Overexpression of EphB2 in the basolateral amygdala is crucial for inducing visceral pain sensitization in rats subjected to water avoidance stress.

AIMS: Basolateral amygdala (BLA), as a center for stress responses and emotional regulation, is involved in visceral hypersensitivity of irritable bowel syndrome (IBS) induced by stress. In the present study, we aimed to investigate the role of EphB2 receptor (EphB2) in BLA and explore the underlying mechanisms in this process. METHODS: Visceral hypersensitivity was induced by water avoidance stress (WAS). Elevated plus maze test, forced swimming test, and sucrose preference test were applied to assess anxiety- and depression-like behaviors. Ibotenic acid or lentivirus was used to inactivate BLA in either the induction or maintenance stage of visceral hypersensitivity. The expression of protein was determined by quantitative PCR, immunofluorescence, and western blot. RESULTS: EphB2 expression was increased in BLA in WAS rats. Inactivation of BLA or downregulation of EphB2 in BLA failed to induce visceral hypersensitivity as well as anxiety-like behaviors. However, during the maintenance stage of visceral pain, visceral hypersensitivity was only partially relieved but anxiety-like behaviors were abolished by inactivation of BLA or downregulation of EphB2 in BLA. Chronic WAS increased the expression of EphB2, N-methyl-D-aspartate receptors (NMDARs), and postsynaptic density protein (PSD95) in BLA. Downregulation of EphB2 in BLA reduced NMDARs and PSD95 expression in WAS rats. However, activation of NMDARs after the knockdown of EphB2 expression still triggered visceral hypersensitivity and anxiety-like behaviors. CONCLUSIONS: Taken together, the results suggest that EphB2 in BLA plays an essential role in inducing visceral hypersensitivity. In the maintenance stage, the involvement of EphB2 is crucial but not sufficient. The increase in EphB2 induced by WAS may enhance synaptic plasticity in BLA through upregulating NMDARs, which results in IBS-like symptoms. These findings may give insight into the treatment of IBS and related psychological distress.

Paxlovid-tacrolimus drug-drug interaction caused severe diarrhea that induced combined diabetic ketoacidosis and a hyperglycemic hyperosmolar state in a kidney transplant patient: a case report.

BACKGROUND: Transplant recipients are at high risk of coronavirus disease 2019, and a timely supply of antivirals should be prioritized for those patients. Complicated drug‒drug interactions limit the use of Paxlovid (nirmatrelvir/ritonavir) coadministered with tacrolimus. Here, we report a patient with a kidney transplant who received Paxlovid and reduced-dose tacrolimus at the same time and suffered a severe tacrolimus toxicity. CASE PRESENTATION: We present a 56-year-old man of Han ethnicity with a kidney transplant who suffered from coronavirus disease 2019 twice. For the first infection, the immunosuppressants were substituted by dexamethasone when the patient used Paxlovid, and everything went well. For the second time, tacrolimus at a reduced dose concomitant with Paxlovid caused severe diarrhea, inducing combined diabetic ketoacidosis and a hyperglycemic hyperosmolar state. CONCLUSION: This case challenges the dose-adjustment strategy of managing drug‒drug interactions. We suggest that tacrolimus should be stopped when Paxlovid is applied and that corticosteroids could be a good substitution.

Correlation analysis between morphologic characteristics of the thoracolumbar basivertebral foramen and Kummell's disease in patients with osteoporosis using imaging techniques.

