Preliminary results of randomized phase II study of etoposide plus lobaplatin or etoposide plus cisplatin with concurrent thoracic radiotherapy in the treatment of limited-stage small cell lung cancer.

The purpose is to compare the clinical efficacy and toxicity of etoposide plus lobaplatin (EL) or etoposide plus cisplatin (EP) with concurrent thoracic radiotherapy during the treatment of limited-stage small cell lung cancer (LS-SCLC). Forty-two patients with LS-SCLC were randomly divided into EL ( n = 19) or EP ( n = 23) regimens combined with thoracic intensity-modulated radiotherapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The 1-, 2-, and 3-year PFS rates in the EL and EP cohorts were 50.8, 38.1, and 12.7%; and 56.5, 43.5, and 29.0%, respectively ( P = 0.527), whereas the 1-, 2-, and 3-year overall survival (OS) rates were 72.2, 52.5, and 43.8%; and 73.9, 48.4, and 48.4%, respectively ( P = 0.923). The hematological toxicities were similar in two cohorts. However, gastrointestinal reactions were more severe in the EP group. The incidence of nausea and vomiting in EL and EP cohorts were 31.6% vs. 73.9% ( P = 0.006) and 20.1% vs. 60.9% ( P = 0.009), respectively. The two cohorts did not show ≥grade 4 radiation esophagitis and ≥grade 3 radiation pneumonitis. The incidence of acute radiation esophagitis in EL group was lower ( P = 0.038), both groups showed a similar incidence of radiation pneumonitis ( P = 1.000). EL or EP chemotherapy with concurrent thoracic radiotherapy showed similar PFS and OS. The EL group showed milder gastrointestinal toxicity and radiation esophagitis. Radiation pneumonitis and hematological toxicity were similar in the two regimens, which can be tolerated by patients.

Pemetrexed plus cisplatin versus docetaxel plus cisplatin for stage IV lung adenocarcinoma based on propensity score matching.

The aim of this study was to compare the clinical efficacy of pemetrexed+cisplatin (PP) versus docetaxel+cisplatin (DP) for the treatment of stage IV lung adenocarcinoma. We retrospectively analyzed the clinical data of 147 patients with stage IV lung adenocarcinoma treated between January 2011 and December 2015, 100 of which were in the DP group whereas 47 were in the DP group. Main inclusion criteria were treatment-naive patients, first-line treatment with PP or DP with no molecular targeted therapy during treatment, 2-6 cycles of first-line chemotherapy with unknown status of epidermal growth factor receptor (EGFR) mutation, 18-75 years of age, and Karnofsky performance status score of at least 70. Prognostic factors for survival were identified by using univariate and multivariate analyses. Propensity score matching was performed to further adjust for confounding. A total of 47 pairs were successfully matched between the two groups. The median overall survival was 9.0 months in the DP group and 17.0 months in the PP group; the 1-year survival rate was 29.8 and 59.6%, respectively; the 2-year survival rate was 12.8 and 21.1%, respectively (χ=4.128, P=0.042); and median progression-free survival was 6.0 and 8.0 months, respectively (χ=4.839, P=0.028). Cox multivariate analysis showed that chemotherapy regimen and number of metastatic organs were independent factors for OS. The effect of the radiotherapy dose on the primary tumor on OS was close to statistically significant. The incidence of grade 3-4 neutropenia was more significantly reduced in the DP group than in the PP group after matching (61.7 vs. 27.7%, P=0.002), with no between-group difference for adverse effects on platelets or hemoglobin. For patients with stage IV lung adenocarcinoma and unknown EGFR mutation status, PP was more effective than DP in prolonging survival and had a less adverse effect on neutrophils.

Enhancing overall properties of epoxy-based composites using polydopamine-coated edge-carboxylated graphene prepared via one-step high-pressure ball milling.

