in metastatic castration-resistant prostate cancer: Primary analysis of a multicenter, randomized, open-label, phase 2 trial.

We aim to assess the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, for men with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter, randomized, open-label, phase 2 trial. In our study, the enrolled mCRPC patients were randomized to 100, 200 and 300 mg dose groups at 1:1:1. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and time to PSA and radiographic progression. Safety and pharmacokinetics were also assessed. Finally, there were 108 patients from 17 centers being enrolled. By week 16, there were 13 (35.1%), 12 (36.4%) and 15 (42.9%) patients with confirmed 50% or greater PSA decline in 100 mg (n = 37), 200 mg (n = 33) and 300 mg (n = 35) groups, respectively. Among the 19 patients with target lesions at study entry, three (15.8%) had a partial response and 12 (63.2%) had stable disease. The ORRs of 20.0%, 22.2%, 0% and DCRs of 80.0%, 88.9%, 60.0% were, respectively, achieved in 100, 200 and 300 mg groups. By the maximum follow-up time of 24 weeks, there were 42.6% and 10.2% of cases experiencing PSA progression and radiographic progression, respectively. Overall, adverse events (AEs) were experienced by 94.4% of patients, most of which were mild or moderate. There were 28 patients experiencing ≥grade 3 AEs. The most common AEs were fatigue (17.6%), anemia (14.8%), elevated AST (14.8%) and ALT (13.0%), decreased appetite (13.0%). These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial (Clinical trial registration no. CTR20170177).

Transfer RNA-derived fragment 5'tRF-Gly promotes the development of hepatocellular carcinoma by direct targeting of carcinoembryonic antigen-related cell adhesion molecule 1.

Transfer RNA-derived fragments are a group of small noncoding single-stranded RNA that play essential roles in multiple diseases. However, their biological functions in carcinogenesis are not well understood. In this study, 5'tRF-Gly was found to have significantly high expression in hepatocellular carcinoma (HCC), and the upregulation of 5'tRF-Gly was positively correlated with tumor size and tumor metastasis. Overexpression of 5'tRF-Gly induced increased growth rate and metastasis in HCC cells in vitro and in nude mice, while knockdown showed the opposite effect. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) was confirmed to be a direct target of 5'tRF-Gly in HCC. In addition, the cytological effect of CEACAM1 knockdown proved to be similar to the overexpression of 5'tRF-Gly. Moreover, attenuation of CEACAM1 expression rescued the 5'tRF-Gly-mediated promoting effects on HCC cells. These data show that 5'tRF-Gly is a new tumor-promoting factor and could be a potential diagnostic biomarker or new therapeutic target for HCC.

Activity and safety of SHR3680, a novel antiandrogen, in patients with metastatic castration-resistant prostate cancer: a phase I/II trial.

BACKGROUND: Antagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC. METHODS: This phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12. RESULTS: A total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0-74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2-95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7-47.7) of 61 patients. CONCLUSION: SHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study. TRIAL REGISTRATION: Clinical trials.gov NCT02691975; registered February 25, 2016.

Cell-derived extracellular vesicles and membranes for tissue repair.

Humans have a limited postinjury regenerative ability. Therefore, cell-derived biomaterials have long been utilized for tissue repair. Cells with multipotent differentiation potential, such as stem cells, have been administered to patients for the treatment of various diseases. Researchers expected that these cells would mediate tissue repair and regeneration through their multipotency. However, increasing evidence has suggested that in most stem cell therapies, the paracrine effect but not cell differentiation or regeneration is the major driving force of tissue repair. Additionally, ethical and safety problems have limited the application of stem cell therapies. Therefore, nonliving cell-derived techniques such as extracellular vesicle (EV) therapy and cell membrane-based therapy to fulfil the unmet demand for tissue repair are important. Nonliving cell-derived biomaterials are safer and more controllable, and their efficacy is easier to enhance through bioengineering approaches. Here, we described the development and evolution from cell therapy to EV therapy and cell membrane-based therapy for tissue repair. Furthermore, the latest advances in nonliving cell-derived therapies empowered by advanced engineering techniques are emphatically reviewed, and their potential and challenges in the future are discussed.