BACKGROUND: The aging of the population is a social problem faced by many countries in the world. With the increase in the elderly population, the number of patients with Kummell's disease is also gradually increasing. No study has demonstrated that Kummell's disease has a clear correlation with the foramen of a vertebrobasilar vein. OBJECTIVES: The research was conducted to describe and evaluate the morphological characteristics of a basivertebral foramen in patients with osteoporosis and Kummell's disease by CT; to infer whether the specific morphological characteristics of basivertebral foramen may be one of the risk factors of Kummell's disease; to provide clinical suggestions for the treatment of Kummell's disease. DESIGN: Retrospective analysis from January 2020 to December 2021 on 83 patients with 83 vertebral bodies (T8-L5) diagnosed with senile osteoporosis and Kummell's disease hospitalized in our hospital due to chronic low back pain, including 57 women and 23 men. Group A was assigned for the following patients: the age ranged from 59 to 86 years old, with the average age of 67.30 ± 7.32 years old; the body mass index ranged from 20.01 to 29.46 kg/m2, with the average body mass index of 23.51 ± 3.03 kg/m2.Group B was assigned for the following patients: 83 patients diagnosed with senile osteoporosis in our outpatient department from January 2020 to December 2021, including 41 males and 42 females; the age ranged from 60 to 85 years, with an average age of 68.52 ± 4.68 years old; the height to weight ratio met the normal reference standard (except 20% above or 10% below the standard weight). Through the lanwon PACS imaging system, the related parameters of the vertebrobasilar foramen in patients with osteoporosis and Kummell's disease were measured to evaluate and analyze the correlation between the morphological characteristics of the vertebrobasilar foramen in patients with osteoporosis and Kummell's disease. RESULTS: In patients with osteoporosis, the distribution of incidence rate of Kummell's disease in the spine was consistent with that of osteoporotic compression fractures. Sagittal view of the vertebral body on CT scan and the triangular-shaped, trapezoidal-shaped, and irregular-shaped basivertebral foramen in group A accounted for 18%,57%,and 36%,respectively. In group B, triangular-shaped, trapezoidal-shaped, and irregular-shaped foramen accounted for 51%,17%,and 26%,respectively.The distribution of triangular-shaped, trapezoidal-shaped, and irregular-shaped foramen was compared between groups A and B, and the difference was recorded as statistically significant (P < 0.05). Additionally, the difference in the distribution of triangular-shaped, trapezoidal-shaped, and irregular-shaped foramen in group A was found statistically significant (P < 0.05),while that of Group B was found statistically insignificant (P > 0.05).On a horizontal CT scan of the vertebra of group A, triangles, trapezoids, and irregularities accounted for 28%, 26%, and 47%, respectively. In group B, triangles,trapezoids,and irregularities accounted for 31%, 37%, and 30%, respectively. The difference in the distribution of the triangular-shaped and trapezoidal-shaped foramen in groups A and B was statistically insignificant (P > 0.05), while that of irregular-shaped was statistically significant (P < 0.05). Additionally, there was no statistical significance (P > 0.05) in the difference in the morphological distribution of triangular-shaped and trapezoidal-shaped foramen in group A, while that of irregular-shaped was found to be statistically significant (P < 0.05). Further, the difference in the morphological distribution of triangular-shaped, trapezoidal-shaped, and irregular-shaped foramen in group B was not statistically significant (P > 0.05).In general, about 8% of the vertebral body of BF has an osseous septum. In group A, 97% are single-holed while the remaining 3% are porous; in group B, those with single holes accounted for 76%, while the remaining 24% are porous. In groups A and B, the difference in the morphological distribution of single-holed and multi-holed T8, T11, T12, L1, L2, L4, and L5 vertebral bodies was statistically significant (P < 0.05). In group A, the difference in the distribution of single-holed and multi-holed L1 and L5 vertebral bodies was statistically significant (P < 0.05). Similarly, the difference in the distribution of single-holed and multi-holed T8, T11, T12, L1, L2, and L4 basivertebral foramen was statistically significant (P < 0.05). CONCLUSIONS: In patients with osteoporosis, the incidence of vertebral Kummell's disease can be associated with the morphological characteristics of the basivertebral foramen, as observed in the CT scan. Furthermore, the vertebral body with trapezoidal-shaped and irregular-shaped basivertebral foramen and boneless septum in the foramen is highly susceptible to Kummell's disease.

CDBN-YGXZ, a Novel Small-Molecule Drug, Shows Efficacy against Clostridioides difficile Infection and Recurrence in Mouse and Hamster Infection Models.

