Study of spatiotemporal evolution of coupled airflow-gas-dust multi-field diffusion at low-gas tunnel.

The increasing level of mechanization in coal mining means more dust and gas are generated during excavation operations in tunnels. The high concentrations of dust and gas severely affect production efficiency and the physical and mental health of workers. Here, Ansys Fluent simulations were performed to derive the spatiotemporal evolution of coupled airflow-dust-gas diffusion in a low-gas excavation face. The aim was to optimize pollution control by determining the optimal duct distance, L, from the working face in the excavation tunnel. Our results showed that the airflow field affects the coupled diffusion and transport of dust and gas. According to a comparison of the effects of different duct distances from the working face, when L = 6 m, the average dust concentration in the tunnel is low (257.6 mg/m3), and the average gas concentration in the tunnel is 0.28 %, which does not exceed the safety limit. Accordingly, the optimal distance of the duct for pollution control is 6 m. The results of field measurements supported the validity of the simulation. Our findings can be used to improve the air quality in tunnels, thereby keeping miners safe and the working area clean.

Multimodal image fusion-assisted endoscopic evacuation of spontaneous intracerebral hemorrhage.

PURPOSE: Although traditional craniotomy (TC) surgery has failed to show benefits for the functional outcome of intracerebral hemorrhage (ICH). However, a minimally invasive hematoma removal plan to avoid white matter fiber damage may be a safer and more feasible surgical approach, which may improve the prognosis of ICH. We conducted a historical cohort study on the use of multimodal image fusion-assisted neuroendoscopic surgery (MINS) for the treatment of ICH, and compared its safety and effectiveness with traditional methods. METHODS: This is a historical cohort study involving 241 patients with cerebral hemorrhage. Divided into MINS group and TC group based on surgical methods. Multimodal images (CT skull, CT angiography, and white matter fiber of MRI diffusion-tensor imaging) were fused into 3 dimensional images for preoperative planning and intraoperative guidance of endoscopic hematoma removal in the MINS group. Clinical features, operative efficiency, perioperative complications, and prognoses between 2 groups were compared. Normally distributed data were analyzed using t-test of 2 independent samples, Non-normally distributed data were compared using the Kruskal-Wallis test. Meanwhile categorical data were analyzed via the Chi-square test or Fisher's exact test. All statistical tests were two-sided, and p < 0.05 was considered statistically significant. RESULTS: A total of 42 patients with ICH were enrolled, who underwent TC surgery or MINS. Patients who underwent MINS had shorter operative time (p < 0.001), less blood loss (p < 0.001), better hematoma evacuation (p = 0.003), and a shorter stay in the intensive care unit (p = 0.002) than patients who underwent TC. Based on clinical characteristics and analysis of perioperative complications, there is no significant difference between the 2 surgical methods. Modified Rankin scale scores at 180 days were better in the MINS than in the TC group (p = 0.014). CONCLUSIONS: Compared with TC for the treatment of ICH, MINS is safer and more efficient in cleaning ICH, which improved the prognosis of the patients. In the future, a larger sample size clinical trial will be needed to evaluate its efficacy.

Giving birth after fertility-sparing treatment for primary leiomyosarcoma of the fallopian tube.

Primary leiomyosarcoma of the fallopian tube (PLFT) is an extremely rare gynecological malignancy that has only been described in case reports. Fertility-sparing treatment for PLFT has not been reported previously. A 24-year-old nulligravida woman was diagnosed with stage IC1 PLFT in the right fallopian tube after experiencing right lower quadrant pain for 2 weeks. She underwent laparoscopic right salpingectomy to preserve fertility followed by adjuvant chemotherapy with gemcitabine/docetaxel. She subsequently became pregnant spontaneously, delivering a term baby 27 months after treatment. This appears to be the only report of the use of fertility-preserving treatment for PLFT. The success of the treatment provides valuable information on the preservation of fertility in young women with PLFT.

Associations between UGT1A1, SLCO1B1, SLCO1B3, BLVRA and HMOX1 polymorphisms and susceptibility to neonatal severe hyperbilirubinemia in Chinese Han population.

