Activated hedgehog gene pattern correlates with dismal clinical outcome and tumor microenvironment heterogeneity in hepatocellular carcinoma.

Background: Activation of the Hedgehog signaling pathway is linked to the initiation and development of human hepatocellular carcinoma (HCC). However, its impact on clinical outcomes and the HCC microenvironment remains unclear. Methods: We performed comprehensive analyses of Hedgehog pathway genes in a large cohort of HCC patients. Specifically, we utilized univariate Cox regression analysis to identify Hedgehog genes linked to overall survival, and the LASSO algorithm was used to construct a Hedgehog-related gene pattern. We subsequently examined the correlation between the Hedgehog pattern and the HCC microenvironment employing the CIBERSORT and ssGSEA algorithms. Furthermore, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and the anti-PD-L1 treatment dataset (IMvigor210) are used to evaluate the clinical response of the Hedgehog pattern in predicting immune checkpoint inhibitors. Results: We found that the Hedgehog activation score (HHAS), a prognostic score based on 11 Hedgehog genes, was significantly associated with HCC patient survival. Patients exhibiting high HHAS experienced markedly reduced survival rates compared to those with low HHAS, and HHAS emerged as an independent prognostic factor for HCC. Functional enrichment analysis unveiled the association of the HHAS phenotype with functions related to the immune system, and further investigation demonstrated that HCC patients exhibiting low HHAS displayed elevated levels of anti-tumor immune activation in CD8+ T cells, while high HHAS were linked to immune escape phenotypes and increased infiltration of immune suppressive cells. In addition, in the Immune Checkpoint Inhibitor (ICI) cohort of IMvigor210, patients with higher HHAS had worse ICI treatment outcomes and shortened survival time, indicating that the HHAS is a useful indicator for predicting patient response to immunotherapy. Conclusions: In summary, our study offers valuable insights for advancing research on Hedgehog and its impact on tumor immunity, which provides an opportunity to optimize prognosis and immune therapy for HCC.

Synthesis and Study of Photothermal Properties of a Mixed-Valence Nanocluster CuI/CuII with Strong near-Infrared Optical Absorption Supported by 4-tert-Butylcalix[4]arene Ligand.

The first mixed-valence nanocluster CuI/CuII with the highest percentage of CuII ions was synthesized by using 4-tert-butylcalix[4]arene (Calix4), with the formula DMF2⊂[(CO3)2-@CuII6CuI3(Calix4)3Cl2(DMF)5(H3O)]•DMF (1), as a photothermal nanocluster. Its structure was characterized using single-crystal X-ray diffraction, Fourier-transform infrared spectroscopy, and powder X-ray diffraction. In addition, the charge state and chemical composition of the nanocluster were determined using electrospray ionization spectrometry and X-ray photoelectron spectroscopy (XPS) spectrum. The results of the XPS and X-ray crystallography revealed that there are two independent CuII and CuI centers in nanocluster 1 with the relative abundances of 66.6 and 33.3% for CuII and CuI, respectively. The nanocluster contains three four-coordinated CuI ions with a square-planar geometry and six five-coordinated CuII ions with a square pyramid geometry. The nanocluster shows strong near-infrared optical absorption in the solid state and excellent photothermal conversion ability (the equilibrium temperature ∼78.2 °C) with the light absorption centers in 286-917 nm over previous reported pentanucleus CuI4CuII clusters and CuII compounds.

Construction of eight mixed-valence pentanuclear CuI4CuII clusters using ligands with inhomogeneous electron density distribution: synthesis, characterization and photothermal properties.

To enhance light absorption in the visible region for the utilization of sunlight, eight mixed-valence polynuclear CuI/CuII clusters have been synthesized for evaluating their photothermal conversion performance. They are fabricated considering the ligand's electron density distribution inhomogeneity using 1,2,3-triazole (3N) or tetrazole (4N) and different mono-phosphine ligands. We report here the synthesis, crystal structure, characterization, optical properties, and photothermal conversion performance of these clusters. X-ray crystal structures reveal that those pentanuclear clusters are neutral clusters with octahedrally-coordinated copper(II) ion being surrounded by four tetrahedrally coordinated copper(I) ions. Interestingly, with the introduction of the mixed-valence centers, these compounds show additional light absorption centers in 350-600 nm via the IVCT transition mechanism, compared with our previously reported Cu(II) compounds. These clusters show excellent photothermal conversion performance, with an average equilibrium temperature (∼60 °C) and a temperature increment (∼40 °C), which are also superior to Cu(II) complexes (the average equilibrium temperature ∼55 °C). This work proves that it is possible to design and prepare new polynuclear mixed-valence CuI/CuII clusters for achieving high-performance photothermal conversion materials.

Propofol maintains Th17/Treg cell balance and reduces inflammation in rats with traumatic brain injury via the miR­145­3p/NFATc2/NF­κB axis.

