[Update points for the 2022 edition of the European Association for the Study of Liver Diseases Clinical Practice Guidelines for the Management of Hepatic Encephalopathy and comparison with China's 2018 edition guidelines].

The European Association for the Study of Liver Diseases issued the "Clinical Practice Guidelines for the Management of Hepatic Encephalopathy" in 2022, which included recommendations for clinical diagnosis, assessment, treatment, management, and prevention. The Society's "Hepatic Encephalopathy Clinical Practice Guidelines in Chronic Liver Disease," which was last published in 2014, and the "Guidelines for the Diagnosis and Treatment of Hepatic Encephalopathy in Cirrhosis," which the Chinese Society of Hepatology, Chinese Medical Association, released in 2018, have certain differences and updates in terms of comparison to terminology, grading and classification, diagnosis, clinical evaluation and treatment, management, and prevention. Herein, the updated points of this guideline and the differences between it and our nation's guidelines are summarized in order to refine and understand the guiding role of the new version of the guideline for the clinical treatment of hepatic encephalopathy and provide aid for standardizing clinical diagnosis and treatment.

The effect of immunonutrition in patients with acute pancreatitis: a systematic review and meta-analysis.

BACKGROUND: The effect of immunonutrition is controversial compared to standard supplementation with respect to the management of patients with acute pancreatitis. METHODS: An online literature search on four databases (PubMed, Cochrane, Embase and Web of Science) was performed to identify all of the randomised controlled trials assessing the effects of enteral or parenteral immunonutrition in acute pancreatitis. A fixed or random effects model was chosen using revman, version 5.3 (https://revman.cochrane.org). The count data were analysed using the risk ratio (RR) and 95% confidence interval (CI). RESULTS: Five hundred and sixty-eight patients were included via our search in which 14 articles matched our criteria for enrolling the meta-analysis. Immunonutrition significantly reduced the risk of organ failure (RR = 0.42; 95% CI = 0.26-0.70, P = 0.0008), infectious complications (RR = 0.78; 95% CI = 0.62-0.99; P = 0.04) and mortality (RR = 0.37; 95% CI = 0.21-0.66; P = 0.006). Length of hospital stay was also shorter in patients who received immunonutrition (mean difference = -1.73 days; 95% CI = -2.36 to -1.10; P < 0.00001). Total interventions of patients were decreased (RR = 0.73; 95% CI = 0.55-0.97; P = 0.03). Body mass index in patients with immunonutrition was reduced more than standard nutrition (mean difference = -2.00; 95% CI = -3.96 to -0.04; P = 0.05). CONCLUSIONS: Immunonutrition support such as glutamine and ω-3 fatty acids is potentially beneficial with respect to improving clinical outcomes in patients with acute pancreatitis.

Serum hepatitis B surface antigen correlates with fibrosis and necroinflammation: A multicentre perspective in China.

The kinetics of serum hepatitis B surface antigen (HBsAg) during the natural history of hepatitis B virus (HBV) infection has been studied, but the factors affecting them remain unclear. We aimed to investigate the factors affecting HBsAg titres, using data from multicentre, large-sized clinical trials in China. The baseline data of 1795 patients in 3 multicentre trials were studied, and the patients were classified into 3 groups: hepatitis B early antigen (HBeAg)-positive chronic HBV infection (n = 588), HBeAg-positive chronic hepatitis B (n = 596), and HBeAg-negative chronic hepatitis B (n = 611). HBsAg titres in the different phases were compared, and multiple linear progression analyses were performed to investigate the implicated factors. HBsAg titres varied significantly in different phases (P = .000), with the highest (4.60 log10 IU/mL [10%-90% confidence interval: 3.52 log10 IU/mL-4.99 log10 IU/mL]) in patients with HBeAg-positive chronic HBV infection. In all phases, age and HBV DNA were correlated with serum HBsAg level. In HBeAg-positive chronic hepatitis B patients, a negative correlation between HBsAg titres and fibrosis stage was observed. Alanine amonitransferase or necroinflammatory activity was also correlated with HBsAg titres in HBeAg-negative chronic hepatitis B patients. In conclusion, decreased HBsAg titres may be associated with advancing fibrosis in HBeAg-positive chronic hepatitis B patients or increased necroinflammation in those with HBeAg-negative chronic hepatitis B. Our findings may help clinicians better understand the kinetics of HBsAg and provide useful insights into the management of this disease.