Clostridioides difficile infection (CDI) causes severe diarrhea and colitis, leading to significant morbidity, mortality, and high medical costs worldwide. Oral vancomycin, a first-line treatment for CDI, is associated with a high risk of recurrence, necessitating novel therapies for primary and recurrent CDI. A novel small-molecule compound, CDBN-YGXZ, was synthesized by modifying the benzene ring of nitazoxanide with lauric acid. The mechanism of action of CDBN-YGXZ was validated using a pyruvate:ferredoxin/flavodoxin oxidoreductase (PFOR) inhibition assay. The efficacy of CDBN-YGXZ was evaluated using the MIC test and CDI infection model in mice and hamsters. Furthermore, metagenomics was used to reveal the underlying reasons for the effective reduction or prevention of CDI after CDBN-YGXZ treatment. The inhibitory activity against PFOR induced by CDBN-YGXZ. MIC tests showed that the in vitro activity of CDBN-YGXZ against C. difficile ranging from 0.1 to 1.5 µg/mL. In the mouse and hamster CDI models, CDBN-YGXZ provided protection during both treatment and relapse, while vancomycin treatment resulted in severe relapse and significant clinical scores. Compared with global effects on the indigenous gut microbiota induced by vancomycin, CDBN-YGXZ treatment had a mild influence on gut microbes, thus resulting in the disappearance or reduction of CDI recurrence. CDBN-YGXZ displayed potent activity against C. difficile in vitro and in vivo, reducing or preventing relapse in infected animals, which could merit further development as a potential drug candidate for treating CDI.

A novel gut-restricted RIPK1 inhibitor, SZ-15, ameliorates DSS-induced ulcerative colitis.

As a key mediator of cell death and inflammation, receptor-interacting protein kinase 1 (RIPK1) responds to a broad set of inflammatory and pro-death stimuli in human diseases. Inhibitors targeting RIPK1 are being investigated for the treatment of a wide range of human diseases, including ulcerative colitis. In the present study, we designed, synthesized, and investigated the anti-necroptosis and RIPK1-inhibition effects of SZ-15-a symmetrical high-molecular-weight (>500 Da) compound. SZ-15 effectively inhibited necroptosis in U937 and HT-29 cells at concentrations of 1 nM and 10 nM, respectively, and SZ-15 at a concentration of 10 nM almost completely blocked RIPK1, RIPK3, and mixed-lineage kinase domain-like (MLKL) protein phosphorylation induced by necrosis inducers. SZ-15 suppressed the pro-necroptosis function of RIPK1 by downregulating the mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6. The activities of SZ-15 were effectively restricted to the gut: The percent recovery of the parent form of SZ-15 in mouse feces was 85.75%. Nevertheless, SZ-15 was effectively absorbed and detected in colon tissues after 1 h at a concentration of 3335 ± 868 ng/g, indicating that membrane permeability was maintained. SZ-15 alleviated dextran sulfate sodium (DSS)-induced ulcerative colitis in vivo by decreasing TNF-α, IL-1ß, IL-22, and IL-6 mRNA expression in colonic tissues. Our preclinical study describes a novel gut-restricted RIPK1 inhibitor that shows great potential for use in the clinical treatment of ulcerative colitis.

KC-180-2 Exerts Anti-SCLC Effects via Dual Inhibition of Tubulin Polymerization and Src Signaling.

In this study, a series of N-benzyl-2-(5-phenylpyridin-2-yl) acetamide-based derivatives were successfully designed and synthesized as anti-cancer agents. KC-180-2 was screened as a potentially leading compound with dual mechanisms of action: Src signaling and tubulin polymerization inhibition. It efficiently suppressed the proliferation of five cancer cell lines (MDA-MB-231, H446, SKOV-3, HepG2, and HT29), with IC50 values ranging from 5 to 188 nM, especially small-cell lung cancer (SCLC) cells (IC50, 5 nM). Correspondingly, it exerted a significant therapeutic effect on the H446 small-cell lung cancer xenograft model, significantly reducing the volume of tumors without obvious toxicity. Mechanistically, this compound significantly inhibited the polymerization of purified tubulin in vitro, inducing G2/M cell cycle arrest and binding to the kinase catalytic domain of the Src protein, which reduced the phosphorylation of Src. Thus, KC-180-2 is a potential lead compound for the further development of a new anti-tumor drug against SCLC.