Propofol is a commonly used intravenous anesthetic. The aim of the study was to examine the mechanism of propofol in traumatic brain injury (TBI) by regulating interleukin (IL)­17 activity and maintaining the Th17/Treg balance. A rat model with moderate TBI was established using the weight­drop method. Rats with TBI were regularly injected with propofol and their brain injuries were monitored. The peripheral blood of rats was collected to measure the Th17/Treg ratio. MicroRNA (miR)­145­3p expression was detected in the brain tissues of rats and antagomiR­145­3p was injected into the lateral ventricles of their brains to verify the effect of miR­145­3p on brain injury. The downstream target of miR­145­3p was predicted. The targeting relationship between miR­145­3p and nuclear factor of activated T cells c2 (NFATc2) was confirmed. NFATC2 expression and phosphorylation of NF­κB pathway­related proteins were measured. Propofol alleviated brain injury in rats with TBI and maintained the Th17/Treg balance. Propofol upregulated miR­145­3p expression in rat brains, while the inhibition of miR­145­3p reversed the effect of propofol on brain injury. A binding relationship was observed between miR­145­3p and NFATc2. Furthermore, propofol decreased the phosphorylation of p65 and IκBα, and inhibited activation of the NF­κB pathway in the brains of rats with TBI. In conclusion, propofol maintained Th17/Treg balance and reduced inflammation in the rats with TBI via the miR­145­3p/NFATc2/NF­κB axis.

A single-dose of stellate ganglion block for the prevention of postoperative dysrhythmias in patients undergoing thoracoscopic surgery for cancer: A randomised controlled double-blind trial.

BACKGROUND: New-onset arrhythmias and sleep disturbances are frequently observed during the postoperative period in patients undergoing thoracic surgery. OBJECTIVE: We evaluated the effectiveness of a single-dose stellate ganglion block (SGB) to prevent the occurrence of arrhythmias in patients undergoing thoracic surgery for cancer. DESIGN: Randomised controlled double-blind study. SETTING: Single university hospital. PATIENTS: Ninety patients with lung cancer or oesophagal cancer scheduled for elective video-assisted thoracoscopic surgery were randomly randomised into one of two equal groups (the SGB group and control group, n = 40 each). INTERVENTIONS: Patients received a single dose of 5 ml of 0.5% ropivacaine during ultrasound-guided SGB before induction of general anaesthesia in the SGB group. MAIN OUTCOME MEASURES: Holter ECG was continuously monitored during the first 48 postoperative hours, and sleep state was monitored during the first two postoperative nights. RESULTS: The incidences of postoperative supraventricular tachycardias were lower in the SGB group compared with the control group during the first 48 postoperative hours; 11.6 (5/43) vs. 31.8% (14/44), respectively, P = 0.023 (odds ratio 0.28, 95% confidence interval 0.09 to 0.87). The SGB also prolonged the total sleep time and increased the sleep efficiency during the first two postoperative nights. The duration of stage N2 sleep was longer in the SGB group compared with the control group [28 (interquartile range, 14 to 58) to 94 (interquartile range, 69 to 113) min, P = 0.016] on the first postoperative night. There were no differences in the duration of stage N1 and N3 sleep (P = 0.180, 0.086, respectively) on the first postoperative night, and the duration of stage N1, N2 and N3 sleep (P = 0.194, 0.057, 0.405, respectively) on the second postoperative night between the groups. CONCLUSION: A pre-operative SGB effectively prevented the occurrence of postoperative supraventricular tachycardias and improves the objective sleep quality in patients undergoing thoracic surgery for cancer. TRIAL REGISTRATION NUMBER: ChiCTR-1900023064.

Midazolam prevents sevoflurane-induced death in hippocampal neurons.

Sevoflurane is a widely used anesthetics in surgery and considered as a safe reagent for clinical use. However, recent studies demonstrated that sevoflurane has a neurotoxic effect in central nervous system. Thus, finding ways to alleviate the side effect of sevoflurane is of importance. In this study, we identified the neuroprotective role of midazolam in hippocampal neurons. Midazolam treatment could alleviate the neuronal death and promote the neuronal maturation in hippocampal neurons in vitro. In vivo studies demonstrated that midazolam injection could improve behavioral deficit in sevoflurane-exposed animals. The anti-apoptotic function of midazolam in sevoflurane-exposed neurons was mediated by ERK signaling. Collectively, we elucidated a new role of midazolam in preventing hippocampal neuronal death from sevoflurane exposure, potentially providing a new strategy to resist the neurotoxicity in the clinical application of sevoflurane.

Temporal Profile and Severity Correlation of a Panel of Rat Spinal Cord Injury Protein Biomarkers.