A novel exposure maneuver in laparoscopic right hepatectomy.

BACKGROUND AND OBJECTIVES: Laparoscopic access to the posterosuperior and lateral parts of the right liver is difficult for blocked and deep surgical situations. We invented a novel water bag device (WBD) to improve the exposure of the right liver. METHODS: Eighteen consecutive patients with lesions isolated to the posterosuperior or lateral right liver were included in our research. They underwent laparoscopic right hepatectomy with the help of the device and were compared with previous similar laparoscopic cases of our operating surgeon. RESULTS: The device was successfully employed without related complications and provided enhanced and stable surgical exposure. All patients were operated on without the need for blood transfusions or laparotomy conversion. The median operation time and estimated blood loss were 227 minutes (range, 114-568) and 88 mL (range, 25-250), respectively. In all cases, tumor-free surgical margins were confirmed and no major complications were observed. The results were better than those in previous similar laparoscopic cases. CONCLUSIONS: The WBD is safe and effective for laparoscopic exposure when lesions are located in the posterosuperior and lateral parts of the right liver. With the help of the device, laparoscopic right liver resection is easier to perform instead of undergoing open hepatectomy.

915-MHz microwave-assisted laparoscopic hepatectomy: a new technique for liver resection.

BACKGROUND: Hemorrhage during the liver transection is the major hazard for laparoscopic hepatectomy (LH). We aimed to evaluate the feasibility and safety of a 915-MHz microwave device used in LH. METHODS: Data were retrospectively analyzed regarding 60 patients who underwent LH with or without 915-MHz microwave coagulation at our center from January 2016 to June 2016. 30 patients underwent the 915-MHz microwave-assisted LH (MW group), and 30 patients otherwise were considered as control group. RESULTS: No perioperative mortality was observed. Intraoperative blood loss amounts in microwave group and control group were 26.83 ml and 186.33 ml, respectively (P < 0.001). The durations of parenchyma transaction (55.17 vs. 70.83 min, P < 0.001), blood occlusion (2.17 vs. 25.33 min, P < 0.001), and operation (120.67 vs. 148.00 min, P < 0.001) were much shorter in microwave group compared with control group. Lower incidence of postoperative complications (0.0 vs. 14.3%, P = 0.038) and shorter length of postoperative hospital stay (6.00 vs. 7.23 days, P = 0.027) were also noted in the microwave group, compared with the control group. CONCLUSION: 915-MHz microwave-assisted LH was found to be safe and efficient.

[Application of enhanced recovery program in laparoscopic distal pancreatectomy].

Objective: To evaluate the feasibility and safety of applying enhanced recovery after surgery (ERAS) protocol in patients undergoing laparoscopic distal pancreatectomy. Methods: Data of 36 patients undergoing laparoscopic distal pancreatectomy from May 2016 to May 2017 in the First Affiliated Hospital, Zhejiang University School of Medicine were reviewed. The patients were divided into ERAS group (n=12) and control group (n=24). The patients in ERAS group received a series of enhanced recovery procedures, including multimodal analgesia, early off-bed activity and early oral food-taking, etc. Operation time, intraoperative blood loss, time to first flatus, postoperative complications, and length of postoperative hospital stay were evaluated. Results: There were no statistically significant differences in operation time and intraoperative blood loss between ERAS group and control group (all P>0.05). The time to first flatus and length of postoperative hospital stay were significantly shortened in ERAS group (all P<0.05). The ERAS group had lower incidence of postoperative complications (41.7% vs. 66.7%), and the complications in ERAS group tended to be milder, but the differences failed to show statistical significance (all P>0.05). Conclusion: The ERAS protocol for laparoscopic distal pancreatectomy can significantly promote gastrointestinal function recovery and shorten postoperative hospital stay, and may reduce the incidence of postoperative complications.