Content and distribution of different phosphorus forms in broiler chickens.

To understand the background value of phosphorus in chickens, the quantitative distribution of different phosphorus forms, including total phosphorus (TP), free phosphate (FP) and phospholipid (PL), in viscera, blood and bones of broiler chickens was investigated. Results showed that phosphorus contents exhibited significant differences in different parts of chickens. TP content of breast and thigh meat was over 5.0 g/kg, in which most of the phosphorus was in the form of water-soluble phosphates. TP content in viscera was higher than that in meat, and spleen was observed to contain the highest amount of phosphorus (10.0 g/kg). In all tested organs, FP and PL contents in liver were the highest, ranging between 1207-1989 and 81-369 mg/kg respectively. TP content in chicken bone was in the range of 52,716-136,643 mg/kg, and FP content in the bone was relatively lower than that in chicken meat.

5-aminolevulinic acid combined with sodium ferrous citrate ameliorates H2O2-induced cardiomyocyte hypertrophy via activation of the MAPK/Nrf2/HO-1 pathway.

Hydrogen peroxide (H2O2) causes cell damage via oxidative stress. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that can protect cardiomyocytes against oxidative stress. In this study, we investigated whether the heme precursor 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) could protect cardiomyocytes from H2O2-induced hypertrophy via modulation of HO-1 expression. HL-1 cells pretreated with/without 5-ALA and SFC were exposed to H2O2 to induce a cardiomyocyte hypertrophy model. Hypertrophy was evaluated by planar morphometry, (3)H-leucine incorporation, and RT-PCR analysis of hypertrophy-related gene expressions. Reactive oxygen species (ROS) production was assessed by 5/6-chloromethyl-2',7'-ichlorodihydrofluorescein diacetate acetylester. HO-1 and nuclear factor erythroid 2-related factor 2 (Nrf2) protein expressions were analyzed by Western blot. In our experiments, HL-1 cells were transfected with Nrf2 siRNA or treated with a signal pathway inhibitor. We found several results. 1) ROS production, cell surface area, protein synthesis, and expressions of hypertrophic marker genes, including atrial natriuretic peptide, brain natriuretic peptide, atrial natriuretic factor, and ß-myosin heavy chain, were decreased in HL-1 cells pretreated with 5-ALA and SFC. 2) 5-ALA and SFC increased HO-1 expression in a dose- and time-dependent manner, associated with upregulation of Nrf2. Notably, Nrf2 siRNA dramatically reduced HO-1 expression in HL-1 cells. 3) ERK1/2, p38, and SAPK/JNK signaling pathways were activated and modulate 5-ALA- and SFC-enhanced HO-1 expression. SB203580 (p38 kinase), PD98059 (ERK), or SP600125 (JNK) inhibitors significantly reduced this effect. In conclusion, our data suggest that 5-ALA and SFC protect HL-1 cells from H2O2-induced cardiac hypertrophy via activation of the MAPK/Nrf2/HO-1 signaling pathway.

Permanent acceptance of mouse cardiac allografts with CD40 siRNA to induce regulatory myeloid cells by use of a novel polysaccharide siRNA delivery system.