BACKGROUND: Severe neonatal hyperbilirubinemia could lead to kernicterus and neonatal death. This study aimed to analyze the association between single nucleotide polymorphisms in genes involved in bilirubin metabolism and the incidence of severe hyperbilirubinemia. METHODS: A total of 144 neonates with severe hyperbilirubinemia and 50 neonates without or mild hyperbilirubinemia were enrolled in 3 institutions between 2019 and 2020. Twelve polymorphisms of 5 genes (UGT1A1, SLCO1B1, SLCO1B3, BLVRA, and HMOX1) were analyzed by PCR amplification of genomic DNA. Genotyping was performed using an improved multiplex ligation detection reaction technique based on ligase detection reaction. RESULTS: The frequencies of the A allele in UGT1A1-rs4148323 and the C allele in SLCO1B3-rs2417940 in the severe hyperbilirubinemia group (30.2% and 90.6%, respectively) were significantly higher than those in the controls (30.2% vs.13.0%, 90.6% vs. 78.0%, respectively, both p < 0.05). Haplotype analysis showed the ACG haplotype of UGT1A1 were associated with an increased hyperbilirubinemia risk (OR 3.122, p = 0.001), whereas the GCG haplotype was related to a reduced risk (OR 0.523, p = 0.018). CONCLUSION: The frequencies of the A allele in rs4148323 and the C allele in rs2417940 are highly associated with the incidence of severe hyperbilirubinemia in Chinese Han neonates. TRIAL REGISTRATION: Trial registration number:ChiCTR1800020424; Date of registration:2018-12-29.

Characterization of allosteric modulators that disrupt androgen receptor co-activator protein-protein interactions to alter transactivation-Drug leads for metastatic castration resistant prostate cancer.

Three series of compounds were prioritized from a high content screening campaign that identified molecules that blocked dihydrotestosterone (DHT) induced formation of Androgen Receptor (AR) protein-protein interactions (PPIs) with the Transcriptional Intermediary Factor 2 (TIF2) coactivator and also disrupted preformed AR-TIF2 PPI complexes; the hydrobenzo-oxazepins (S1), thiadiazol-5-piperidine-carboxamides (S2), and phenyl-methyl-indoles (S3). Compounds from these series inhibited AR PPIs with TIF2 and SRC-1, another p160 coactivator, in mammalian 2-hybrid assays and blocked transcriptional activation in reporter assays driven by full length AR or AR-V7 splice variants. Compounds inhibited the growth of five prostate cancer cell lines, with many exhibiting differential cytotoxicity towards AR positive cell lines. Representative compounds from the 3 series substantially reduced both endogenous and DHT-enhanced expression and secretion of the prostate specific antigen (PSA) cancer biomarker in the C4-2 castration resistant prostate cancer (CRPC) cell line. The comparatively weak activities of series compounds in the H3-DHT and/or TIF2 box 3 LXXLL-peptide binding assays to the recombinant ligand binding domain of AR suggest that direct antagonism at the orthosteric ligand binding site or AF-2 surface respectively are unlikely mechanisms of action. Cellular enhanced thermal stability assays (CETSA) indicated that compounds engaged AR and reduced the maximum efficacy and right shifted the EC50 of DHT-enhanced AR thermal stabilization consistent with the effects of negative allosteric modulators. Molecular docking of potent representative hits from each series to AR structures suggest that S1-1 and S2-6 engage a novel binding pocket (BP-1) adjacent to the orthosteric ligand binding site, while S3-11 occupies the AR binding function 3 (BF-3) allosteric pocket. Hit binding poses indicate spaces and residues adjacent to the BP-1 and BF-3 pockets that will be exploited in future medicinal chemistry optimization studies. Small molecule allosteric modulators that prevent/disrupt AR PPIs with coactivators like TIF2 to alter transcriptional activation in the presence of orthosteric agonists might evade the resistance mechanisms to existing prostate cancer drugs and provide novel starting points for medicinal chemistry lead optimization and future development into therapies for metastatic CRPC.