Systematic review and meta-analysis of randomised trials of perioperative outcomes comparing robot-assisted versus open radical cystectomy.

BACKGROUND: With the introduction of robotic surgery, whether the robot-assisted radical cystectomy (RARC) could reduce the perioperative morbidity compared with Open radical cystectomy (ORC) was unknown. METHODS: Studies reported RARC were reviewed based on all randomized controlled trials (RCTs), which focused on the efficacy of RARC versus ORC. RESULTS: Of the 201 studies from preliminary screening, four RCTs were included. By pooling these studies, there were significant differences in comparison of operative time (p = 0.007), estimated blood loss (EBL) (p < 0.001) and time to diet (p < 0.001) between the RARC group and ORC groups. There was no significant difference regarding perioperative complications (Clavien 2-5, Clavien 3-5), length of stay (LOS), positive surgical margins (PSM) and lymph node positive. CONCLUSION: This meta-analysis presented evidence for a benefit of EBL, time to diet, similar perioperative complications and oncological outcomes, but a longer operative time in RARC. It is noted that RARC was considered as a comparable surgical procedure to ORC.

Abiraterone acetate for metastatic castration-resistant prostate cancer after docetaxel failure: A randomized, double-blind, placebo-controlled phase 3 bridging study.

OBJECTIVES: To evaluate the efficacy and safety of abiraterone acetate-prednisone versus placebo-prednisone in Asian metastatic castration-resistant prostate cancer patients who have failed docetaxel-based chemotherapy. METHODS: In this double-blind, phase 3 study from China, 214 patients were randomized (2:1) to abiraterone acetate 1000 mg once daily plus prednisone 5 mg twice daily and placebo plus prednisone 5 mg twice daily in 28-day treatment cycles. RESULTS: Abiraterone acetate-prednisone treatment significantly decreased prostate-specific antigen progression risk by 49%, with longer median time to prostate-specific antigen progression of 5.55 months versus 2.76 months in the placebo-prednisone group (hazard ratio 0.506, P = 0.0001, primary end-point). There was a strong trend for improved overall survival in the abiraterone acetate-prednisone group, with a 40% decrease in the risk of death (hazard ratio 0.604, P = 0.0597); however, median survival was not reached in either group because of the short follow-up period (12.9 months) and limited number of observed death events. The prostate-specific antigen response rate was higher in the abiraterone-prednisone group (49.7%) than in the placebo-prednisone group (14.1%). A total of 37.1% patients in this group had pain progression events compared with 50.7% in the placebo-prednisone group. Abiraterone-prednisone significantly decreased the risk of pain progression by 50% (hazard ratio 0.496, P = 0.0014). The incidence of adverse events was similar between the two groups; the most common adverse events being anemia (25.9% for abiraterone-prednisone vs 22.5% for placebo-prednisone), hypokalemia (25.9% and 11.3%), bone pain (23.8% and 21.1%), hypertension (16.1% and 12.7%) and increased aspartate aminotransferase (14.7% and 15.5%), respectively. CONCLUSIONS: Abiraterone-prednisone significantly delays disease and pain progression, and prostate-specific antigen, with a favorable benefit-risk ratio in Asian metastatic castration-resistant prostate cancer patients in the post-docetaxel setting.

[Updated relationship between testosterone and prostate cancer].

Androgen deprivation therapy can effectively suppress the progression of prostate cancer, but accumulating evidence for the relationship of testosterone with prostate cancer challenges the conventional wisdom. High levels of testosterone are not risk factors for prostate cancer, nor promote its development. On the contrary, a low testosterone level indicates a worse pathological stage. So far there has been no strong evidence to prove the role of testosterone in the occurrence and progression of prostate cancer. Therefore, the relationship between testosterone and prostate cancer is quite complicated and deserves further investigation.