The CD40/CD154 co-stimulatory pathway is crucial in alloimmune response. We developed a novel small interfering RNA (siRNA) delivery system with a poly-dA extension at the 5'-end of the siRNA sense strand that was stably incorporated into 1,3-ß-glucan (schizophyllan, SPG). This was captured and incorporated into dendritic cells (DCs) through its receptor, Dectin-1, specifically silencing CD40 genes (siCD40) to exert immunoregulatory activity. siCD40/SPG-treated CBA mice permanently accepted B10 fully mismatched cardiac allografts. Consistent with graft survival, the infiltration of CD4(+), CD8(+) T cells into the graft was lower, and that the numbers of CD40(low)CD11c(+) DCs cells and CD4(+)Foxp3(+)cells were increased in both the graft and in the recipient spleen. In addition, naive CBA recipients given an adoptive transfer of splenocytes from the primary recipients with siCD40/SPG accepted a heart graft from donor-type B10, but not third-party Balb/c mice. In conclusion, the treatment with siCD40/SPG targeting DCs could generate antigen-specific Tregs, resulting in the permanent acceptance of mouse cardiac allografts. These findings have important implications for clarifying the mechanism underlying the induction of tolerance in DCs, and also highlight the potential of immunomodulation and the feasibility of siRNA-based clinical therapy in the transplantation field.

Influence of sirolimus-induced TGF-ß secretion on mouse Treg cell proliferation.

We examined the effects of co-culturing CD4+ CD25+ Treg cells with sirolimus or cyclosporin A on Treg cell proliferation and differentiation and on transforming growth factor-ß (TGF-ß) and Foxp3 expression. CD4+ CD25+ Treg cells were harvested from mononuclear cells of spleens of C57BL/6 mice using immunomagnetic beads and divided into control, sirolimus, and cyclosporine groups. Following a 96-h co-culture, Treg cells were assayed by flow cytometry. FoxP3 and TGF-ß mRNA levels and secretion were assayed by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Smad protein of the TGF-ß signaling pathway was assayed by western blot and its effect on CD4+ CD25+ FoxP3+ Treg cell proliferation was determined. Sirolimus-promoted differentiation and proliferation was examined using a TGF-ß neutralizing antibody. Sirolimus-treated CD4+ T cell TGF-ß secretion increased 2.5X over control levels (P < 0.01), but that of the cyclosporine group decreased marginally (P > 0.05). The CD4+ cell proportion decreased significantly (41.25 vs 69.22%, P < 0.01) and slightly (65.21 vs 69.22, P > 0.05) in the cyclosporine and sirolimus groups, respectively. T cell Foxp3 mRNA expression was significantly higher in the sirolimus-treated than in the cyclosporine (53.7 vs 40.2%, P < 0.05) and control groups (P < 0.01), but was significantly lower in the cyclosporine group than in controls (23.6 vs 40.2%, P < 0.01). Overall, sirolimus promoted CD4+ CD25+ Treg cell proliferation and growth in vitro, whereas cyclosporin A inhibited proliferation. Sirolimus might promote CD4+ CD25+ FoxP3+ regulatory T cell proliferation by inducing TGF-ß secretion in vivo.

Recombinant VP1 protein of duck hepatitis virus 1 expressed in Pichia pastoris and its immunogenicity in ducks.

The VP1 gene of duck hepatitis virus type 1 (DHV-1) strain VJ09 was amplified by reverse transcription PCR from the liver of a duckling with clinical symptoms of viral hepatitis. The resulting VP1 cDNA was 720 bp in length and encoded a 240-amino-acid protein. In VP1 gene-based phylogenetic analysis, the VJ09 strain grouped with DHV-1 genotype C. The VP1 gene was inserted into the expression vector pPICZαA and expressed in Pichia pastoris. The expressed VP1 protein was purified and identified by western blot analysis. To evaluate the recombinant VP1's immunogenic potential in ducklings, the antibodies raised in the immunized ducklings were titrated by ELISA, and lymphocyte proliferation and virus neutralization assays were performed. The results show that the recombinant VP1 protein induced a significant immune response in ducklings and this could be a candidate for the development of a subunit vaccine against DHV-1 genotype C.

