Targeting PRSS23 with tipranavir induces gastric cancer stem cell apoptosis and inhibits growth of gastric cancer via the MKK3/p38 MAPK-IL24 pathway.

Gastric cancer stem cells (GCSCs) contribute to the refractory features of gastric cancer (GC) and are responsible for metastasis, relapse, and drug resistance. The key factors drive GCSC function and affect the clinical outcome of GC patients remain poorly understood. PRSS23 is a novel serine protease that is significantly up-regulated in several types of cancers and cancer stem cells, and related to tumor progression and drug resistance. In this study, we investigated the role of PRSS23 in GCSCs as well as the mechanism by which PRSS23 regulated the GCSC functions. We demonstrated that PRSS23 was critical for sustaining GCSC survival. By screening a collection of human immunodeficiency virus (HIV) protease inhibitors (PIs), we identified tipranavir as a PRSS23-targeting drug, which effectively killed both GCSC and GC cell lines (its IC50 values were 4.7 and 6.4 µM in GCSC1 cells and GCSC2 cells, respectively). Administration of tipranavir (25 mg·kg-1·d-1, i.p., for 8 days) in GCSC-derived xenograft mice markedly inhibited the growth of subcutaneous GCSC tumors without apparent toxicity. In contrast, combined treatment with 5-FU plus cisplatin did not affect the tumor growth but causing significant weight loss. Furthermore, we revealed that tipranavir induced GCSC cell apoptosis by suppressing PRSS23 expression, releasing MKK3 from the PRSS23/MKK3 complex to activate p38 MAPK, and thereby activating the IL24-mediated Bax/Bak mitochondrial apoptotic pathway. In addition, tipranavir was found to kill other types of cancer cell lines and drug-resistant cell lines. Collectively, this study demonstrates that by targeting both GCSCs and GC cells, tipranavir is a promising anti-cancer drug, and the clinical development of tipranavir or other drugs specifically targeting the PRSS23/MKK3/p38MAPK-IL24 mitochondrial apoptotic pathway may offer an effective approach to combat gastric and other cancers.

Unraveling the Contribution of MulSOS2 in Conferring Salinity Tolerance in Mulberry (Morus atropurpurea Roxb).

Salinity is one of the most serious threats to sustainable agriculture. The Salt Overly Sensitive (SOS) signaling pathway plays an important role in salinity tolerance in plants, and the SOS2 gene plays a critical role in this pathway. Mulberry not only has important economic value but also is an important ecological tree species; however, the roles of the SOS2 gene associated with salt stress have not been reported in mulberry. To gain insight into the response of mulberry to salt stress, SOS2 (designated MulSOS2) was cloned from mulberry (Morus atropurpurea Roxb), and sequence analysis of the amino acids of MulSOS2 showed that it shares some conserved domains with its homologs from other plant species. Our data showed that the MulSOS2 gene was expressed at different levels in different tissues of mulberry, and its expression was induced substantially not only by NaCl but also by ABA. In addition, MulSOS2 was exogenously expressed in Arabidopsis, and the results showed that under salt stress, transgenic MulSOS2 plants accumulated more proline and less malondialdehyde than the wild-type plants and exhibited increased tolerance to salt stress. Moreover, the MulSOS2 gene was transiently overexpressed in mulberry leaves and stably overexpressed in the hairy roots, and similar results were obtained for resistance to salt stress in transgenic mulberry plants. Taken together, the results of this study are helpful to further explore the function of the MulSOS2 gene, which provides a valuable gene for the genetic breeding of salt tolerance in mulberry.

Interpretable machine-learning model for Predicting the Convalescent COVID-19 patients with pulmonary diffusing capacity impairment.