Study on dust-gas coupling pollution law and selection of optimal purification distance of air duct during tunneling process.

During the excavation of high gas mine, gas and dust often exist at the same time. In order to ensure that the gas concentration remains within a safe range and minimize the risk of workers' pneumoconiosis, we simulated the interaction mechanism of airflow, gas, and dust, explored the pollution law of gas and dust, and obtained the optimal purification distance (Lp) by the CFD method. The reliability of the numerical simulation was verified by field measurements. Firstly, the properties of the gas and dust affected the structure of the airflow field. At the same time, the change in the airflow field affected the concentration distributions of the gas and dust. During the diffusion process, some high-risk regions in which the gas or dust concentrations exceeded 0.80% or 200 mg/m3, respectively, were discovered. Moreover, we have found that the airflow velocity in the top region of the tunnel and at the intersection corner between the cutting face and tunnel wall was the main factor affecting the purification effects. When Lp = 5-8 m, the gas concentration remained below 0.50%. When Lp = 6 m, the dust concentration reached a minimum of 287.5 mg/m3. Therefore, the optimal purification distance was determined to be 6 m; in which case, the gas and dust concentrations decreased by 32.84% and 47.02%, respectively.

Contradictory regulation of macrophages on atherosclerosis based on polarization, death and autophagy.

The main pathological feature of atherosclerosis is lipid metabolism disorder and inflammation. Macrophages, as the most important immune cells in the body, run through the beginning and end of disease development. After macrophages overtake the atherosclerosis-susceptible area apolipoprotein low-density lipoprotein ox-LDL, they transform into foam cells that adhere to blood vessels and recruit a large number of pro-inflammatory factors to initiate the disease. Promoting the outflow of lipids in foam cells and alleviating inflammation have become the basic ideas for the study of atherosclerosis treatment strategies. The polarization of macrophages refers to the estimation of the activation of macrophages at a specific point in space and time. Determining the proportion of different macrophage phenotypes in the plaque can help identify delay or prevent disease development. However, the abnormal polarization of macrophages and the accumulation of lipid also affect the growth state of cells to some extent, thus aggravate the influence on plaque area and stability. Besides, overactive or deficient autophagy of macrophages may also lead to cell death and participate in lipid metabolism and inflammation regression. In this paper, the role of macrophages in atherosclerosis was discussed from three aspects: polarization, death, and autophagy.

Exosomal CLIC1 released by CLL promotes HUVECs angiogenesis by regulating ITGß1-MAPK/ERK axis.

Accumulating evidences have suggested that exosomes are closely associated with tumor progression by affecting cell-cell communication. Here, we aimed to investigate the roles and regulatory mechanism of exosomes released from chronic lymphocytic leukemia (CLL). The expression levels of genes and proteins in cells and exosomes were examined by quantitative real-time PCR and Western blotting, respectively. MEC-1 cell-derived exosomes were obtained and co-cultured with human umbilical vein endothelial cells (HUVECs), then the capabilities of cell proliferation, metastasis and angiogenesis of HUVECs were measured by CCK-8, wound healing, transwell and tube formation assay, respectively. Chloride intracellular channel 1 (CLIC1) was significantly increased in CLL patients and markedly enriched in exosomes secreted by CLL cells. Exosomal CLIC1 secreted from MEC-1 cells were successfully transferred into HUVECs and significantly promoted the phenotypes of proliferation, metastasis and angiogenesis of HUVECs. Mechanically, exosomal CLIC1 secreted from MEC-1 cells obviously activated MAPK/ERK signaling through upregulating integrin ß1 (ITGß1) expression in HUVECs. Furthermore, rescue experiments revealed that either silencing ITGß1 or PD98059 treatment obviously reversed the regulatory effects of exosomal CLIC1 secreted from MEC-1 cells in HUVECs. In conclusion, CLL cell-derived exosomes accelerated HUVECs metastasis and angiogenesis through transferring CLIC1 to regulate ITGß1-MAPK/ERK signaling, indicating that CLIC1 may be a therapeutic target of CLL exosomes in the tumor microenvironment.