Clinical Feasibility of Using Single-isocentre Non-coplanar Volumetric Modulated Arc Therapy Combined with Non-coplanar Cone Beam Computed Tomography in Hypofractionated Stereotactic Radiotherapy for Five or Fewer Multiple Intracranial Metastases.

AIMS: To evaluate the clinical feasibility of single-isocentre non-coplanar volumetric modulated arc therapy (NC-VMAT) with non-coplanar cone beam computed tomography (NC-CBCT) in hypofractionated stereotactic radiotherapy (HSRT) for five or fewer multiple brain metastases. MATERIALS AND METHODS: Ten patients with multiple brain metastases who underwent single-isocentre NC-VMAT HSRT with limited couch rotations (within ±45°) and NC-CBCT with a limited scanning range (150-200°) were included in the current analysis. Conventional single-isocentre coplanar VMAT (C-VMAT) plans were generated and compared with NC-VMAT plans. The intracranial response and toxicities of single-isocentre NC-VMAT HSRT were also evaluated. RESULTS: Compared with C-VMAT, NC-VMAT generated better target conformity (P < 0.05), a lower gradient index (P < 0.05) and better normal brain tissue sparing, especially for volume ≥12 Gy, with a median reduction of 12.65 cm3. For 45° couch rotation, NC-CBCT produced sufficient image quality to differentiate bony anatomy, even with a 150° scanning range, which could be successfully used for patient set-up correction. After NC-CBCT, 57.1% of the measured non-coplanar set-up errors exceeded the threshold value. The median gamma passing rate of NC-VMAT was higher than that of C-VMAT plans (P < 0.05). The non-coplanar beam of NC-VMAT with NC-CBCT corrections exhibited superior gamma passing rate to that without NC-CBCT corrections. The intracranial objective response rate and disease control rate for all patients were 80% (8/10) and 100% (10/10), respectively, and the most common toxicities were headache (20%) and dizziness (20%). CONCLUSION: NC-VMAT with limited couch rotation (within ±45°) combined with NC-CBCT with a limited scanning range (150-200°) markedly improves the plan quality and set-up accuracy in single-isocentre multiple-target HSRT.

Can Optical Surface Imaging Replace Non-coplanar Cone-beam Computed Tomography for Non-coplanar Set-up Verification in Single-isocentre Non-coplanar Stereotactic Radiosurgery and Hypofractionated Stereotactic Radiotherapy for Single and Multiple Brain Metastases?

AIMS: To conduct a direct comparison regarding the non-coplanar positioning accuracy between the optical surface imaging system Catalyst HDTM and non-coplanar cone-beam computed tomography (NC-CBCT) in intracranial single-isocentre non-coplanar stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (HSRT). MATERIALS AND METHODS: Twenty patients with between one and five brain metastases who underwent single-isocentre non-coplanar volumetric modulated arc therapy (NC-VMAT) SRS or HSRT were enrolled in this study. For each non-zero couch angle, both Catalyst HDTM and NC-CBCT were used for set-up verification prior to beam delivery. The set-up error reported by Catalyst HDTM was compared with the set-up error derived from NC-CBCT, which was defined as the gold standard. Additionally, the dose delivery accuracy of each non-coplanar field after using Catalyst HDTM and NC-CBCT for set-up correction was measured with SRS MapCHECKTM. RESULTS: The median set-up error differences (absolute values) between the two positioning methods were 0.30 mm, 0.40 mm, 0.50 mm, 0.15°, 0.10° and 0.10° in the vertical, longitudinal, lateral, yaw, pitch and roll directions, respectively. The largest absolute set-up error differences regarding translation and rotation were 1.5 mm and 1.1°, which occurred in the longitudinal and yaw directions, respectively. Only 35.71% of the pairs of measurements were within the tolerance of 0.5 mm and 0.5° simultaneously. In addition, the non-coplanar field with NC-CBCT correction yielded a higher gamma passing rate than that with Catalyst HDTM correction (P < 0.05), especially for evaluation criteria of 1%/1 mm with a median increase of 12.8%. CONCLUSIONS: Catalyst HDTM may not replace NC-CBCT for non-coplanar set-up corrections in single-isocentre NC-VMAT SRS and HSRT for single and multiple brain metastases. The potential role of Catalyst HDTM in intracranial SRS/HSRT needs to be further studied in the future.