Graphene (GN) nanofillers have been widely used to enhance the overall performance of polymer composites due to their various superior properties, which strongly rely on the uniform dispersion and strong interfacial bonding of GN with high-quality polymer matrices. In the present study, the strengthening and functional effects of polydopamine-coated edge-carboxylated graphene (p-ECG) on the mechanical, moisture-barrier and electromagnetic properties of epoxy (EP)-based composites were systematically evaluated. p-ECG was successfully prepared via one-step high-pressure ball milling through the edge-selective functionalization and exfoliation of pristine graphite in the presence of dry ice, followed by synchronous reduction and coating via the mild oxidative polymerization of mussel-inspired dopamine. p-ECG showed prominent advantages of a small sheet size, excellent dispersibility and high chemical reactivity in the EP matrix. Obvious enhancements were achieved in the tensile and flexural properties and moisture-barrier performance of EP composites as well as the interlaminar shear strength (ILSS) and transverse fiber bundle tensile (TFBT) strength of carbon fiber (CF)/EP composites, which confirmed the excellent dispersion and chemically strengthened interfacial bonding of p-ECG in the EP matrix. More importantly, p-ECG introduced onto the surface of desized CF led to significant enhancement in the electromagnetic interference (EMI) shielding capability of CF/EP composites, which was primarily ascribed to the polarization relaxation effect induced by the defects and functional groups in p-ECG as well as the increase in electrical conductivity derived from the "bridging effect" of p-ECG. Specifically, with p-ECG content of 0.5 wt%, the increments in tensile strength, TFBT strength, shielding effectiveness (total, SET) and shielding effectiveness (reflection loss, SER) were as high as 33.3, 34.3, 31.3 and 71.0%, respectively.

Ferrocene-based inhibitors of hepatitis C virus replication that target NS5A with low picomolar in vitro antiviral activity.

An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1'-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat.

Thoracic Endovascular Aortic Repair for Traumatic Thoracic Aortic Injury: A Single-Center Initial Experience.

BACKGROUND: Several publications have documented the technical feasibility and efficacy of stent grafting for aortic injuries. We report short- and mid-term results of thoracic endovascular repair with covered stent grafts for type B blunt thoracic aortic injury. METHODS: We performed a retrospective review of patients who had sustained blunt thoracic aortic injuries. From January 2010 to March 2014, 13 patients (12 men and 1 woman) were admitted and treated in our department for type B thoracic aortic injury. The patients' ages ranged from 19 to 62 years. Traffic accidents were responsible for 10 of the 13 blunt thoracic aortic injuries, and the remainder was caused by blunt trauma from falls. Medical records were examined to identify the clinical outcomes of the procedures, and follow-up computed tomography scans were reviewed to document the efficacy of thoracic endovascular aortic repair. RESULTS: Endovascular stent grafting was technically successful in all cases, and no paraplegia or stroke-like events were reported. No major cardiac, neurologic, or peripheral vascular complications were observed during early or late follow-up. None of the patients died from procedure-related complications. CONCLUSIONS: Our single-center experience demonstrates the feasibility of performing endovascular repair for type B blunt aortic injury. As experience with endovascular surgery accumulates, this method of treatment promises to become the first-choice option for repairing this type of aortic injury, with less associated morbidity and mortality relative to conventional surgical repair.

MiR-31 Downregulation Protects Against Cardiac Ischemia/Reperfusion Injury by Targeting Protein Kinase C Epsilon (PKCε) Directly.

BACKGROUND: Various miRNAs have been shown to participate in cardiac ischemia/reperfusion injury (I/R). miR-31 was identified as the most strikingly upregulated miRNA after acute myocardial infarction; therefore, the underlying role and mechanism of miR-31 in cardiac I/R was investigated. METHODS: miR-31 expression was detected after cardiac I/R in mice. The cardioprotective effect of miR-31 downregulation was assessed in vitro and in vivo. The functional target gene and its downstream molecule were determined. RESULTS: miR-31 expression increased after I/R. miR-31 downregulation increased cell viability and SOD activity and decreased LDH activity and MDA content in vitro. Additionally, miR-31 downregulation alleviated myocardial infarct size in vivo. PKCε was identified as the functional target gene of miR-31, and NFκB was identified as its downstream molecule that was involved in the miR-31-mediated cardioprotective effect. CONCLUSION: miR-31 expression increased throughout the cardiac I/R process, and miR-31 downregulation induced a cardioprotective effect via a miR-31/PKCε/NFκB-dependent pathway.