Perioperative blood transfusion has distinct postsurgical oncologic impact on patients with different stage of hepatocellular carcinoma.

BACKGROUND: The influence of perioperative blood transfusion (PBT) on postsurgical survival of patients with different stage of hepatocellular carcinoma (HCC) is not well clarified. This study aimed to evaluate the impact of PBT on survival outcomes of different stage of HCC patients. METHODS: Consecutive patients who underwent liver resection for HCC between January 2009 and November 2015 were identified from an HCC prospective database in authors' center. The survival outcomes were compared between patients receiving PBT and those without PBT before and after propensity score matching (PSM) in different stage subsets. Cox regression analysis was performed to verify the impact of PBT on outcomes of HCC. RESULTS: Among 1255 patients included, 804 (64.1%) were Barcelona Clinic Liver Cancer (BCLC) stage 0-A, and 347 (27.6%) received PBT. Before PSM, patients with PBT had worse disease free survival (DFS) and overall survival (OS) compared with those without PBT in both BCLC 0-A subset and BCLC B-C subset (all P < 0.05). After PSM, 288 pairs of patients (with and without PBT) were created. In the subset of BCLC 0-A, the median DFS of patients with PBT was shorter than those without PBT (12.0 months vs. 36.0 months, P = 0.001) Similar result was observed for OS (36.0 months vs. 96.0 months, P = 0.001). In the subset of BCLC B-C, both DFS and OS were comparable between patients with PBT and those without PBT. Cox regression analysis showed that PBT involved an increasing risk of DFS (HR = 1.607; P < 0.001) and OS (HR = 1.756; P < 0.001) for this subset. However, PBT had no impact on DFS (P = 0.126) or OS (P = 0.139) for those with stage B-C HCC. CONCLUSIONS: PBT negatively influenced oncologic outcomes of patient with BCLC stage 0-A HCC, but not those with stage B-C after curative resection.

Microbial aging of hydrochar as a way to increase cadmium ion adsorption capacity: Process and mechanism.

Microbially-aged hydrochar were prepared to investigate how aging affected their ability to remove Cd2+ from aqueous solutions. Based on aging time in an anaerobic fermenter, four samples were produced: HC, M20-HC, M40-HC, and M60-HC. Results indicated increases in specific surface area, pH, and negative charge on hydrochar surface with aging process. Also, there were a decrease in O/C and an increase in surface functional groups, such as -COOH. The adsorption experiments confirmed the positive correlation between aging time and adsorption performance. The 60-day-aged M60-HC treatment displayed the maximum adsorption capacity, which was 3.8 times higher than that of HC. The Langmuir and pseudo-second-order kinetic equations fitted well with isothermal and kinetic data, respectively. Thermodynamic study indicated that Cd2+ adsorption is dominated by chemisorption. This study showed that microbial aging process is an effective and promising measure to improve hydrochar adsorption capacity for Cd2+.

Direct analysis of bromine and iodine in dried serum spots by laser ablation inductively coupled plasma mass spectrometry.

RATIONALE: Accurate quantitative analysis of bromine and iodine in serum is an important aspect of monitoring body condition, but the volatile loss of halogen in sample pretreatment is a troublesome problem. We present a validated and flexible high-throughput method for quantification of bromine and iodine in dried serum spots (DSS) using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and an external aqueous standard calibration curve. The influence of serum matrix and laser ablation (LA) conditions on the analysis of bromine and iodine in DSS was researched systematically. METHODS: Aqueous standards without matrix matching were used for calibration to analyze bromine and iodine in serum by LA-ICP-MS. 5-µL volumes of the aqueous standard solution and serum samples in 10 times diluted concentration were deposited on the PTFE paper to form dried standard calibration spots (DSCS) and DSS, of less than 2 mm in diameter. LA was performed using a focused Nd:YAG laser beam in raster lineal scan mode. RESULTS: The limits of detection (LODs) for bromine and iodine in DSS were 0.23 and 0.03 mg L-1 , respectively. The relative standard deviation (RSD) for this method was less than 10%. The samples were also detected with matrix matching calibration by ICP-MS. The accuracy of the method was verified by statistical analysis of these results from ICP-MS and LA-ICP-MS. The accuracy is satisfactory with recoveries ranging from 81.5% to 118%. CONCLUSIONS: A novel and simple approach for high-throughput screening of bromine and iodine in DSS has been established by LA-ICP-MS. Calibration could be achieved using an aqueous standard solution instead of a matrix-matching solution. The method allowed analysis of low-volume biological samples without derivatization and decreased the risk of contamination or loss.