The Slack Channel Regulates Anxiety-Like Behaviors via Basolateral Amygdala Glutamatergic Projections to Ventral Hippocampus.

Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. In the present study, we find that the global Slack KO male mice exhibit anxious behaviors, whereas the Slack Y777H male mice manifest anxiolytic behaviors. The expression of Slack channels is rich in basolateral amygdala (BLA) glutamatergic neurons and downregulated in chronic corticosterone-treated mice. In addition, electrophysiological data show enhanced excitability of BLA glutamatergic neurons in the Slack KO mice and decreased excitability of these neurons in the Slack Y777H mice. Furthermore, the Slack channel deletion in BLA glutamatergic neurons is sufficient to result in enhanced avoidance behaviors, whereas Kcnt1 gene expression in the BLA or BLA-ventral hippocampus (vHPC) glutamatergic projections reverses anxious behaviors of the Slack KO mice. Our study identifies the role of the Slack channel in controlling anxious behaviors by decreasing the excitability of BLA-vHPC glutamatergic projections, providing a potential target for anxiolytic therapies.SIGNIFICANCE STATEMENT Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. Here, we examined the behaviors of loss- and gain-of-function of Slack channel mice in elevated plus maze and open field tests and found the anxiolytic role of the Slack channel. By altering the Slack channel expression in the specific neuronal circuit, we demonstrated that the Slack channel played its anxiolytic role by decreasing the excitability of BLA-vHPC glutamatergic projections. Our data reveal the role of the Slack channel in the regulation of anxiety, which may provide a potential molecular target for anxiolytic therapies.

Computed tomography features of COVID-19 in children: A systematic review and meta-analysis.

BACKGROUND: There are few reports on the chest computed tomography (CT) imaging features of children with coronavirus disease 2019 (COVID-19), and most reports involve small sample sizes. OBJECTIVES: To systematically analyze the chest CT imaging features of children with COVID-19 and provide references for clinical practice. DATA SOURCES: We searched PubMed, Web of Science, and Embase; data published by Johns Hopkins University; and Chinese databases CNKI, Wanfang, and Chongqing Weipu. METHODS: Reports on chest CT imaging features of children with COVID-19 from January 1, 2020 to August 10, 2020, were analyzed retrospectively and a meta-analysis carried out using Stata12.0 software. RESULTS: Thirty-seven articles (1747 children) were included in this study. The heterogeneity of meta-analysis results ranged from 0% to 90.5%. The overall rate of abnormal lung CT findings was 63.2% (95% confidence interval [CI]: 55.8%-70.6%), with a rate of 61.0% (95% CI: 50.8%-71.2%) in China and 67.8% (95% CI: 57.1%-78.4%) in the rest of the world in the subgroup analysis. The incidence of ground-glass opacities was 39.5% (95% CI: 30.7%-48.3%), multiple lung lobe lesions was 65.1% (95% CI: 55.1%-67.9%), and bilateral lung lesions was 61.5% (95% CI: 58.8%-72.2%). Other imaging features included nodules (25.7%), patchy shadows (36.8%), halo sign (24.8%), consolidation (24.1%), air bronchogram signs (11.2%), cord-like shadows (9.7%), crazy-paving pattern (6.1%), and pleural effusion (9.1%). Two articles reported 3 cases of white lung, another reported 2 cases of pneumothorax, and another 1 case of bullae. CONCLUSIONS: The lung CT results of children with COVID-19 are usually normal or slightly atypical. The lung lesions of COVID-19 pediatric patients mostly involve both lungs or multiple lobes, and the common manifestations are patchy shadows, ground-glass opacities, consolidation, partial air bronchogram signs, nodules, and halo signs; white lung, pleural effusion, and paving stone signs are rare. Therefore, chest CT has limited value as a screening tool for children with COVID-19 and can only be used as an auxiliary assessment tool.