Different sedation profiles with ciprofol compared to propofol represented by objective sedation level assessments by BIS and its acute hemodynamic impact in 3 escalated doses of ciprofol and propofol in healthy subjects: a single-center, open-label, randomized, 2-stage, 2-way crossover trial.

OBJECTIVE: To compare the sedation profiles and the pharmacokinetic, pharmacodynamic and safety characteristics of ciprofol and propofol at 3 escalated dose levels in healthy Chinese male subjects. PATIENTS AND METHODS: Eighteen subjects were planned to be enrolled into 3 dose groups in turn: group 1 (ciprofol-0.4 mg/kg vs. propofol-2.0 mg/kg), group 2 (ciprofol-0.6 mg/kg vs. propofol-3.0 mg/kg) and group 3 (ciprofol-0.8 mg/kg vs. propofol-4.0 mg/kg). They were randomly assigned into a ciprofol or propofol group in a ratio of 1:1, with sequences of ciprofol-propofol or propofol-ciprofol, separated with a washout period of at least 48 h. RESULTS: A total of 19 subjects were enrolled and 18 completed the trial. The median time to being fully alert after induction by ciprofol was longer than for propofol. The bispectral index (BIS) recovered significantly slower with ciprofol than with propofol 5 min and 10 min after reaching its lowest points. Systolic blood pressure (group 1: p=0.041; group 2: p=0.015; group 3: p=0.004) and mean arterial pressures (group 1: p=0.026; group 2: p=0.015; group 3: p=0.004) measured by the area under the curve below the baseline during the 2 min after induction were significantly less for ciprofol compared to propofol, but a significant change in diastolic blood pressure was only observed in group 3 (p=0.002). Eighteen (100.0%) subjects experienced 47 ciprofol-related treatment emergent adverse events (TEAEs) and 17 (94.4%) subjects had 54 propofol-related TEAEs, which were mainly hypotension, involuntary movements, respiratory depression, and pain at the injection site with severity of grade 1 or 2. CONCLUSIONS: Ciprofol may be well tolerated at higher doses in the clinical practice and exhibited significantly different sedation profiles to propofol.

[Establishment of "Chinese way" for trauma and burn management based on the engineered growth factors research and application].

Innovation and translation application are important topics that have been discussed repeatedly in national community of science and technology in recent years. We do a systemic review about the research and development history of growth factors, their application in trauma and burn management in China, and the conception and experience about the establishment of "Chinese way" for trauma and burn management in the process of constructing a disciplinary system for wound treatment with Chinese characteristics. It is our hope that these precious experiences will provide references and inspiration to our peers, especially the young generation in their research.

A laparoscopic approach to ventriculoperitoneal shunt placement with a novel fixation method for distal shunt catheter in the treatment of hydrocephalus.

BACKGROUND: The laparoscopically assisted ventriculoperitoneal (VP) shunt has been widely used in the clinical treatment of hydrocephalus for its simplicity and reliability. Despite significant improvements in shunt procedures, shunt complications remain common. Our clinical experiences suggest that the fixation of the distal (peritoneal) shunt catheter using threads and hemoclips may partially contribute to complications of the distal shunt including obstruction of the shunt and infection. In this study, we explored a novel fixation method in the laparoscopically assisted VP shunt with use of the liver falciform ligament as a natural support for fixation of the distal shunt catheter. METHODS: 10 patients with hydrocephalus underwent laparoscopically assisted VP shunt and the distal shunt catheter was placed into the hepatodiaphragmatic space and the catheter was traversed through 2-3 drilled holes in the liver falciform ligament without using any artificial material for fixation. RESULTS: In all the patients who received surgery with the adopted new procedure the clinical symptoms were alleviated. The size of cerebral ventricles returned to normal after 1 week. The distal catheters were in the hepatodiaphragmatic space in 9 of 10 patients, while in 1 patient it migrated to the peritoneal cavity underneath the liver. All the 9 patients were followed up for 1 year and no surgery-related catheter obstructions and infections were observed. CONCLUSIONS: The modified laparoscopically assisted VP shunt in the treatment of hydrocephalus with fixation of the distal shunt catheter to a natural anatomic structure could potentially reduce the necessity of repeat surgery for addressing the complications caused by catheter obstruction and infections, reduce the chance of adhesions, and would be of benefit to those patients who need future revisions.