Endoscopic surgery for thalamic hemorrhage breaking into ventricles: Comparison of endoscopic surgery, minimally invasive hematoma puncture, and external ventricular drainage.

PURPOSE: Thalamic hemorrhage breaking into ventricles (THBIV) is a devastating disease with high morbidity and mortality rates. Endoscopic surgery (ES) may improve outcomes, although there is no consensus on its superiority. We investigated the efficacy and safety of ES and compared the outcomes of different management strategies by ES, hematoma puncture and drainage (HPD), and external ventricular drainage (EVD) in patients with THBIV. METHODS: We retrospectively analyzed patients with THBIV treated by ES, HPD, or EVD at our hospital from June 2015 to June 2018. Patients were categorized into anteromedial and posterolateral groups based on THBIV location, and then the two groups were further divided into ES, HPD, and EVD subgroups. Individualized surgical approach was adopted according to the location of the hematoma in the ES subgroups. Patient characteristics and surgical outcomes were investigated. RESULTS: We analyzed 211 consecutive patients. There were no significant differences in clinical characteristics or incidence of perioperative procedure-related complications (postoperative rebleeding and intracranial infection) in either anteromedial or posterolateral groups. Compared with other therapeutic methods, the ES subgroups had the highest hematoma evacuation rate, shortest drainage time, and lowest incidence of chronic ventricular dilatation (all p < 0.05). Among the three anteromedial subgroups, ES subgroup had the best clinical outcomes which was assessed by the modified Rankin Scale, followed by HPD and EVD subgroups (p < 0.01); while in the posterolateral subgroups, clinical outcomes in the ES and HPD subgroups were similar and better than that in the EVD subgroup (p = 0.037). CONCLUSION: Individualized surgical ES approach for removal of thalamic and ventricular hematomas is a minimally invasive, safe, and effective strategy for the treatment of THBIV with a thalamic hematoma volume of 10-30 mL.

Assays to Interrogate the Ability of Compounds to Inhibit the AF-2 or AF-1 Transactivation Domains of the Androgen Receptor.

Prostate cancer is the leading cause of cancer and second leading cause of cancer-related death in men in the United States. Twenty percent of patients receiving the standard of care androgen deprivation therapy (ADT) eventually progress to metastatic and incurable castration-resistant prostate cancer (CRPC). Current FDA-approved drugs for CRPC target androgen receptor (AR) binding or androgen production, but only provide a 2- to 5-month survival benefit due to the emergence of resistance. Overexpression of AR coactivators and the emergence of AR splice variants, both promote continued transcriptional activation under androgen-depleted conditions and represent drug resistance mechanisms that contribute to CRPC progression. The AR contains two transactivation domains, activation function 2 (AF-2) and activation function 1 (AF-1), which serve as binding surfaces for coactivators involved in the transcriptional activation of AR target genes. Full-length AR contains both AF-2 and AF-1 surfaces, whereas AR splice variants only have an AF-1 surface. We have recently prosecuted a high-content screening campaign to identify hit compounds that can inhibit or disrupt the protein-protein interactions (PPIs) between AR and transcriptional intermediary factor 2 (TIF2), one of the coactivators implicated in CRPC disease progression. Since an ideal inhibitor/disruptor of AR-coactivator PPIs would target both the AF-2 and AF-1 surfaces, we describe here the development and validation of five AF-2- and three AF-1-focused assays to interrogate and prioritize hits that disrupt both transactivation surfaces. The assays were validated using a test set of seven known AR modulator compounds, including three AR antagonists and one androgen synthesis inhibitor that are FDA-approved ADTs, two investigational molecules that target the N-terminal domain of AR, and an inhibitor of the Hsp90 (heat shock protein) molecular chaperone.