Anchored-fusion enables targeted fusion search in bulk and single-cell RNA sequencing data.

Here, we present Anchored-fusion, a highly sensitive fusion gene detection tool. It anchors a gene of interest, which often involves driver fusion events, and recovers non-unique matches of short-read sequences that are typically filtered out by conventional algorithms. In addition, Anchored-fusion contains a module based on a deep learning hierarchical structure that incorporates self-distillation learning (hierarchical view learning and distillation [HVLD]), which effectively filters out false positive chimeric fragments generated during sequencing while maintaining true fusion genes. Anchored-fusion enables highly sensitive detection of fusion genes, thus allowing for application in cases with low sequencing depths. We benchmark Anchored-fusion under various conditions and found it outperformed other tools in detecting fusion events in simulated data, bulk RNA sequencing (bRNA-seq) data, and single-cell RNA sequencing (scRNA-seq) data. Our results demonstrate that Anchored-fusion can be a useful tool for fusion detection tasks in clinically relevant RNA-seq data and can be applied to investigate intratumor heterogeneity in scRNA-seq data.

Prognostic value of E­26 transformation­specific­related gene in prostate cancer based on immunohistochemistry analysis.

E-26 transformation-specific-related gene (ERG) has been implicated in prostate cancer; however, its prognostic role remains unclear. Therefore, the present study aimed to investigate the association of ERG with the prognosis after radical prostatectomy in patients with prostate cancer. Patient data were collected at the Huadong Hospital, affiliated with Fudan University, between January 2016 and March 2020. ERG protein expression was detected using immunohistochemistry. Independent-sample t-tests and χ2 tests were used to evaluate prostate cancer prognosis depending on ERG levels. The Kaplan-Meier method was used to estimate biochemical failure-free survival (BFFS) and the log-rank test was used to test the distribution. Prognostic factors were determined using Cox regression analysis. The median patient age was 69 years (range, 47-82 years). The median prostate-specific antigen (PSA) and free-PSA levels before treatment were 9.58 ng/ml (range, 0.003-187.400 ng/ml) and 1.13 ng/ml (range, 0.0059-30.6100 ng/ml), respectively. ERG protein expression was positive in 43 (16.6%) and negative in 216 (83.4%) cases. The median follow-up period and BFFS were 30 and 28 months, respectively. There was a significant difference in biochemical recurrence (P=0.017) between patients with positive and negative ERG expression. Patients with positive ERG expression had significantly worse BFFS curves compared with those with negative ERG expression (P=0.0038). In the multivariate Cox regression analysis, positive ERG expression was found to be an independent prognostic factor in patients with prostate cancer who underwent radical prostatectomy (hazard ratio, 4.08; 95% confidence interval, 2.03-8.17; P=0.000074). In conclusion, positive ERG expression is an independent prognostic risk factor for prostate cancer. These findings may be valuable for improvements in the clinical application of ERG immunohistochemistry.

5'-tiRNA-Gln inhibits hepatocellular carcinoma progression by repressing translation through the interaction with eukaryotic initiation factor 4A-I.