PI-3K/AKT signal pathway modulates vascular smooth muscle cells migration under cyclic mechanical strain.

BACKGROUND: The migration of vascular smooth muscle cells (VSMCs), exposed to altered mechanical strain, contributes to vascular remodeling which is the key event underlying the pathogenesis of vascular diseases such as atherosclerosis and restenosis. Signal transduction pathways in VSMCs activated by mechanical strain that influence cell migration remain unclear. Herein, we provide evidence that higher mechanical strain enhances VSMCs migration, which is mediated, at least in part, through Akt/protein kinase B (PKB) included pathway. MATERIAL AND METHODS: VSMCs were exposed to mechanical strain at 15 % elongation and 5 % elongation, 60 cycles/min using FX-4000T system from at least three independent experiments. VSMCs were incubated with 100nmol/L wortmannin, 10 uM Akti, 10 uM PD98059 and 10 uM SB202190 prior to strain for inhibitor studies, respectively. VSMCs migration,the activation of Akt/PKB, the inhibition of STI-571 and immunofluorescence for actin fibers were detected, respectively. Activation of the Akt pathway and inhibition of STI-571 were assessed with the Western blot technique. RESULTS: (1) Our study demonstrated that VSMCs migration under 15 % strain was facilitated compared with 5 % strain (15 % strain vs. 5 % strain, P < 0.01); and the activation of P-Akt was enhanced compared to the control (15 % strain and 5 % strain vs. static control, P < 0.01, respectively); whereas wortmannin could markedly inhibit serine/threonine kinase Akt/PKB phosphorylation, reduced VSMCs migration following higher mechanical strain stimulation (15 % strain + wortmannin vs. 15 % strain, P < 0.01). Immunofluorescence revealed actin rearrangement, which could also be inhibited by wortmannin in VSMCs induced by cyclic strain. (2) Akti significantly inhibited VSMCs migration (15 % strain + Akti and 5 % strain + Akti vs. static control, P < 0.05,respectively), neither PD98059 nor SB202190 inhibited VSMCs migration (5 % strain + PD98059 or +SB202190 vs. static control, P < 0.01; 15 % strain + PD98059 or +SB202190 vs. static control P < 0.01,respectively). (3) Higher mechanical strain inhibits STI-571 activity in VSMCs (5 % strain vs. static control, P < 0.05; 15 % strain vs. static control, P < 0.01). CONCLUSIONS: Our data shows that higher mechanical strain activated-Akt/PKB is required for VSMC migration and probably functions through its effects on actin rearrangement.

PD-1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft.

The programmed death-1 (PD-1)/B7-H1 pathway acts as an important negative regulator of immune responses. We herein investigated the role of the PD-1/B7-H1 pathway in establishing an immunological spontaneous tolerance status in mouse liver allografting. B7-H1 is highly expressed on the donor-derived tissue cells and it is also associated with the apoptosis of infiltrating T cells in the allografts. Strikingly, a blockade of the PD-1/B7-H1 pathway via anti-B7-H1mAb or using B7-H1 knockout mice as a donor led to severe cell infiltration as well as hemorrhaging and necrosis, thus resulting in mortality within 12 days. Furthermore, the expression of the FasL, perforin, granzyme B, iNOS and OPN mRNA in the liver allografts increased in the antibody-treated group in comparison to the controls. Taken together, these data revealed that the B7-H1 upregulation on the tissue cells of liver allografts thus plays an important role in the apoptosis of infiltrating cells, which might play a critical role of the induction of the spontaneous tolerance after hepatic transplantation in mice.