INTRODUCTION: The COVID-19 patients in the convalescent stage noticeably have pulmonary diffusing capacity impairment (PDCI). The pulmonary diffusing capacity is a frequently-used indicator of the COVID-19 survivors' prognosis of pulmonary function, but the current studies focusing on prediction of the pulmonary diffusing capacity of these people are limited. The aim of this study was to develop and validate a machine learning (ML) model for predicting PDCI in the COVID-19 patients using routinely available clinical data, thus assisting the clinical diagnosis. METHODS: Collected from a follow-up study from August to September 2021 of 221 hospitalized survivors of COVID-19 18 months after discharge from Wuhan, including the demographic characteristics and clinical examination, the data in this study were randomly separated into a training (80%) data set and a validation (20%) data set. Six popular machine learning models were developed to predict the pulmonary diffusing capacity of patients infected with COVID-19 in the recovery stage. The performance indicators of the model included area under the curve (AUC), Accuracy, Recall, Precision, Positive Predictive Value(PPV), Negative Predictive Value (NPV) and F1. The model with the optimum performance was defined as the optimal model, which was further employed in the interpretability analysis. The MAHAKIL method was utilized to balance the data and optimize the balance of sample distribution, while the RFECV method for feature selection was utilized to select combined features more favorable to machine learning. RESULTS: A total of 221 COVID-19 survivors were recruited in this study after discharge from hospitals in Wuhan. Of these participants, 117 (52.94%) were female, with a median age of 58.2 years (standard deviation (SD) = 12). After feature selection, 31 of the 37 clinical factors were finally selected for use in constructing the model. Among the six tested ML models, the best performance was accomplished in the XGBoost model, with an AUC of 0.755 and an accuracy of 78.01% after experimental verification. The SHAPELY Additive explanations (SHAP) summary analysis exhibited that hemoglobin (Hb), maximal voluntary ventilation (MVV), severity of illness, platelet (PLT), Uric Acid (UA) and blood urea nitrogen (BUN) were the top six most important factors affecting the XGBoost model decision-making. CONCLUSION: The XGBoost model reported here showed a good prognostic prediction ability for PDCI of COVID-19 survivors during the recovery period. Among the interpretation methods based on the importance of SHAP values, Hb and MVV contributed the most to the prediction of PDCI outcomes of COVID-19 survivors in the recovery period.

Banxia-Houpu decoction diminishes iron toxicity damage in heart induced by chronic intermittent hypoxia.

CONTEXT: Obstructive sleep apnoea (OSA) causes chronic intermittent hypoxia (CIH), which results in mitochondrial dysfunction and generates reactive oxygen species (ROS) in the heart. Excessive free iron could accelerate oxidative damage, which may be involved in this process. Banxia-Houpu decoction (BHD) was reported to improve the apnoea hypopnoea index in OSA patients, but the specific mechanism was still unclear. OBJECTIVE: To investigate whether BHD could reduce CIH-induced heart damage by regulating iron metabolism and mitochondrial function. MATERIALS AND METHODS: C57BL/6N mice were randomly divided into control, CIH and BHD groups. Mice were exposed to CIH (21 - 5% O2, 20 times/h, 8 h/d) and administered BHD (3.51, 7.01 and 14.02 g/kg, intragastrically) for 21 d. Cardiac and mitochondrial function, iron levels, apoptosis and mitophagy were determined. RESULTS: BHD (7.01 g/kg) significantly improved cardiac dysfunction, pathological change and mitochondrial structure induced by CIH. BHD increased the Bcl-2/Bax ratio (1.4-fold) and inhibited caspase 3 cleavage in CIH mice (0.45-fold). BHD activated mitophagy by upregulating Parkin (1.94-fold) and PINK1 (1.26-fold), inhibiting the PI3K-AKT-mTOR pathway. BHD suppressed ROS generation by decreasing NOX2 (0.59-fold) and 4-HNE (0.83-fold). BHD reduced the total iron in myocardial cells (0.72-fold) and mitochondrial iron by downregulating Mfrn2 (0.81-fold) and MtFt (0.78-fold) proteins, and upregulating ABCB8 protein (1.33-fold). Rosmarinic acid, the main component of Perilla Leaf in BHD, was able to react with Fe2+ and Fe3+ in vitro. DISCUSSION AND CONCLUSIONS: These findings encourage the use of BHD to resist cardiovascular injury and provide the theoretical basis for clinical treatment in OSA patients.

Nomograms to Predict Overall and Cancer-Specific Survival in Gastric Signet-Ring Cell Carcinoma.