tRNA-derived small RNAs (tsRNAs) are novel non-coding RNAs that are involved in the occurrence and progression of diverse diseases. However, their exact presence and function in hepatocellular carcinoma (HCC) remain unclear. Here, differentially expressed tsRNAs in HCC were profiled. A novel tsRNA, tRNAGln-TTG derived 5'-tiRNA-Gln, is significantly downregulated, and its expression level is correlated with progression in patients. In HCC cells, 5'-tiRNA-Gln overexpression impaired the proliferation, migration, and invasion in vitro and in vivo, while 5'-tiRNA-Gln knockdown yielded opposite results. 5'-tiRNA-Gln exerted its function by binding eukaryotic initiation factor 4A-I (EIF4A1), which unwinds complex RNA secondary structures during translation initiation, causing the partial inhibition of translation. The suppressed downregulated proteins include ARAF, MEK1/2 and STAT3, causing the impaired signaling pathway related to HCC progression. Furthermore, based on the construction of a mutant 5'-tiRNA-Gln, the sequence of forming intramolecular G-quadruplex structure is crucial for 5'-tiRNA-Gln to strongly bind EIF4A1 and repress translation. Clinically, 5'-tiRNA-Gln expression level is negatively correlated with ARAF, MEK1/2, and STAT3 in HCC tissues. Collectively, these findings reveal that 5'-tiRJNA-Gln interacts with EIF4A1 to reduce related mRNA binding through the intramolecular G-quadruplex structure, and this process partially inhibits translation and HCC progression.

Mitochondrial-Targeted Delivery of Polyphenol-Mediated Antioxidases Complexes against Pyroptosis and Inflammatory Diseases.

Excess accumulation of mitochondrial reactive oxygen species (mtROS) is a key target for inhibiting pyroptosis-induced inflammation and tissue damage. However, targeted delivery of drugs to mitochondria and efficient clearance of mtROS remain challenging. In current study, it is discovered that polyphenols such as tannic acid (TA) can mediate the targeting of polyphenol/antioxidases complexes to mitochondria. This affinity does not depend on mitochondrial membrane potential but stems from the strong binding of TA to mitochondrial outer membrane proteins. Taking advantage of the feasibility of self-assembly between TA and proteins, superoxide dismutase, catalase, and TA are assembled into complexes (referred to as TSC) for efficient enzymatic activity maintenance. In vitro fluorescence confocal imaging shows that TSC not only promoted the uptake of biological enzymes in hepatocytes but also highly overlapped with mitochondria after lysosomal escape. The results from an in vitro model of hepatocyte oxidative stress demonstrate that TSC efficiently scavenges excess mtROS and reverses mitochondrial depolarization, thereby inhibiting inflammasome-mediated pyroptosis. More interestingly, TSC maintain superior efficacy compared with the clinical gold standard drug N-acetylcysteine in both acetaminophen- and D-galactosamine/lipopolysaccharide-induced pyroptosis-related hepatitis mouse models. In conclusion, this study opens a new paradigm for targeting mitochondrial oxidative stress to inhibit pyroptosis and treat inflammatory diseases.

Adjuvant therapy for cholangiocarcinoma after surgery and prognosis factors for cholangiocarcinoma: A single-center retrospective cohort study.

Background: Cholangiocarcinoma (CCA) is a highly heterogeneous malignant tumor, and more than 60% of patients have recurrence and metastasis after surgery. The efficacy of postoperative adjuvant therapy for CCA remains unclear. This study aimed to explore whether adjuvant therapy benefits patients with CCA and examine the independent prognostic factors for overall survival (OS) and progression-free survival (PFS). Methods: Patients with CCA undergoing surgery were retrospectively enrolled in this study from June 2016 to June 2022. The chi-square test or Fisher exact test was used to analyze the correlation between clinicopathologic characteristics. Survival curves were plotted using the Kaplan-Meier method, and the Cox regression model was used for univariate and multivariate analysis to search for independent prognostic factors. Results: Of the 215 eligible patients, 119 patients received adjuvant therapy, and the other 96 patients did not. The median follow-up was 37.5 months. The median OS of CCA patients with and without adjuvant therapy was 45 and 18 months (P < 0.001), respectively. The median PFS of CCA patients with and without adjuvant therapy was 34 and 8 months (P < 0.001), respectively. The Cox univariate and multivariate regression analysis showed that preoperative aspartate transaminase and carbohydrate antigen 19-9, microvascular invasion, lymph node metastasis, differentiation degree, and adjuvant therapy were independent prognostic factors for OS (all P values < 0.05). Preoperative carbohydrate antigen 125, microvascular invasion, lymph node metastasis, differentiation degree, and adjuvant therapy were independent prognostic factors for PFS (all P values < 0.05). The stratified analysis by TMN stage detected significant differences in the early stages (median OS [mOS]: P = 0.0128; median PFS [mPFS]: P = 0.0209) and advanced stages (mOS and mPFS: both P values < 0.001). Adjuvant therapy was also identified as a significantly favorable prognostic factor for OS and PFS in the early stages and advanced stages. Conclusion: Postoperative adjuvant therapy can improve the prognosis of patients with CCA, even in the early stages and advanced stages. All data suggest that adjuvant therapy should be incorporated into the treatment of CCA in all cases, where appropriate.