The use of statins to prevent postoperative atrial fibrillation after coronary artery bypass grafting: a meta-analysis of 12 studies.

There is no agreement on whether statins influence the incidence of atrial fibrillation after coronary artery bypass grafting. We performed a meta-analysis of 12 studies that compared statins with controls. Statin therapy significantly reduced the incidence of postoperative atrial fibrillation (POAF) (odds ratio, 0.50; 95% confidence interval, 0.35-0.73) and length of hospital stay (weighted mean difference, -0.72; 95% confidence interval, -0.99 to -0.45), an effect that survived detailed subgroup analysis. Meta-regression analysis revealed that patient characteristics did not influence the extent of improvement in the incidence of POAF attributable to statins. In conclusion, patients undergoing coronary artery bypass grafting benefit from perioperative treatment with statins, which significantly reduce the incidence of POAF and length of hospital stay.

Image fusion guidance for left subclavian artery in situ fenestration during thoracic endovascular repair.

OBJECTIVES: To evaluate the feasibility and clinical benefit of utilizing image fusion for thoracic endovascular repair (TEVAR) with in situ fenestration (ISF-TEVAR). MATERIALS AND METHODS: Between January 2020 and December 2020, we prospectively collected 18 consecutive cases with complex thoracic aortic lesions who underwent image fusion guided ISF-TEVAR. As a control group, 18 patients were collected from historical medical records from June 2019 to December 2019. The fusion group involved the use of 3D fusion of CTA and fluoroscopic images for real-time 3D guidance, and the control group involved the use of only regular fluoroscopic images for guidance. The total contrast medium volume, hand-injected contrast medium volume, overall operative time, radiation dose and fluoroscopy time were compared between the two groups. Accuracy was measured based on preoperative CTA and intraoperative digital subtraction angiography. RESULTS: 3D fusion imaging guidance was successfully implemented in all patients in the fusion group. Hand-injected contrast medium volume and overall operative time were significantly lower in the fusion group than in the control group (p = .028 and p = .011). Compared with the control group, the fusion group showed a significant reduction in time and radiation dose-area product (DAP) for fluoroscopy (p = .004 and p = .010). No significant differences in total radiation dose (DAP) or total contrast medium volume were observed (p = .079 and p = .443). Full accuracy was achieved in 8 cases (44%), with a mean deviation of 2.61 mm ± 3.1 (range 0.0-8.4 mm). CONCLUSIONS: 3D image fusion for ISF-TEVAR was associated with a significant reduction in hand-injected contrast medium, time and radiation exposure for fluoroscopy and overall operative time. The image fusion guidance showed potential clinical benefits towards improved treatment safety and accuracy for complex thoracic endovascular interventions.

ACH-806, an NS4A antagonist, inhibits hepatitis C virus replication by altering the composition of viral replication complexes.

Treatment of hepatitis C patients with direct-acting antiviral drugs involves the combination of multiple small-molecule inhibitors of distinctive mechanisms of action. ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). It inhibits viral RNA replication in HCV replicon cells and was active in genotype 1 HCV-infected patients in a proof-of-concept clinical trial (1). Here, we describe a potential mechanism of action (MoA) wherein ACH-806 alters viral replication complex (RC) composition and function. We found that ACH-806 did not affect HCV polyprotein translation and processing, the early events of the formation of HCV RC. Instead, ACH-806 triggered the formation of a homodimeric form of NS4A with a size of 14 kDa (p14) both in replicon cells and in Huh-7 cells where NS4A was expressed alone. p14 production was negatively regulated by NS3, and its appearance in turn was associated with reductions in NS3 and, especially, NS4A content in RCs due to their accelerated degradation. A previously described resistance substitution near the N terminus of NS3, where NS3 interacts with NS4A, attenuated the reduction of NS3 and NS4A conferred by ACH-806 treatment. Taken together, we show that the compositional changes in viral RCs are associated with the antiviral activity of ACH-806. Small molecules, including ACH-806, with this novel MoA hold promise for further development and provide unique tools for clarifying the functions of NS4A in HCV replication.