Regenerated host axons form synapses with neurons derived from neural stem cells transplanted into peripheral nerves.

It is reported that neural stem cells (NSC) can arrest denervated muscle atrophy and promote nerve regeneration when transplanted into injured peripheral nerves, and that regenerated host axons can form synapses with transplanted and differentiated NSC. In this study, F344 rat nerve segments and F344 rat NSC were transplanted into host green fluorescence protein (GFP) transgenic F344 rats. This allowed transplanted F344 rat tissue to be used as a nonluminous background for the clear visualization of regenerated host GFP axons. Regenerated host axons grew into the transplanted F344 nerve segment 2 weeks after nerve anastomosis. Immunohistochemical staining and confocal microscope analysis revealed that regenerated host axons formed synapses with NSC-derived neurons. The findings confirmed that regenerated peripheral axons form synapses with neurons in peripheral nerves, possibly forming the basis for clinical application in peripheral nerve injury.

[Seizing the day and living it to the full: thirty years' independent innovation of growth factors and wound repair].

Since the discovery of fibroblast growth factor (FGF) in the early 20th century, the multiple regulatory function of FGF has been found in development, metabolic regulation and tissue regeneration. Although FGF has the potential in wound healing of clinical practice, several technical bottlenecks occurred in the development of FGF drugs. Since 1992, our team has had many technical breakthroughs and developed some class Ⅰ new drugs of FGF and medical device. At the same time, we further investigated the network of metabolic regulation and signal transduction of FGF. All the efforts were for the purpose of the development of FGF new drugs and bringing benefit to patients.

Tri-domain proteins 27 reduce inflammation and apoptosis in HK-2 cells and protect against acute kidney injury in mice.

OBJECTIVE: The kidney is one of the most commonly damaged organs in sepsis. Acute kidney injury (AKI) induced by sepsis is a clinically dangerous disease with a high mortality rate. Therefore, it is particularly important to find a way to prevent and treat sepsis-induced AKI. MATERIALS AND METHODS: Human renal tubular epithelial cell line (HK-2) and 8-week-old C57BL/6 mice were used. Lipopolysaccharide (LPS) was used to induce HK-2 cell injury and mouse AKI. Lentiviruses overexpressing TRIM27 were constructed to increase TRIM27 expression in HK-2 cells. Then, the effects of TRIM27 on the inflammation and apoptosis of HK-2 cells were analyzed, and those of TRIM27 recombinant protein on AKI in mice was detected by immunohistochemical staining and Western blot. RESULTS: It was found that TRIM27 overexpression reduced the expressions of inflammatory factors and signaling molecules in apoptosis-related pathways in HK-2 cells, but increased the ratio of Bcl-2 to Bax in HK-2 cells, indicating the anti-apoptotic effect of TRIM27. Toll-like receptor 4 (TLR4)/NF-κB signaling pathway is an important mechanism of LPS mediated renal injury, and TRIM27 overexpression in HK-2 cells significantly inhibited the activity of TLR4/NF-κB signaling pathway. In addition, AKI was significantly relieved in mice treated with TRIM27 recombinant. CONCLUSIONS: TRIM27 exerts anti-inflammatory and anti-apoptotic effects by inhibiting the TLR4/NF-κB signaling pathway, which effectively alleviates LPS-induced HK-2 cell damage and mouse AKI.

Effects of dexmedetomidine on sepsis-induced liver injury in rats.