Metallic air pollutants and breast cancer heterogeneity.

BACKGROUND: Emerging evidence suggests airborne metals may be associated with breast cancer risk. However, breast cancer is heterogenous and associations with heavy metals vary by subtype. Heavy metals possess both carcinogenic and xenoestrogenic properties which may be related to different tumor etiologies. Therefore, we tested for etiologic heterogeneity, using a case-series approach, to determine whether associations between residential airborne metal concentrations and breast cancer differed by tumor subtype. METHODS: Between 2005 and 2008, we enrolled incident breast cancer cases into the Breast Cancer Care in Chicago study. Tumor estrogen and progesterone receptors status was determined by medical record abstraction and confirmed immunohistochemically (N = 696; 147 ER/PR-negative). The 2002 USEPA's National Air Toxics Assessment census-tract estimates of metal concentrations (antimony, arsenic, beryllium, cadmium, chromium, cobalt, lead, manganese, mercury, nickel and selenium) were matched to participants' residences of the same year. Adjusted logistic regression models were used to examine whether the airborne heavy metal associations differed by tumor ER/PR status. Principal component analysis was performed to assess associations by metal co-exposures. RESULTS: Comparing the highest and lowest quintiles, higher concentrations of antimony (odds ratio[OR]: 1.8, 95% confidence interval[CI]: 0.9, 3.7, P-trend: 0.05), cadmium (OR: 2.3, 95% CI: 1.2, 4.4, P-trend: 0.04) and cobalt (OR: 2.0, 95% CI: 0.9, 4.4, P-trend: 0.04) were associated with ER/PR-negative breast cancer. Mixture analysis using principal components suggested co-exposures to multiple airborne heavy metals may drive associations with tumor receptor status. CONCLUSIONS: Among women diagnosed with breast cancer, metallic air pollutants were associated with increased odds of developing ER/PR-negative breast cancer.

Isoliquiritigenin suppresses the proliferation and induced apoptosis via miR-32/LATS2/Wnt in nasopharyngeal carcinoma.

Nasopharyngeal Carcinoma is limited by the various severe side-effects and surgery is rarely performed. Iosliquiritigenin has a series of biological activities, such as antiviral, anti-free radical and antitumor. However, the role and underlying mechanism of isoliquiritigenin in nasopharyngeal carcinoma have not been understood yet. Herein, the results revealed that isoliquiritigenin could inhibit cell proliferation in nasopharyngeal carcinoma cell lines, including C666-1 and CNE2, in both Cell Counting Kit-8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU) assay. In addition, isoliquiritigenin promoted nasopharyngeal carcinoma cell apoptosis, with the up-regulations of Bax, Caspase-3 and Caspase-9 and the down-regulation of Bcl-2. Meanwhile, isoliquiritigenin suppressed nasopharyngeal carcinoma cells migration and invasion with the down-regulation of matrix metalloproteinases (MMP)-2 and MMP-9. Furthermore, the expression of miR-32 was up-regulated in the nasopharyngeal carcinoma tissues, while isoliquiritigenin could significantly down-regulate the expression of miR-32. And over-expression of miR-32 promoted the nasopharyngeal carcinoma cells growth, migration and invasion, and suppressed apoptosis. However, isoliquiritigenin treatment dramatically inhibited the effect of miR-32. Besides, luciferase reporter assay confirmed that large tumor suppressor 2 (LATS2) was a direct target of miR-32. And isoliquiritigenin increased the expression of LATS2, while silencing of LATS2 promoted the nasopharyngeal carcinoma cells growth. Moreover, western blotting discovered that isoliquiritigenin inhibited nasopharyngeal carcinoma cells growth via Wnt signaling pathway. Finally, CNE2 cells transplanted xenografts tumor model in nude mice were performed and it suggested that isoliquiritigenin could inhibit the development of xenografts nude mice, along with the decrease of tumor volume and the expression of miR-32 and LATS2. Overall, isoliquiritigenin was confirmed to be a potent anti-nasopharyngeal carcinoma compound both in vitro and in vivo, and accomplished by regulation of miR-32/LATS2/Wnt.