Characterization of nucleosome positioning in hepadnaviral covalently closed circular DNA minichromosomes.

Hepadnaviral covalently closed circular DNA (cccDNA) exists as an episomal minichromosome in the nucleus of virus-infected hepatocytes, and serves as the transcriptional template for the synthesis of viral mRNAs. To obtain insight on the structure of hepadnaviral cccDNA minichromosomes, we utilized ducks infected with the duck hepatitis B virus (DHBV) as a model and determined the in vivo nucleosome distribution pattern on viral cccDNA by the micrococcal nuclease (MNase) mapping and genome-wide PCR amplification of isolated mononucleosomal DHBV DNA. Several nucleosome-protected sites in a region of the DHBV genome [nucleotides (nt) 2000 to 2700], known to harbor various cis transcription regulatory elements, were consistently identified in all DHBV-positive liver samples. In addition, we observed other nucleosome protection sites in DHBV minichromosomes that may vary among individual ducks, but the pattern of MNase mapping in those regions is transmittable from the adult ducks to the newly infected ducklings. These results imply that the nucleosomes along viral cccDNA in the minichromosomes are not random but sequence-specifically positioned. Furthermore, we showed in ducklings that a significant portion of cccDNA possesses a few negative superhelical turns, suggesting the presence of intermediates of viral minichromosomes assembled in the liver, where dynamic hepatocyte growth and cccDNA formation occur. This study supplies the initial framework for the understanding of the overall complete structure of hepadnaviral cccDNA minichromosomes.

Enhancing the Interfacial Shear Strength and Tensile Strength of Carbon Fibers through Chemical Grafting of Chitosan and Carbon Nanotubes.

Multi-scale "rigid-soft" material coating has been an effective strategy for enhancing the interfacial shear strength (IFSS) of carbon fibers (CFs), which is one of the key themes in composite research. In this study, a soft material, chitosan (CS), and a rigid material, carbon nanotubes (CNTs), were sequentially grafted onto the CFs surface by a two-step amination reaction. The construction of the "rigid-soft" structure significantly increased the roughness and activity of the CFs surface, which improved the mechanical interlocking and chemical bonding between the CFs and resin. The interfacial shear strength (IFSS) of the CS- and CNT-modified CFs composites increased by 186.9% to 123.65 MPa compared to the desized fibers. In addition, the tensile strength of the modified CFs was also enhanced by 26.79% after coating with CS and CNTs. This strategy of establishing a "rigid-soft" gradient modulus interfacial layer with simple and non-destructive operation provides a valuable reference for obtaining high-performance CFs composites.

Nanoparticle-dsRNA Treatment of Pollen and Root Systems of Diseased Plants Effectively Reduces the Rate of Tobacco Mosaic Virus in Contemporary Seeds.

Most crop viruses are carried and spread by seeds. Virus-infected seeds are seed-borne viral disease infections, and thus, reducing the rate of seed infection is an urgent problem in the seed-production industry. The objective of this study was to use nanoparticles (NPs) to directly deliver dsRNA into plants or pollen to initiate RNA interference (RNAi) to reduce viral carryover in seeds. Chitosan quaternary ammonium salt (HACC), complexed with dsRNAs, was selected for targeting the genes for the tobacco mosaic virus (TMV) coat protein (CP) and TMV RNA-dependent RNA polymerase (RdRP) to form HACC-dsRNA NPs. These NP-based dsRNAs were delivered to the plants using four different methods, including infiltration, spraying, root soaking, and pollen internalization. All four methods were able to reduce the seed-carrying rate of offspring seeds of the TMV-infected plants, with pollen internalization being the most effective in reducing the TMV-carrying rate from 95.1 to 61.1% in the control group. By measuring the plant uptake of fluorescence-labeled NPs and dsRNAs, the transportation of the HACC-dsRNA NPs into the plants was observed, and the uptake of dsRNA in combination with small RNA sequencing was further confirmed, resulting in the silencing of homologous RNA molecules during the topical application. The results demonstrated that the incidence of TMV infection was reduced by various degrees via RNAi induction without the need to develop transgenic plants. These results demonstrate the advantages of NP-based RNAi technology in breeding for disease resistance and developing a new strategy for virus-resistant breeding in plants.