BACKGROUND: The objective of our study was to develop and validate nomograms to predict the overall survival (OS) and cancer-specific survival (CSS) of patients with signet-ring cell carcinoma (SRCC) of the stomach. METHODS: Data were collected from the Surveillance, Epidemiology, and End Results (SEER) database. A total of 1781 patients were randomly allocated to a training set (n = 1335) and a validation set (n = 446). Univariate and multivariate analyses were used to determine the prognostic effect of variables. Nomograms were developed to estimate OS and CSS and assessed using the concordance index (C-index), calibration curves, receiver operating characteristic (ROC), and decision curve analyses (DCA). DCA was utilized to compare the nomograms and the Tumor-Node-Metastasis (TNM) staging system. RESULTS: Age, race, tumor size, T, N, M stage, and use of surgery and/or radiotherapy were included in the nomograms. C-indexes for OS and CSS were 0.74 and 0.75 in the training set, respectively. C-indexes for OS and CSS were 0.76 and 0.76 in the validation set. Calibration plots and receiver operating characteristic (ROC) curves showed good predictive accuracy. According to the decision curve analyses (DCA), the new model was more useful than the TNM staging system. CONCLUSIONS: We developed nomograms to predict OS and CSS in patients with SRCC of the stomach. Nomograms may be a valuable clinical supplement of the conventional TNM staging system.

Assembly of polycyclic N-heterocycles via copper-catalyzed cycloamination of indolylquinones and aromatic amines.

The copper-catalyzed cycloamination of indolylquinones and various (hetero)aromatic amines under ligand-free conditions for the synthesis of polycyclic N-heterocycles has been developed. This method allows facile access to polycyclic N-heterocycles with the tolerance of chloride, bromide, amino, thio, etc. groups in moderate to high yields (60-89%).

Early Use of Corticosteroid May Prolong SARS-CoV-2 Shedding in Non-Intensive Care Unit Patients with COVID-19 Pneumonia: A Multicenter, Single-Blind, Randomized Control Trial.

BACKGROUND: There is still no clinical evidence available to support or to oppose corticosteroid treatment for coronavirus disease 2019 (COVID-19) pneumonia. OBJECTIVE: To investigate the efficacy and safety of corticosteroid given to the hospitalized patients with COVID-19 pneumonia. METHODS: This was a prospective, multicenter, single-blind, randomized control trial. Adult patients with COVID-19 pneumonia who were admitted to the general ward were randomly assigned to either receive methylprednisolone or not for 7 days. The primary end point was the incidence of clinical deterioration 14 days after randomization. RESULTS: We terminated this trial early because the number of patients with COVID-19 pneumonia in all the centers decreased in late March. Finally, a total of 86 COVID-19 patients underwent randomization. There was no difference of the incidence of clinical deterioration between the methylprednisolone group and control group (4.8 vs. 4.8%, p = 1.000). The duration of throat viral RNA detectability in the methylprednisolone group was 11 days (interquartile range, 6-16 days), which was significantly longer than that in the control group (8 days [2-12 days], p = 0.030). There were no significant differences between the 2 groups in other secondary outcomes. Mass cytometry discovered CD3+ T cells, CD8+ T cells, and NK cells in the methylprednisolone group which were significantly lower than those in the control group after randomization (p < 0.05). CONCLUSIONS: From this prematurely closed trial, we found that the short-term early use of corticosteroid could suppress the immune cells, which may prolong severe acute respiratory syndrome coronavirus 2 shedding in patients with COVID-19 pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04273321.

Analysis of the Relationship Between Modic Change and Spinopelvic Parameters in the Sagittal Plane.

BACKGROUND This study explored relationship between Modic change and spinopelvic parameters in the sagittal plane. MATERIAL AND METHODS We divided 80 patients into 4 groups: 60 subjects diagnosed with Modic changes (MC) were enrolled in the MC groups (MC1, MC2, and MC3) with each MC type consisting of 20 subjects, and 60 healthy subjects were enrolled in the control group. Spinopelvic parameters in the sagittal plane were calculated to assess their associations with MC. Multivariate logistic regression was used to explore possible risk factors for MC. RESULTS PI and LL in the MC groups were significant smaller than in the control group (p<0.05). PI, SS, and PT were significantly correlated with LL with a correlation coefficient of 0.75PI, 0.71SS and 0.69PT (p<0.05). Multivariate logistic regression of the significant variables showed that PI (less than 43.2°) is an independent significant risk factor for MC. ROC analysis showed that moderate diagnostic value was obtained for the significant variable, with an area under the curve (AUC) of 0.80 (p>0.05). CONCLUSIONS We concluded that PI is risk factor for MC, and smaller PI is associated with higher incidence of MC.

Integrated Phloem Sap mRNA and Protein Expression Analysis Reveals Phytoplasma-infection Responses in Mulberry.