Genetic and molecular characterization of determinant of six-rowed spike of barley carrying vrs1.a4.

KEY MESSAGE: Decisive role of reduced vrs1 transcript abundance in six-rowed spike of barley carrying vrs1.a4 was genetically proved and its potential causes were preliminarily analyzed. Six-rowed spike 1 (vrs1) is the major determinant of the six-rowed spike phenotype of barley (Hordeum vulgare L.). Alleles of Vrs1 have been extensively investigated. Allele vrs1.a4 in six-rowed barley is unique in that it has the same coding sequence as Vrs1.b4 in two-rowed barley. The determinant of row-type in vrs1.a4 carriers has not been experimentally identified. Here, we identified Vrs1.b4 in two-rowed accessions and vrs1.a4 in six-rowed accessions from the Qinghai-Tibet Plateau at high frequency. Genetic analyses revealed a single nuclear gene accounting for row-type alteration in these accessions. Physical mapping identified a 0.08-cM (~ 554-kb) target interval on chromosome 2H, wherein Vrs1 was the most likely candidate gene. Further analysis of Vrs1 expression in offspring of the mapping populations or different Vrs1.b4 and vrs1.a4 lines confirmed that downregulated expression of vrs1.a4 causes six-rowed spike. Regulatory sequence analysis found a single 'TA' dinucleotide deletion in vrs1.a4 carriers within a 'TA' tandem-repeat-enriched region ~ 1 kb upstream of the coding region. DNA methylation levels did not correspond to the expression difference and therefore did not affect Vrs1 expression. More evidence is needed to verify the causal link between the 'TA' deletion and the downregulated Vrs1 expression and hence the six-rowed spike phenotype.

Occurrence, Human Exposure, and Risk Assessment of Polybrominated Dibenzo-p-Dioxins and Dibenzofurans, Polychlorinated Naphthalenes, and Metals in Atmosphere Around Industrial Parks in Jiangsu, China.

Air samples were collected around industrial parks in Jiangsu, China, to allow the concentrations, profiles, and risk assessment of polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs), polychlorinated naphthalenes (PCNs), and metals to be investigated. The concentrations of ΣPBDD/Fs and ΣPCNs were 1324.26-2080.98 fg/m3 (11.35-42.57 fg I-TEQ/m3) and 10,404.9-29,322.9 fg/m3 (1.32-7.19 fg I-TEQ/ m3), respectively. The highest concentration of ΣPBDD/Fs and ΣPCNs were observed at site C. PBDD/Fs were mainly dominated by PBDFs. The main contributor to the ΣPBDD/Fs in all samples was 1,2,3,4,6,7,8-HpBDF, which accounted for 25.75%-39.4%. For PCNs, the predominating homologues were tetra-, tri- and penta-CNs, which contributed 30.7%-43.3%, 24.7%-31.0%, and 10.6%-21.6%, respectively. As for metals, the pollution of As, Mn, Cr, and Ni in most samples exceeded National Ambient Air Quality Standards of China. Assessing the risk of inhalation exposure showed that there were potential carcinogenic risks to local residents.

Computed Tomography Features of COVID-19 in Children: A Systematic Review and Meta-analysis