MiRNA-21 promotes differentiation of bone marrow mesenchymal stem cells into cardiomyocyte-like cells by regulating the Ajuba/Isl1 axis pathway.

Introduction: In this study, we aimed to investigate the role of miRNA-21 and the regulating pathway that promotes the differentiation of bone marrow mesenchymal stem cells (BMSCs). Methods: We used miR-21-OE, miR-21-KD, ajuba-OE and ajuba-KD plasmids to infect BMSCs. The expression of miRNA-21, ajuba, Isl1 and cTnI was detected by RT-qPCR, WB and immunofluorescence staining in groups. Results: MiRNA-21 over-expression increased the expression of Isl1, and vice versa. Ajuba over-expression decreased the expression of Isl1, and vice versa. Ajuba negatively regulated the differentiation of BMSCs into cardiomyocyte-like cells. Conclusions: MiRNA-21 could regulate differentiation of bone marrow mesenchymal stem cells (BMSCs) to cardiomyocyte-like cells through the ajuba/Isl1 axis pathway.

Toll-like receptor 7/8 agonist resiquimod induces late preconditioning in neonatal cardiac myocytes.

AIM: To investigate whether R-848 (resiquimod, toll-like receptor 7/8 agonist) can induce late preconditioning in neonatal cardiac myocytes. METHODS: The protective effects of R-848 on neonatal myocytes against anoxia-reoxygenation-induced injury were tested, and intracellular reactive oxygen species (ROS) were determined. The protein synthesis inhibitor cyclohexamide (CH) and the ROS scavenger N-acetylcysteine (NAC) were used in this model to test if new protein synthesis and oxidative stress were necessary for their cardioprotective effects. The activation of nuclear factor kappa B (NFκB) and hypoxia inducible factor 1 (HIF1) was investigated by electrophoretic mobility shift assays (EMSA), and inducible nitric oxide synthase (iNOS) was assessed by immunoblotting. After iNOS was down-regulated by small interfering RNA (siRNA) transfection, the cardioprotective effect was reassessed. RESULTS: ROS were triggered soon after R-848 (0.01-1.0 µg/L) administration, however, the cardioprotective effect of which was induced 24 h later. This protection was abolished by CH or NAC pretreatment. NFκB and HIF1 activation and iNOS up-regulation were involved in this protective mechanism. The cardioprotective effect was also attenuated after iNOS was knocked down. CONCLUSION: R-848 provided a cardioprotective effect through a late preconditioning mechanism via a ROS/NFκB-HIF1/iNOS-dependent pathway.

Enhancing the reinforcing efficiency in CNT nanocomposites via the development of pyrene-based active dispersants.

Various preforms of carbon nanotubes (CNTs), such as fibers, yarns, or buckypapers (BP), have been developed over the last few years in order to fabricate advanced nanocomposites containing a high volume fraction of the reinforcing phase. However, a homogeneous dispersion and an even isolation of CNTs during the fabrication process of many preforms such as BP is often challenging, while the poor interaction between CNTs and the matrix also limits the final performance of the nanocomposites. Herein, a new route to overcome these two challenges simultaneously has been demonstrated based on an active dispersant (noted as Py-PEI) developed through the quaternization reaction of pyrene derivatives (Py-Br) and polyethylenimine (PEI). The existence of pyrene groups leads to the formation of π-π stacking with CNTs, successfully hindering the re-aggregation of dispersed CNTs. Meanwhile, the amine groups of Py-PEI can establish covalent bonds with epoxy, leading to an enhanced load transfer efficiency between CNTs and epoxy in the composites. Systematic characterization of both fabricated BP and BP-reinforced nanocomposites have been performed, with significantly enhanced CNT dispersion stability in water together with improved mechanical performance of the as-obtained BP/epoxy nanocomposites. This study provides a new strategy in fabricating high performance nanocomposites with the ease of nanofiller dispersion and enhanced reinforcing efficiency.