Low levels of glycoprotein 96 indicate a worse prognosis in early-stage hepatocellular carcinoma patients after hepatectomy.

Heat shock proteins are a highly conserved group of cellular proteins and are up-expressed in hepatocellular carcinoma (HCC). As a member of the heat shock protein-90 family, glycoprotein 96 (gp96) modulates immunity and tumorigenicity, is increased during the development of HCC from normal liver tissue, and is considered a pro-oncogenic chaperone. However, the prognostic value of gp96 has not been well clarified. The purpose of this study was to investigate the relationship between gp96 and survival of postoperative HCC patients. The expressions of gp96 protein and messenger RNA were measured by immunohistochemistry and real-time quantitative polymerase chain reaction, respectively. The relations between gp96 expression level and clinicopathological factors were analyzed. Kaplan-Meier survival and Cox regression analyses were used to identify factors associated with prognosis. All normal liver tissue exhibited low gp96 expression, whereas high gp96 expression was present in 54% of HCC tissues. The expression of gp96 protein was inversely correlated with TNM stage (P = .037) and tumor recurrence (P = .004). Low gp96 expression was an independent risk factor for poor postoperative disease-free survival (hazard ratio, 0.385; 95% confidence interval, 0.226-0.655; P < .001), and overall survival (hazard ratio, 0.345; 95% confidence interval, 0.187-0.637; P = .001). Stratification analysis indicated that high gp96 had better predictive value for tumor recurrence in HCC patients with normal serum α-fetoprotein levels or with TNM stage I and tumor differentiation I-II HCC. In conclusion, gp96 is a potential and reliable prognostic biomarker for tumor recurrence and overall survival in HCC patients after curative resection.

Effect of melatonin on attenuating the isoflurane-induced oxidative damage is related to PKCα/Nrf2 signaling pathway in developing rats.

Isoflurane, an inhalational anesthesia, has frequently been used in pediatric anesthesia. However, research indicates that isoflurane can induce oxidative stress and affect neural and cognitive development. Melatonin, an endogenous hormone that exhibits antioxidant functions, can play a neuroprotective role by activating the PKCα/Nrf2 signaling pathway in response to oxidative stress. This study aims to determine whether the effect of melatonin on isoflurane-induced oxidative stress is related to activation of the PKCα/Nrf2 signaling pathway. Rat pups at postnatal day 7 were treated with control or 1.5% isoflurane for 4 h after pretreatment for 15 min with either melatonin (10 mg/kg i.p.) or 1% ethanol. The hematoxylin and eosin staining and transmission electron microscopic examination were used for observation of histopathology. The oxidative stress-related indicators were detected by using assay kits. The western blotting, immunohistochemistry and immunofluorescence were used to detect the activation of PKCα/Nrf2 signaling pathway. Results showed that isoflurane induced nerve damage in the hippocampus, and melatonin could reduce this injury. Oxidative stress-related indicators suggested that isoflurane can significantly increase reactive oxygen species and malondialdehyde levels, and decrease superoxide dismutase and glutathione activity compared with the control group, whereas melatonin ameliorated these indices. Expression of proteins associated with the PKCα/Nrf2 signaling pathway indicated that the neuroprotective effect of melatonin is related to activation of the PKCα/Nrf2 signaling pathway. These results suggest that the attenuating effect of melatonin on isoflurane-induced oxidative stress is related to activation of the PKCα/Nrf2 signaling pathway. These findings promote further research into underlying mechanisms and effective treatments to attenuate anesthesia neurotoxicity.

Hornerin promotes tumor progression and is associated with poor prognosis in hepatocellular carcinoma.