To gain insight into the response of mulberry to phytoplasma-infection, the expression profiles of mRNAs and proteins in mulberry phloem sap were examined. A total of 955 unigenes and 136 proteins were found to be differentially expressed between the healthy and infected phloem sap. These differentially expressed mRNAs and proteins are involved in signaling, hormone metabolism, stress responses, etc. Interestingly, we found that both the mRNA and protein levels of the major latex protein-like 329 (MuMLPL329) gene were increased in the infected phloem saps. Expression of the MuMLPL329 gene was induced by pathogen inoculation and was responsive to jasmonic acid. Ectopic expression of MuMLPL329 in Arabidopsis enhances transgenic plant resistance to Botrytis cinerea, Pseudomonas syringae pv tomato DC3000 (Pst. DC3000) and phytoplasma. Further analysis revealed that MuMLPL329 can enhance the expression of some defense genes and might be involved in altering flavonoid content resulting in increased resistance of plants to pathogen infection. Finally, the roles of the differentially expressed mRNAs and proteins and the potential molecular mechanisms of their changes were discussed. It was likely that the phytoplasma-responsive mRNAs and proteins in the phloem saps were involved in multiple pathways of mulberry responses to phytoplasma-infection, and their changes may be partially responsible for some symptoms in the phytoplasma infected plants.

Characterization of NPR1 and NPR4 genes from mulberry (Morus multicaulis) and their roles in development and stress resistance.

The quality and quantity of mulberry leaves are often affected by various environmental factors. The plant NPR1 and its homologous genes are important for plant systemic acquired resistance. Here, the full-length cDNAs encoding the NPR1 and NPR4 genes (designated MuNPR1 and MuNPR4, respectively) were isolated from Morus multicaulis. Sequence analysis of the amino acids and protein modeling of the MuNPR1 and MuNPR4 proteins showed that MuNPR1 shares some conserved characteristics with its homolog MuNPR4. MuNPR1 was shown to have different expression patterns than MuNPR4 in mulberry plants. Interestingly, MuNPR1 or MuNPR4 transgenic Arabidopsis produced an early flowering phenotype, and the expression of the pathogenesis-related 1a gene was promoted in MuNPR1 transgenic Arabidopsis. The MuNPR1 transgenic plants showed more resistance to Pseudomonas syringae pv. tomato DC3000 (Pst. DC3000) than did the wild-type Arabidopsis. Moreover, the ectopic expression of MuNPR1 might lead to enhanced scavenging ability and suppress collase accumulation. In contrast, the MuNPR4 transgenic Arabidopsis were hypersensitive to Pst. DC3000 infection. In addition, transgenic Arabidopsis with the ectopic expression of either MuNPR1 or MuNPR4 showed sensitivity to salt and drought stresses. Our data suggest that both the MuNPR1 and MuNPR4 genes play a role in the coordination between signaling pathways, and the information provided here enables the in-depth functional analysis of the MuNPR1 and MuNPR4 genes and may promote mulberry resistance breeding in the future.

Percutaneous full endoscopic posterior decompression of thoracic myelopathy caused by ossification of the ligamentum flavum.

PURPOSE: Ossification of ligamentum flavum (OLF) is the leading cause of progressive thoracic myelopathy (TM) in East Asian countries. Surgical decompression is the general treatment for TM. This study investigated the application of percutaneous full endoscopic posterior decompression (PEPD) for the treatment of thoracic OLF. METHODS: Eighteen patients with TM were treated by PEPD under local anaesthesia. Patients had an average age of 59.1 years and single-level lesions mostly at the lower thoracic vertebrae. Computed tomography and magnetic resonance imaging were used to classify the OLF. The pre- and postoperative neurological statuses were evaluated using the American Spinal Injury Association (ASIA) sensory and motor score, modified Japanese Orthopaedic Association (mJOA) score and Frankel grade. RESULTS: OLF for all patients was classed as lateral, extended, and enlarged types without comma and tram track signs. Decompression was completed, and a dome-shaped laminotomy was performed through limited laminectomy and flavectomy. Dural tears in 2 patients were the only observed complication. The average score of ASIA sensory and motor, mJOA, as well as the Frankel grade improved significantly after surgery at an average follow-up time of 17.4 months. The average recovery rate (RR) was 47.5% as calculated from the mJOA scores. According to RR, 10 cases were classified as good, 4 cases fair, and 4 cases unchanged. CONCLUSIONS: For patients with thoracic OLF at a single level and lateral, extended, and enlarged types without comma and tram track signs, it is safe and reliable to perform PEPD, which has satisfactory clinical results. These slides can be retrieved under Electronic Supplementary Material.