Beyond radiologist-level liver lesion detection on multi-phase contrast-enhanced CT images by deep learning.

Accurate detection of liver lesions from multi-phase contrast-enhanced CT (CECT) scans is a fundamental step for precise liver diagnosis and treatment. However, the analysis of multi-phase contexts is heavily challenged by the misalignment caused by respiration coupled with the movement of organs. Here, we proposed an AI system for multi-phase liver lesion segmentation (named MULLET) for precise and fully automatic segmentation of real-patient CECT images. MULLET enables effectively embedding the important ROIs of CECT images and exploring multi-phase contexts by introducing a transformer-based attention mechanism. Evaluated on 1,229 CECT scans from 1,197 patients, MULLET demonstrated significant performance gains in terms of Dice, Recall, and F2 score, which are 5.80%, 6.57%, and 5.87% higher than state of the arts, respectively. MULLET has been successfully deployed in real-world settings. The deployed AI web server provides a powerful system to boost clinical workflows of liver lesion diagnosis and could be straightforwardly extended to general CECT analyses.

Preclinical validation of silibinin/albumin nanoparticles as an applicable system against acute liver injury.

BACKGROUND: Silibinin (SIL) has been extensively studied for its therapeutic effects on various liver diseases. However, its effect on acute liver injury was limited for poor solubility and low bioavailability. Thus, we prepared SIL and bovine serum albumin (SIL/BSA) nanoparticles and further evaluated their therapeutic efficacy against acute liver injury in mouse models. METHODS: SIL/BSA nanoparticles were prepared via a nanoprecipitation method. Both in vitro cell culture model and in vivo mouse models of acetaminophen (APAP) and lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury were used to evaluate the therapeutic effect of SIL/BSA nanoparticles and potential mechanisms. RESULTS: The SIL/BSA nanoparticles with hydrophilic diameters of 90 ± 29 nm were stably suspended. SIL/BSA nanoparticles presented better biocompatibility and more liver distribution in vivo than SIL microparticles. SIL/BSA nanoparticles significantly alleviated APAP and LPS/D-GalN induced acute liver injury in mice. Similarly, SIL/BSA nanoparticles remarkably enhanced the viability of hepatocytes in vitro against both APAP and LPS/D-GalN induced hepatocyte damage. Moreover, SIL/BSA nanoparticles exhibited antioxidant effects against intracellular oxidative stress via upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway, decreasing ROS and regulating antioxidant enzyme reactivity. And the downstream of mitochondria damage and caspase 9/3 related apoptosis pathway was also inhibited CONCLUSION: SIL/BSA nanoparticles were successfully prepared to enhance the liver availability of SIL. Both in vivo and in vitro, SIL/BSA nanoparticles exerted ideal hepatoprotective and antioxidant efficacy against acute liver injury, suggesting the promising future in clinical transfer. STATEMENT OF SIGNIFICANCE: In our study, we prepared small-size, stable and well-dispersed silibinin/bovine serum albumin (SIL/BSA) nanoparticles via using simple and cost-effective nanoprecipitation techniques. Their physicochemical and pharmacokinetic characteristics were analyzed. We systematically studied the hepatoprotective and antioxidant efficacy of SIL/BSA both in vivo and in vitro, using two acute liver injury models. These findings revealed that SIL/BSA nanoparticles exerted ideal hepatoprotective and antioxidant efficacy against acute liver injury, suggesting the promising future in clinical transfer.