BACKGROUND: The function of hornerin (HRNR), a member of the S100 protein family, is poorly clarified in the development of human tumors. The role of HRNR in hepatocellular carcinoma (HCC) progression is investigated in the study. METHODS: The expression levels of HRNR were assessed in tumor samples from a cohort of 271 HCC patients. The effect of HRNR on proliferation, colony formation and invasion of tumor cells was examined. We further determined the role of HRNR in tumor growth in vivo by using xenograft HCC tumor models. The possible mechanism of the HRNR promotion of HCC progression was explored. RESULTS: We found that HRNR was overexpressed in HCC tissues. The high expression of HRNR in HCCs was significantly associated with vascular invasion, poor tumor differentiation, and advanced TNM stage. The disease-free survival (DFS) and overall survival (OS) of HCC patients with high HRNR expression were poorer than those in the low HRNR expression group. HRNR expression was an independent risk factor linked to both poor DFS (HR = 2.209, 95% CI = 1.627-2.998,P <  0.001) and OS (HR = 2.459,95% CI = 1.736-3.484, P <  0.001). In addition, the knockdown of HRNR by shRNAs significantly inhibited the proliferation, colony formation, migration and invasion of HCC tumor cells. HRNR silencing led to the decreased phosphorylation of AKT signaling. Notably, tumor growth was markedly inhibited by HRNR silencing in a xenograft model of HCC. CONCLUSIONS: HRNR promotes tumor progression and is correlated with a poor HCC prognosis. HRNR may contribute to HCC progression via the regulation of the AKT pathway.

High-Content Screening Campaign to Identify Compounds That Inhibit or Disrupt Androgen Receptor-Transcriptional Intermediary Factor 2 Protein-Protein Interactions for the Treatment of Prostate Cancer.

Twenty percent of prostate cancer (PCa) patients develop a noncurable drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC). Overexpression of Androgen Receptor (AR) coactivators such as transcriptional intermediary factor 2 (TIF2) is associated with poor CRPC patient outcomes. We describe the implementation of the AR-TIF2 protein-protein interaction biosensor (PPIB) assay in a high-content screening (HCS) campaign of 143,535 compounds. The assay performed robustly and reproducibly and enabled us to identify compounds that inhibited dihydrotestosterone (DHT)-induced AR-TIF2 protein-protein interaction (PPI) formation or disrupted preexisting AR-TIF2 PPIs. We used multiparameter HCS data z-scores to identify and deprioritize cytotoxic or autofluorescent outliers and confirmed the resulting qualified actives in triplicate. None of the confirmed AR-TIF2 PPIB inhibitors/disruptors exhibited activity in a p53-hDM2 PPIB counter screen, indicating that they were unlikely to be either nonselective PPI inhibitors or to interfere with the biosensor assay format. However, eight confirmed AR-TIF2 PPIB actives also inhibited the glucocorticoid receptor (GR) nuclear translocation counter screen by >50%. These compounds were deprioritized because they either lacked AR specificity/selectivity, or they inhibited a shared component of the AR and GR signaling pathways. Twenty-nine confirmed AR-TIF2 PPIB actives also inhibited the AR nuclear localization counter screen, suggesting that they might indirectly inhibit the AR-TIF2 PPIB assay rather than directly blocking/disrupting PPIs. A total of 62.2% of the confirmed actives inhibited the DHT-induced AR-TIF2 PPI formation in a concentration-dependent manner with IC50s < 40 µM, and 59.4% also disrupted preexisting AR-TIF2 PPI complexes. Overall, the hit rate for the AR-TIF2 PPIB HCS campaign was 0.12%, and most hits inhibited AR-TIF2 PPI formation and disrupted preexisting AR-TIF2 complexes with similar AR-red fluorescent protein distribution phenotypes. Further secondary and tertiary hit characterization assays are underway to select AR-TIF2 PPI inhibitor/disruptor hits suitable for medicinal chemistry lead optimization and development into novel PCa/CRPC therapeutics.