[Research on influence of environment factors to yield and quality traits of Perilla frutescen].

The research is aimed to study of the influence of environmental factors on the yield and quality traits, and find out the regularity of the growth and development of perilla. The main environmental factor data in six ecological area in Guizhou province were collected, and the correlation analysis with yield and quality traits of 15 perilla strains was conducted. The results showed that the cultivation environment has significant effects on the yield and quality traits of perilla. The effect of environment on main yield composed traits, contained grain number in top spike, effective panicle number per plant, plant height, top spike length, growth period, and thousand seed weight was degressive. In the different environmental factors, the latitude showed positive correlation with yield, growth period and effective panicle number per plant, and negative correlation with top spike length and grain number in top spike. Elevation showed negative correlation with the growth period of perilla. The perilla yield increased at first and then decreased with altitude rising, with the maximum in the 800 m altitude. The 600-900 m altitude is suitable area for perilla. Except for positive correlation with the plant height, and negative correlation with top spike length, the longitude showed in apparent impact on other traits. Sunshine duration, temperature and rainfall accumulation showed different effect on the different perilla strains. For yield composed traits, the sunshine duration was negatively correlation with the plant length. The accumulated temperature and mean temperature showed negative correlation with the main spike length, the rainfall showed negative correlation with the precipitation and growth period, plant height, ear number. The environmental impact on the oil compounds decreased with oleic acid, stearic acid, linoleic acid, α-linolenic acid, palmitic acid and oil content. Correlation analysis showed that the significantly negative correlation between the oil content and palmitic acid and linoleic acid content, and the positive correlation between linolenic acid content, α-linolenic acid content showed significant negative correlation with other fatty acids composition, and palmitic acid, stearic acid, oleic acid, linoleic acid showed significant positive correlation with each other. The influence of different environmental factors on the quality of perilla were as follows: the oil content was positively associated with elevation and sunshine duration. α-Linolenic acid content showed negative correlation with longitude, latitude, accumulated temperature and mean temperature, but positive correlation with altitude, sunlight and rainfall capacity. The correlation between palmitic acid, stearic acid, oleic acid, linoleic acid and environmental factors showed contrast character of α-linolenic acid. This study detailed discussed the influence of environmental factors on the quality of perilla, which provided the foundation of ecological planting technology and geoherbalism research of perilla.

SPOP promotes SIRT2 degradation and suppresses non-small cell lung cancer cell growth.

SIRT2 is a NAD-dependent deacetylase and inhibition of SIRT2 has a broad anticancer activity. Here we report that SPOP binds to SIRT2 and mediates its degradation by the 26S proteasome, which can be blocked by MG132 treatment. We also found that the levels of SPOP significantly decreased, while the levels of SIRT2 significantly increased in non-small cell lung cancer (NSCLC) cell lines, compared to normal bronchial epithelial cell line and NSCLC specimens, compared to the paired non-tumor lung tissue. Furthermore, SPOP can suppress NSCLC cell growth. Notably, mutations in NSCLC inhibit the abilities of SPOP to degrade SIRT2 and suppress NSCLC cell growth. These results reveal a novel regulation of SIRT2 by SPOP mediated degradation, which is important for the growth of lung tumor cells.

Clinical Analysis of Polyethylene Glycol Interferon-α Treatment in 155 Hepatitis B e Antigen (HBeAg)-Positive Chronic Hepatitis B (CHB) Patients.