An NIR Discrete Metallacycle Constructed from Perylene Bisimide and Tetraphenylethylene Fluorophores for Imaging-Guided Cancer Radio-Chemotherapy.

To promote the clinical theranostic performances of platinum-based anticancer drugs, imaging capability is urgently desired, and their chemotherapeutic efficacy needs to be upgraded. Herein, a theranostic metallacycle (M) is developed for imaging-guided cancer radio-chemotherapy using perylene bisimide fluorophore (PPy) and tetraphenylethylene-based di-Pt(II) organometallic precursor (TPE-Pt) as building blocks. The formation of this discrete supramolecular coordination complex facilitates the encapsulation of M by a glutathione (GSH)-responsive amphiphilic block copolymer to prepare M-loaded nanoparticles (MNPs). TPE-Pt acts as a chemotherapeutic drug and also an excellent radiosensitizer, thus incorporating radiotherapy into the nanomedicine to accelerate the therapeutic efficacy and overcome drug resistance. The NIR-emission of PPy is employed to detect the intracellular delivery and tissue distribution of MNPs in real time. In vitro and in vivo investigations demonstrate the excellent anticancer efficacy combining chemotherapy and radiotherapy; the administration of this nanomedicine effectively inhibits the tumor growth and greatly extends the survival rate of cisplatin-resistant A2780CIS-tumor-bearing mice. Guided by in vivo fluorescence imaging, radio-chemotherapy is precisely carried out, which facilitates boosting of the therapeutic outcomes and minimizing undesired side effects. The success of this theranostic system brings new hope to supramolecular nanomedicines for their potential clinical translations.

Long-term prognosis and prognostic factors of brachytherapy and propensity score matched comparisons of the outcomes between brachytherapy and radical prostatectomy: a retrospective cohort study.

Background: To report outcomes of patients undergoing brachytherapy (BT), investigate factors associated with biochemical progression-free survival (bPFS) and to compare its long-term prognosis with that of radical prostatectomy (RP) in localized prostate cancer. Methods: The clinical data of 87 elderly patients with localized prostate cancer who underwent BT at Huadong Hospital affiliated to Fudan University from January 2009 to December 2016 were retrospectively analyzed. Patient prognoses and associated factors were investigated using univariate and multivariate Cox regression models. The clinical data of the 142 patients with localized prostate cancer who underwent RP during the same period were also collected. By using propensity score matching (PSM), the 42 patients who underwent BT were matched to 42 patients who underwent RP, and the differences in the survival curves were investigated using the Kaplan-Meier method. Results: The median follow-up period of the patients who underwent BT was 101 months. The 5- and 10-year overall survival (OS) rates of the patients who underwent BT were 82.8% and 64.0%, respectively, while the 5- and 10-year bPFS rates were 97.2% and 87.5%, respectively. The preoperative clinical Tumor (T) stage was identified as a prognostic factor of bPFS, as patients who underwent BT whose clinical stage was T3 had a worse prognosis than those whose clinical stage was T1-T2 (HR =0.097, P=0.049). After PSM, the average follow-up time of the BT group was 90 months and that of the RP group was 94 months. No significant differences in bPFS or cause-specific survival were observed between the 2 groups. The OS of the RP group was significantly higher than that of the BP group (P=0.030). Among the patients with a prostate volume >35 mL, those who underwent BT had significantly higher pPFS than those who underwent RP (P=0.041). Conclusions: In the localized prostate cancer, BT and RP offered similar oncological control in the localized prostate cancer. Stage T3 prostate cancer who undergo BT was associated with worse biochemical failure and was the only variable significantly predictive of biochemical recurrence.