In the USA, there are approximately 12,000 new cases of spinal cord injury (SCI) each year and some 1.2 million people living with paralysis due to SCI. Seven percent of them are paralyzed due to an accident or injury occurring while serving in the military. Here, we report a systematic study on protein biomarker candidates in a rat SCI model with either moderate or severe injury. Tissue, cerebrospinal fluid (CSF), and serum samples were obtained at 4 h, 24 h, and 7 days post-injury. The candidate biomarkers included axonal injury markers αII-spectrin breakdown products (SBDP150/145/120), neuronal cell body injury marker ubiquitin C-terminal hydrolase-L1 (UCH-L1), astrogliosis/astroglial injury markers S100 calcium-binding protein-ß (S100ß), glial fibrillary acidic protein (GFAP) and GFAP breakdown products (GBDPs), demyelination marker myelin basic protein (MBP), axonal injury marker phosphorylated neurofilament-H (pNF-H), and neuroinflammation marker interleukin-6 (IL-6). SBDP150/145, UCH-L1, GFAP, and S100ß were found as acute biomarkers with significantly elevated levels within 24 h. GBDP44, GBDP38, and pNF-H are acute and subacute biomarkers that were found to have increased at 4 h, 24 h, and 7 days. MBP and SBDP120 were considered subacute biomarkers which were only detectable at 7 days post-injury. These results not only allow us to gain important insight into the patho-mechanisms of SCI but also showcase the possibility of using some of the protein biomarkers to track injury severity and disease progression and resolution. These biomarkers can potentially serve as tools that assist therapy development and clinical trials.

The effect of ulinastatin on hyperglycemia in patients undergoing hepatectomy.

BACKGROUND: To identify the effect of ulinastatin (UTI) administration on stress-induced hyperglycemia and acute insulin (INS) resistance experienced by patients undergoing partial hepatectomy. METHODS: Forty-six patients undergoing partial hepatectomy were assigned randomly to the control group (group C) or UTI treatment group (group U). Six cases underwent partial hepatectomy but were not eligible for inclusion. The patients in group U had an intravenous infusion of a total amount of 5000 IU/kg UTI before the induction of anesthesia and at the start of surgery. The patients in group C were given an identical volume of physiological saline in the same manner. Blood samples for the measurement of interleukin-6, cortisol, INS, and glucagon were obtained. Fasting plasma glucose concentration was measured immediately before skin incision (T1), 20 min after the liver lesion was removed (T2), at the end of surgery (T3), as well as on the first (T4) and second mornings after partial hepatectomy (T5). The insulin sensitivity index (ISI) was calculated at these time points. RESULTS: The fasting plasma glucose concentration in group U was significantly lower than that in group C at all time points except for T1. In group U, the insulin sensitivity index was higher, and the levels of interleukin-6, cortisol, and INS were lower than that in group C (P < 0.05). CONCLUSIONS: The data suggest that UTI administration improves perioperative hyperglycemia by inhibiting the inflammatory reaction, as well as excessive release of inflammatory factors, and improves INS resistance.

[Effect of acute hemorrhage on cognitive function of aged spontaneously hypertensive rats].

OBJECTIVE: To investigate the effect of acute blood loss on postoperative cognitive function of aged spontaneously hypertensive rats (SHRs). METHODS: Forty aged male SHRs were randomized into sham hemorrhage group (group A, n=13), 20% hemorrhage group (group B, n=13) and 40% hemorrhage group (group C, n=14). The rats were subjected to acute loss from the femoral artery and subsequent fluid replacement with lactated Ringer's Solution (3 folds of the blood loss volume). All the rats underwent Morris water maze test to assess the visuospatial memory and learning ability, and were then decapitated to observe the pathological changes of the hippocampus. RESULTS: The latency of reference memory in group C was significantly prolonged after the operation (P=0.002), but the working memory and learning capacity showed no significant differences between the 3 groups. Immunochemistry did not reveal significant differences in p-CREB expressions in the hippocampal CA1 region among the groups, but volume reduction of some neurons was noted in the CA1 region in group C. CONCLUSION: Varying degrees of acute hemorrhage can result in different effect on postoperative cognition in aged SHR. Acute hemodilutional anemia to 40% of baseline can cause reference memory impairment with cell volume reduction of the neurons in the hippocampal CA1 region but does not affect the working memory and learning capacity or p-CREB expression.

[Anesthetic management during resection of intratracheal tumor: report of 23 cases].

OBJECTIVE: To summarize our experience in anaesthetic management during the resection of intratracheal tumor. METHODS: A retrospective analysis of the anaesthetic management was conducted in 23 cases of intratracheal tumor resection. The anaesthetic methods were determined according to the location of tumor, the degree of tracheal obstruction and the surgical procedures. RESULTS: No severe complications occurred in relation to the anesthetic procedures. During the operation, the saturation of pulse oxygen (SpO(2)) transiently decreased to below 90 % in 5 cases (21.7 %) but recovered to normal level by aspiration of airway secretions and/or lung inflation. Seventeen patients (73.9 %) were extubated after the operation and returned to the ward safely, while another 6 (26.1 %) were sent to intensive care unit and extubated within 24 h. CONCLUSION: Case-specific anaesthetic plan is necessary before the operation, and it is crucial to maintain good ventilation without interfering with the surgical procedures during the operation.