PURPOSE: This study aims to investigate the antiviral effect of polyethylene glycol (PEG)-interferon α-2a and PEG-interferon α-2b treatment on hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) at the 48th week of treatment and the 24th and 48th week after withdrawal, in order to provide guidance on the antiviral treatment of HBeAg-positive CHB patients. MATERIAL AND METHODS: Antiviral treatment was performed on 155 HBeAg-positive CHB patients. Among these patients, 66 patients received PEG-interferon α-2a treatment and 89 patients received PEG-interferon α-2b treatment; and these treatments were administered by subcutaneous injection, once per week, which lasted for 48 weeks. Other antiviral and hepatoprotective drugs were not used during the treatment. RESULTS: At the 48th week of treatment, ALT recovery rate, HBsAg seroconversion rate, HBeAg seroconversion rate and HBV DNA titers dropped below 200 IU/mL rate were 69.7%, 6.1%, 27.3% and 50.0%, respectively, in the PEG-interferon α-2a group; and were 70.8%, 6.7%, 33.7% and 62.9%, respectively, in the PEG-interferon α-2b group. At the 24th and 48th week of follow-up after withdrawal, HBsAg seroconversion rate in these two groups did not change; and HBeAg seroconversion rate further increased. Furthermore, HBV DNA revealed a low recurrence rate. The difference between these two groups was not significantly significant. CONCLUSIONS: PEG-interferon α-2a and PEG-interferon α-2b are effective antiviral drugs for the treatment of HbeAgpositive CHB, which has a HBsAg seroconversion rate of more than 5%. Furthermore, this sustained response effect was maintained at the 24th and 48th week of follow-up after withdrawal.

Cardioprotective effect of nicorandil against myocardial injury following cardiac arrest in swine.

INTRODUCTION: Nicorandil, a vasodilatory drug used to treat angina, was reported to protect against myocardial ischemia-reperfusion injury in various animal models. However, its cardioprotective action following cardiac arrest is unknown. We examined the cardioprotective effects of nicorandil in a porcine model of cardiac arrest and resuscitation. METHODS: Ventricular fibrillation was induced electrically for 4min in anesthetized domestic swine, followed by cardiopulmonary resuscitation. Sixteen successfully resuscitated animals were randomized to saline control (n=8) or nicorandil (n=8) groups. Nicorandil (150µg/kg) was administered by central intravenous injection at onset of restoration of spontaneous circulation (ROSC), followed by 3µg/kg/min infusion until reperfusion end. Sham-operated animals received surgery only (n=4). Hemodynamic parameters were monitored continuously. Blood samples were taken at baseline, 5, 30, 180, and 360min after ROSC. Left ventricular ejection fraction was assessed by echocardiography at baseline and 6h after ROSC. The animals were euthanized 6h after ROSC, and the cardiac tissue was removed for analysis. RESULTS: 6 h after ROSC, nicorandil had significantly improved all hemodynamic variables (all P<0.05) except the maximum rate of left ventricular pressure decline and heart rate (P>0.05) compared with the control group. Control animals showed elevated cardiac troponin I and lactate levels compared with sham animals, which were significantly decreased following nicorandil treatment (P<0.05). In the saline control group, the adenosine triphosphate (ATP) content was largely reduced but subsequently rescued by nicorandil (P<0.05). Histopathologic injury was reduced with nicorandil treatment. Nicorandil reduced cardiomyocyte apoptosis as evidenced by reduced terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, decreased Bax and caspase-3 expression, and increased Bcl-2 expression in the myocardium (all P<0.05). CONCLUSION: Nicorandil exhibited cardioprotective effects on myocardial injury following cardiac arrest via improvement in post-resuscitation myocardial dysfunction and energy metabolism, reduction in myocardial histopathologic injury, and antiapoptotic effects.

Domino Cyclization of 1,n-Enynes (n = 7, 8, 9) Giving Derivatives of Pyrane, Chromene, Fluorene, Phenanthrene and Dibenzo[7]annulene by Ruthenium Complexes.

Cyclization of the ether enyne 1 catalyzed by [Ru]NCCH3(+) ([Ru] = Cp(PPh3)2Ru) in CHCl3 generates a diastereomeric mixture of the substituted tetrahydropyran 11. Presumably, formation of an allenylidene complex is followed by a cyclization by nucleophilic addition of the olefinic group to Cγ of the ligand giving a boat-like six-membered ring. The diastereoselectivity is controlled by the 1,3-diaxial interaction. The vinylidene complex 7, a precursor of 11, is obtained from 1 and [Ru]Cl. In a mixture of MeOH/CHCl3, the domino cyclization of 1 further affords 14a, a chromene product catalytically. The second cyclization proceeds via nucleophilic addition of the resulting olefinic unit to Cα of 7. But the ether enyne 3 with a cyclopentyl ring on the olefinic unit undergoes only single cyclization due to steric effect. The propargyl alcohol and the two terminal methyl groups on the olefinic unit shape the cyclization. Thus, similar all-carbon 1,n-enynes (n = 7, 8, 9) 4-6 each with an aromatic linker undergo direct domino cyclization catalyzed by [Ru]NCCH3(+), to give derivatives of tricyclic fluorene, phenanthrene and dibenzo[7]annulene, respectively, with no intermediate observed.