ObjectivesTo systematically analyze the chest CT imaging features of children with COVID-19 and provide references for clinical practice. MethodsWe searched PubMed, Web of Science, and Embase; data published by Johns Hopkins University; and Chinese databases CNKI, Wanfang, and Chongqing Weipu. Reports on chest CT imaging features of children with COVID-19 from January 1, 2020, to August 10, 2020, were analyzed retrospectively and a meta-analysis carried out using Stata12.0 software. ResultsThirty-seven articles (1747 children) were included in this study. The overall rate of abnormal lung CT findings was 63.2% (95% confidence interval [CI]: 55.8-70.6%), with a rate of 61.0% (95% CI: 50.8-71.2%) in China and 67.8% (95% CI: 57.1-78.4%) in the rest of the world in the subgroup analysis. The incidence of ground-glass opacities was 39.5% (95% CI: 30.7-48.3%), multiple lung lobe lesions 65.1% (95% CI: 55.1-67.9%), and bilateral lung lesions 61.5% (95% CI: 58.8-72.2%). Other imaging features included nodules (25.7%), patchy shadows (36.8%), halo sign(24.8%), consolidation (24.1%), air bronchogram signs (11.2%), cord-like shadows (9.7%), crazy-paving pattern (6.1%), and pleural effusion (9.1%). Two articles reported three cases of white lung, another reported two cases of pneumothorax, and another one case of bullae. CONCLUSIONThe lung CT results of children with COVID-19 are usually normal or slightly atypica, with a low sensitivity and specificity compared with that in adults. The lung lesions of COVID-19 pediatric patients mostly involve both lungs or multiple lobes, and the common manifestations are patchy shadows, ground-glass opacities, consolidation, partial air bronchogram signs, nodules, and halo signs; white lung, pleural effusion, and paving stone signs are rare. CLINICAL IMPACTTherefore, chest CT has limited value as a screening tool for children with COVID-19 and can only be used as an auxiliary assessment tool. RegistrationThis systematic review and meta-analysis was registered in the Prospero International Prospective Register of Systemic Reviews (CRD42020196602). Strengths and limitations of this studyThe lung CT findings of children with COVID-19 are usually normal or slightly atypical, with a low sensitivity and specificity compared with that in adults. From a systematic review of current literature, the overall rate of abnormal lung CT findings in children was revealed to be 63.2%. Chest CT has limited value as a screening tool for children with COVID-19 and can only be used as an auxiliary assessment tool. The sample size of some included studies is small, which may affect the results.

Concentrations, Sources, and Potential Human Health Risks of PCDD/Fs, dl-PCBs, and PAHs in Rural Atmosphere Around Chemical Plants in Jiangsu Province, China.

Concentrations and sources of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (dl-PCBs), and polycyclic aromatic hydrocarbons (PAHs) in a rural atmosphere near industrial zones in Jiangsu, China were determined and the associated risks were assessed. The concentrations of ΣPCDD/Fs, ΣPCBs, and ΣPAHs ranged from 11.9-57.7 pg·m-3, 0.58-2.71 pg m-3, and 11-18 ng m-3, respectively. Principal component analysis suggested that the contamination of air with PCDD/Fs and PCBs mainly originated from industrial activities and combustion processes. In contrast, the major source of PAHs was the combustion of petroleum, coal, and biomass. These data were used to estimate the exposure of the population living nearby to these persistent organic pollutants and to evaluate the non-carcinogenic and carcinogenic risks associated with their inhalation. Our study are likely to be helpful for developing and implementing regulation strategies for PCDD/Fs, dl-PCBs, and PAHs in the atmosphere around industrial and surrounding residential areas.

Synthesis, Characterization, and In Vivo Evaluation of Desmethyl Anethole Trithione Phosphate Prodrug for Ameliorating Cerebral Ischemia-Reperfusion Injury in Rats.

Anethol trithione (ATT) has a wide range of physiological activities, but its use is limited due to its poor water solubility. To improve the solubility of ATT, we synthesized and characterized a novel phosphate prodrug (ATXP) relying on the availability of the hydroxy group in 5-(4-hydroxyphenyl)-3H-1,2-dithiole3-thione (ATX), which was transformed from ATT rapidly and extensively in vivo. Our results showed that ATXP significantly improved drug solubility. ATXP was rapidly converted to ATX and reached a maximum plasma concentration with a T max of approximately 5 min after intravenous (iv) administration. Furthermore, after the oral administration of ATXP, the C max was 3326.30 ± 566.50 ng/mL, which was approximately 5-fold greater than that of the parent drug form, indicating that ATXP has greater absorption than that of ATT. Additionally, the oral phosphate prodrug ATXP increased the ATX in the area under the plasma concentration vs time curves (AUC0-t = 3927.40 ± 321.50 and AUC0-∞ = 4579.0 ± 756.30), making its use in practical applications more meaningful. Finally, compared to the vehicle, ATXP was confirmed to maintain the bioactivity of the parent drug for a significant reduction in infarct volume 24 h after reperfusion. Based on these findings, the phosphate prodrug ATXP is a potentially useful water-soluble prodrug with improved pharmacokinetic properties.