Genetic characteristics of a patient with multiple primary cancers: A case report.

BACKGROUND: Two or multiple primary malignant neoplasms (MPMNs) rarely occur in the same patient. It has been reported that MPMNs are easily misdiagnosed as the recurrence or metastasis of malignancies in clinical practice, affecting the choice of treatment for the patients, thereby resulting in the delay of optimal diagnosis. Next generation sequencing (NGS) can be used to distinguish between multiple primary lung cancers and intrapulmonary metastasis, and may distinguish the origin of tumours in different sites of the body. CASE SUMMARY: We report the case of 66-year-old woman who suffered from different malignant neoplasms in the rectum and esophageal and gastrointestinal tract. The first neoplasm rectal adenocarcinoma was diagnosed and removed in 2016. The second and third lesions were diagnosed with esophageal squamous-cell carcinoma (ESCC) and gastrointestinal stromal tumour (GIST), respectively, in 2019. Next-generation whole exome sequencing was performed on the tissue specimens of rectal carcinoma, esophageal cancer, GIST, and white blood cells to investigate the relationship between malignancies at different timeframe and determine whether the ESCC and GIST evolved from the rectal adenocarcinoma. Mutations including v-Ki-ras2-Kirsten rat sarcoma viral oncogene homolog, adenomatosis polyposis coli, and mothers against decapentaplegic homolog 4 were detected in rectal adenocarcinoma sample, mast/stem cell growth factor receptor was detected in GIST tissue, and lysine methyltransferase 2D was detected in ESCC specimen. Overall, ESCC and GIST were not genetically evolved from rectal adenocarcinoma, and this patient did not have a trunk driven clone. CONCLUSION: NGS is an effective tool to study clonal evolution of tumours and distinguish between MPMNs and intrapulmonary metastasis.

Prognostic Model to Predict Overall Survival for Metastatic Non-Small Cell Lung Cancer Patients Treated With Chemotherapy Combined With Concurrent Radiation Therapy to the Primary Tumor: Analysis From Two Prospective Studies.

PURPOSE: The role of radiotherapy, in addition to chemotherapy, has not been thoroughly determined in metastatic non-small cell lung cancer (NSCLC). The purpose of the study was to investigate the prognostic factors and to establish a model for the prediction of overall survival (OS) in metastatic NSCLC patients who received chemotherapy combined with the radiation therapy to the primary tumor. METHODS: The study retrospectively reviewed 243 patients with metastatic NSCLC in two prospective studies. A prognostic model was established based on the results of the Cox regression analysis. RESULTS: Multivariate analysis showed that being male, Karnofsky Performance Status score < 80, the number of chemotherapy cycles <4, hemoglobin level ≤120 g/L, the count of neutrophils greater than 5.8 ×109/L, and the count of platelets greater than 220 ×109/L independently predicted worse OS. According to the number of risk factors, patients were further divided into one of three risk groups: those having ≤ 2 risk factors were scored as the low-risk group, those having 3 risk factors were scored as the moderate-risk group, and those having ≥ 4 risk factors were scored as the high-risk group. In the low-risk group, 1-year OS is 67.7%, 2-year OS is 32.1%, and 3-year OS is 19.3%; in the moderate-risk group, 1-year OS is 59.6%, 2-year OS is 18.0%, and 3-year OS is 7.9%; the corresponding OS rates for the high-risk group were 26.2%, 7.9%, and 0% (P<0.001) respectively. CONCLUSION: Metastatic NSCLC patients treated with chemotherapy in combination with thoracic radiation may be classified as low-risk, moderate-risk, or high-risk group using six independent prognostic factors. This prognostic model may help design the study and develop the plans of individualized treatment.

Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats.

Hepatocellular apoptosis, hepatic inflammation, and fibrosis are prominent features in chronic liver diseases. However, the linkage among these processes remains mechanistically unclear. In this study, we examined the apoptosis and activation of Kupffer cells (KCs) as well as their pathophysiological involvement in liver fibrosis process. Hepatic fibrosis was induced in rats by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4) treatment. KCs were isolated from normal rats and incubated with lipopolysaccharide (LPS) or from fibrotic rats. The KCs were stained immunohistochemically with anti-CD68 antibody, a biomarker for KC. The level of expression of CD68 was analyzed by western blot and real-time PCR methods. The apoptosis and pathophysiological involvement of KCs in the formation of liver fibrosis were studied using confocal microscopy. The mRNA and protein expression of CD68 were significantly increased in DMN- and CCL4-treated rats. Confocal microscopy analysis showed that CD68-positive KCs, but not α-smooth muscle actin (SMA)-positive cells, underwent apoptosis in the liver of DMN- and CCL4-treated rats. It was also revealed that the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and CD68-double-positive apoptotic KCs located in the portal or fibrotic septa area were situated next to hepatic stellate cells (HSCs). Tumor necrosis factor-α (TNF-α) and KC co-localized in the liver in the neighbor of HSCs. The double α-SMA- and collagen type I-positive cells predominantly existed in fibrotic septa, and those cells were co-localized clearly with CD68-positive cells. Interestingly, some CD68 and Col (1) double positive, but completely negative for α-SMA, were found in the portal areas and hepatic sinusoids; this phenomenon was also validated in primary isolated KCs after 6 h LPS exposure or fibrotic rats in vitro. These results show that KCs are associated with hepatocellular apoptosis, inflammation, and fibrosis process in a liver fibrosis models.

Discovery of novel 1-phenyl-cycloalkane carbamides as potent and selective influenza fusion inhibitors.

A novel class of HA inhibitors (4a) was identified based on ligand similarity search of known HA inhibitors. Parallel synthesis and further structural modifications resulted in 1-phenyl-cyclopentanecarboxylic acid (4-cyano-phenyl)-methyl-amide 4t as a potent and selective inhibitor to phylogenetic H1 influenza viruses with an EC(50) of 98 nM against H1N1 A/Weiss/43 strain and over 1000-fold selectivity against host MDCK cells.

MicroRNA­542­3p represses OTUB1 expression to inhibit migration and invasion of esophageal cancer cells.

Dysregulation of microRNAs (miRNAs) is involved in the pathogenesis of esophageal cancer. miRNA (miR)­542­3p is a tumor suppressor in multiple types of cancer. However, whether and how miR­542­3p contributes to the progression of esophageal cancer remains unknown, and this is the aim of the present study. In the current study, decreased expression of miR­542­3p was detected in tumor tissues compared with normal tissues from patients with esophageal cancer, and miR­542­3p expression was negatively correlated with mRNA expression levels of ovarian tumor domain­containing ubiquitin aldehyde­binding protein 1 (OTUB1) in tumor tissues from patients with esophageal cancer. In KYSE150 human esophageal squamous cell carcinoma cells, overexpression of miR­542­3p significantly decreased OTUB1 at mRNA and protein levels, whereas downregulation of miR­542­3p significantly increased OTUB1 expression. Using a dual­luciferase assay, OTUB1 was validated to be a target gene of miR­542­3p in KYSE150 cells. Functionally, miR­542­3p significantly inhibited the migration and invasion of KYSE150 cells by repression of OTUB1 expression. These results demonstrated that miR­542­3p may promote the metastasis of esophageal cancer cells, and indicated that miR­542­3p may be a treatment target for esophageal cancer.