Effective targeting of colorectal cancer cells using TORC1/2 kinase inhibitors in vitro and in vivo.

AIM: We investigated the effects of TORC1/2 kinase inhibitors on colorectal cancer (CRC) cell lines. MATERIALS & METHODS: Using selective TORC1/2 inhibitors, rapamycin and PP242, we assessed their effect on the growth of CRC cells in vitro and tumor growth in vivo. RESULTS: Rapamycin and PP242 inhibit proliferation and induce apoptosis of CRC cells. They also enhance proapoptotic effect of conventional chemo drug doxorubicin in CRC cells in vitro. When combined with doxorubicin, rapamycin and PP242 almost completely inhibit tumor growth in vivo. Rapamycin and PP242 inhibit phosphorylation of Akt, ribosomal S6 kinase, 4EBP1 and mTOR. CONCLUSION: Our study suggests rapamycin and PP242 may be a useful therapeutic agent and inhibiting mTOR signaling pathway represents a new targeted therapy for CRC.

SURGICAL REMOVAL OF DENSE POSTERIOR CAPSULE OPACIFICATION AND VITREOUS FLOATERS IN ADULTS BY POSTERIOR CONTINUOUS CURVILINEAR CAPSULORHEXIS THROUGH THE PARS PLANA AND 23-GAUGE VITRECTOMY.

PURPOSE: To evaluate the safety and efficacy of posterior continuous curvilinear capsulorhexis through the pars plana and 23-gauge vitrectomy in surgical management of dense posterior capsule opacification and vitreous floaters. METHODS: Fifteen pseudophakic eyes of 15 patients with dense posterior capsule opacification and vitreous floaters between September 2012 and June 2014 were included; after vitrectomy, posterior continuous curvilinear capsulorhexis through the pars plana was performed. Data were collected, including baseline preoperative characteristics, postoperative outcomes, complications, and a modified quality-of-life survey that patients completed. RESULTS: No intraoperative or postoperative complications were encountered in any of the 15 cases. Mean Snellen best-corrected visual acuity was 20/250 preoperatively and improved to 20/32 postoperatively (P < 0.001). All patients showed normal intraocular pressure 7 days after the procedure. The mean overall corneal endothelial cell loss at postoperative Month 3 was 1.2%. Approximately 80% of the patients had no complaint of vitreous floaters after the procedure. Except for 1 patient (7%) diagnosed with age-related macular degeneration, the rest of the patients (93%) were satisfied with the procedure and would recommend it to friends with dense posterior capsule opacification and vitreous floaters. CONCLUSION: Posterior continuous curvilinear capsulorhexis through the pars plana combined with 23-gauge vitrectomy may be used to remove dense posterior capsule opacification and vitreous floaters in pseudophakic eyes.

Overexpression of miR-100 inhibits cancer growth, migration, and chemosensitivity in human NSCLC cells through fibroblast growth factor receptor 3.

Nonsmall cell lung cancer (NSCLC) is a commonly occurring lung cancer. A combination of molecular biological treatments with regular chemotherapy may result in improved therapeutic outcome. Here, we reported significantly higher levels of fibroblast growth factor receptor 3 (FGFR3) and significantly lower levels of miR-100 in the NSCLC specimen, compared to the paired NSCLC-adjacent normal lung tissues. Moreover, the levels of FGFR3 and miR-100 were inversely correlated. Bioinformatics analyses followed by luciferase reporter assay showed that miR-100 bound to the 3'-UTR of FGFR3 messenger RNA (mRNA) to inhibit its translation. Overexpression of miR-100 in NSCLC cells decreased FGFR3 protein levels, whereas inhibition of miR-100 increased FGFR3 protein levels, without affecting FGFR3 mRNA levels. Furthermore, overexpression of miR-100 suppressed cancer growth, migration, and chemosensitivity in NSCLC cells, while inhibition of miR-100 significantly facilitated them. Taken together, our data demonstrate that miR-100 may inhibit NSCLC through FGFR3.