Role of HGF/c-Met in the treatment of colorectal cancer with liver metastasis.

The system of hepatocyte growth factor (HGF) and its receptor c-Met plays a critical role in tumor invasive growth and metastasis. The mortality rate of colorectal cancer (CRC), one of the most commonly diagnosed malignancies, is increased by it gradual development into metastasis, most frequently in the liver. Overexpression of c-Met, the protein tyrosine kinase receptor for the HCF/scatter factor, has been implicated in the progression and metastasis of human colorectal carcinoma. In this study, we aimed to investigate the role of c-Met in CRC liver metastasis and illustrate the clinical impact of regulating HGF/c-Met signaling in patients with CRC liver metastasis. We found that (I) higher levels of c-Met expression (mRNA and Protein) in CRC liver metastasis than primary CRC by assessing the patient tissue samples; (II) a positive correlation of c-Met expression with tumor stages of CRC liver metastasis, as well as c-Met expression in CRC, live metastasis concurred with regional lymph node metastasis; (III) the clinical impact of downregulation of HGF/c-Met signaling on the reduction of proliferation and invasion in CRC liver metastasis. Therefore, we demonstrate that the regulation of HGF/c-Met pathways may be a promising strategy in the treatment of patients with CRC liver metastasis.

Cancer cell membrane-cloaked mesoporous silica nanoparticles with a pH-sensitive gatekeeper for cancer treatment.

Nanoparticular drug delivery system (NDDS) has great potential for enhancing the efficacy of traditional chemotherapeutic drugs. However, it is still a great challenge to fabricate a biocompatible NDDS with simple structure capable of optimizing therapeutic efficacy, such as high tumor accumulation, suitable drug release profile (e.g. no premature drug leakage in normal physiological conditions while having a rapid release in cancer cells), low immunogenicity, as well as good biocompatibility. In this work, a simple core/shell structured nanoparticle was fabricated for prostate cancer treatment, in which a mesoporous silica nanoparticle core was applied as a container to high-efficiently encapsulate drugs (doxorubicin, DOX), CaCO3 interlayer was designed to act as sheddable pH-sensitive gatekeepers for controlling drug release, and cancer cell membrane wrapped outlayer could improve the colloid stability and tumor accumulation capacity. In vitro cell experiments demonstrated that the as-prepared nanovehicles (denoted as DOX/MSN@CaCO3@CM) could be efficiently uptaken by LNCaP-AI prostate cancer cells and even exhibited a better anti-tumor efficiency than free DOX. In addition, Live/Dead cell detection and apoptosis experiment demonstrated that MSN/DOX@CaCO3@CM could effectively induce apoptosis-related death in prostate cancer cells. In vivo antitumor results demonstrated that DOX/MSN@CaCO3@CM administration could remarkably suppress the tumor growth. Compared with other tedious approaches to optimize the therapeutic efficacy, this study provides an effective drug targeting system only using naturally biomaterials for the treatment of prostate cancer, which might have great potential in clinic usage.

Synthesis, characterization and in vivo evaluation of honokiol bisphosphate prodrugs protects against rats' brain ischemia-reperfusion injury.