OBJECTIVE: To explore the effect of dexmedetomidine (DEX) on sepsis-induced liver injury in rats and the mechanism of action, providing certain references for the prevention and treatment of sepsis-induced liver injury in clinical practice. MATERIALS AND METHODS: A total of 60 male Sprague Dawley (SD) rats were randomly divided into 3 groups, namely sham operation group (Sham group, n=20), sepsis-induced liver injury group [lipopolysaccharides (LPS) group, n=20], and sepsis-induced liver injury + DEX group (LPS + DEX group, n=20) using a random number table. Rat models of sepsis-induced liver injury were established by intraperitoneal injection of LPS (10 mg/kg), and at the same time, DEX was intragastrically injected at a dose of 50 µg/kg. After 24 h, the survival analysis curves of each group of rats were plotted. Meanwhile, the levels of liver function indexes and oxidative stress markers were measured at 12 h in each group of rats. Hematoxylin-eosin (H&E) staining assay was carried out to detect the morphological changes of rat liver cells in each group. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) staining assay was performed to detect the apoptosis level in rat liver tissues in each group. In addition, the expression level of Caspase 3 in three groups of rats was measured through immunohistochemical staining assay. Lastly, the effect of DEX on the protein expression of extracellular signal-regulated kinases 1/2 (ERK1/2) in liver tissues was detected via Western blotting. RESULTS: DEX significantly improved liver dysfunction induced by LPS and raised the 24 h-survival rates of rats (p<0.05). Besides, H&E staining results showed that DEX clearly relieved the pathological damage of rat liver cells caused by LPS. In comparison with LPS group, LPS + DEX group displayed more neatly arranged liver cells, less degradation and necrosis, and evidently attenuated cellular edema. Immunohistochemistry results revealed that DEX significantly reversed the increase in Caspase 3 expression resulting from LPS. The results of the TUNEL staining assay showed that DEX clearly inhibited the apoptosis of rat liver cells induced by LPS. The results of Western blotting revealed that DEX notably reversed the decrease of phosphorylated ERK1/2 (p-ERK1/2) in rat liver tissues compared with LPS group. CONCLUSIONS: DEX is able to markedly relieve LPS-induced liver injury in rats and the underlying mechanism may be related to the activation of the ERK1/2 signaling pathway.

The role novel targeted agents in the treatment of previously treated patients with advanced urothelial carcinoma (UC): a meta-analysis.

OBJECTIVE: Second-line treatment options for advanced urothelial carcinoma (UC) patients are limited. We aim to investigate the efficacy and toxicities of novel targeted agents (TAs) as salvage treatment for advanced UC by using a meta-analysis. MATERIALS AND METHODS: Relevant trials published from 1994 to 2017 were identified by an electronic search of public databases. Demographic data, treatment regimens, objective response rate (ORR), disease control rate (DCR), median progression-free and overall survival (PFS, OS) and grade 3/4 toxicities were extracted and analyzed using open Meta-Analyst software version 4.16.12 (Tufts University, URL http://tuftscaes.org/open_meta/). RESULTS: Eleven trials with 1,630 previously treated UC patients were included for analysis. The pooled ORR, DCR and 1-year OS for single targeted agent in pre-treated UC patients was 10.7% (95% CI: 10.7-19.6%), 33.2% (95% CI: 25-41.4%), and 31% (95%: 23.6-39.4%), respectively. Sub-group analysis based on specific targeted agents showed that the efficacy of immune checkpoints inhibitors (ICIs) was significantly higher than that of small molecular tyrosine-kinase inhibitors (TKIs) concerning ORR and 1-year OS. Also, a meta-analysis of three randomized controlled trials showed that the use of TAs in advanced UC patients significantly improved ORR, but not for DCR. As for grade 3 and 4 toxicities, more incidences of severe anemia, fatigue, and diarrhea were observed in the TKIs group than in ICIs group, but not for hypertension. CONCLUSIONS: Our findings support the use of immune checkpoints inhibitors, but not for tyrosine kinase inhibitors as salvage treatment for previously treated UC patients due to its potential survival benefits.