Honokiol (HK) usage is greatly restricted by its poor aqueous solubility and limited oral bioavailability. We synthesized and characterized a novel phosphate prodrug of honokiol (HKP) for in vitro and in vivo use. HKP greatly enhanced the aqueous solubility of HK (127.54 ±â€¯15.53 mg/ml) and the stability in buffer solution was sufficient for intravenous administration. The enzymatic hydrolysis of HKP to HK was extremely rapid in vitro (T1/ 2  = 8.9 ±â€¯2.11 s). Pharmacokinetics studies demonstrated that after intravenous administration of HKP (32 mg/kg), HKP was converted rapidly to HK with a time to reach the maximum plasma concentration of ∼5 min. The prodrug HKP achieved an improved T1/2 (7.97 ±â€¯1.30 h) and terminal volume of distribution (26.02 ±â€¯6.04 ml/kg) compared with direct injection of the equimolar parent drug (0.66 ±â€¯0.01 h) and (2.90 ±â€¯0.342 ml/kg), respectively. Furthermore, oral administration of HKP showed rapid and improved absorption compared with the parent drug. HKP was confirmed to maintain the bioactivity of the parent drug for ameliorating ischemia-reperfusion injury by decreasing brain infarction and improving neurologic function. Taken together, HKP is a potentially useful aqueous-soluble prodrug with improved pharmacokinetic properties which may merit further development as a potential drug candidate.

Observation and comparison of tower vibration and underwater noise from offshore operational wind turbines in the East China Sea Bridge of Shanghai.

Underwater operational turbine noise emitted by China's first offshore wind farm in the East China Sea Bridge of Shanghai was measured and analyzed in this study. Two sensors were used in the measurement: a hydrophone recording the underwater sound and an accelerometer placed in the turbine tower detecting the tower vibrations. Measurements were performed at two different types of wind turbines: a Sinovel 3 MW SL3000 turbine and a Shanghai Electric 3.6 MW W3600 turbine. The two turbines show similar tower vibration characteristics, characterized by a number of tonal components, mainly in the low-frequency domain (30-500 Hz). The peak vibration frequencies changed with the wind speed until the turbine approached its nominal power rating. Spectral analysis of the underwater acoustic data showed that the amplitude spectra had a strong correlation with the spectra of the turbine vibration intensity level, indicating that the measured underwater noise was generated by the tower mechanical vibration.

TNF-α promotes the proliferation of colon cancer cells by activating the Wnt/β-catenin pathway / 西安交通大学学报(医学版)

Objective To investigate the effect of treatment with TNF-α on growth ability of colon cancer cells and its possible mechanism.Methods Human colon cancer HT-29 cells were treated with TNF-α(10 nmol/L). The effect of TNF-αon the proliferative ability was examined by cell growth curve assay and MTT assay,respectively. Cell cycle was detected by flow cytometry.Protein levels ofβ-catenin,c-myc and cyclinD1 were detected by Western blot.We also observed the effect of the Wnt/β-catenin pathway blockage by XAV9 3 9 on TNF-α's promoting prolif-eration of colon cancer cells and proteins related to the Wnt/β-catenin pathway.Results Upon treatment with TNF-α,the proliferative ability of HT-29 cells was enhanced (all P＜0.05),G0/G1 phase cell ratio was decreased (P＜0.05),and S phase cell ratio was increased (P＜0.05).The protein levels ofβ-catenin,c-myc and cyclinD1 were increased in TNF-α-treated HT-29 cells (all P＜0.05).XAV939 treatment resulted in a significant inhibition of cell proliferation ability (all P＜0.05)as well as the protein levels ofβ-catenin,c-myc and cyclinD1 (all P＜0.05) in the TNF-α-treated HT29 cells.Conclusion TNF-αmay be involved in the occurrence and development of colon cancer by activating the Wnt/β-catenin pathway and promoting the proliferation of colon cancer cells.

Satellite-based entanglement distribution over 1200 kilometers.

Long-distance entanglement distribution is essential for both foundational tests of quantum physics and scalable quantum networks. Owing to channel loss, however, the previously achieved distance was limited to ~100 kilometers. Here we demonstrate satellite-based distribution of entangled photon pairs to two locations separated by 1203 kilometers on Earth, through two satellite-to-ground downlinks with a summed length varying from 1600 to 2400 kilometers. We observed a survival of two-photon entanglement and a violation of Bell inequality by 2.37 ± 0.09 under strict Einstein locality conditions. The obtained effective link efficiency is orders of magnitude higher than that of the direct bidirectional transmission of the two photons through telecommunication fibers.