Hepatocyte growth factor promotes retinal pigment epithelium cell activity through MET/AKT signaling pathway

AIM:To explore the effects of hepatocyte growth factor(HGF)on retinal pigment epithelium(RPE)cell behaviors.METHODS:The human adult retinal pigment epithelial cell line-19(ARPE-19)were treated by HGF or mesenchymalepithelial transition factor(MET)inhibitor SU11274 in vitro.Cell viability was detected by a Cell Counting Kit-8 assay.Cell proliferation and motility was detected by a bromodeoxyuridine incorporation assay and a wound healing assay,respectively.The expression levels of MET,phosphorylated MET,protein kinase B(AKT),and phosphorylated AKT proteins were determined by Western blot assay.The MET and phosphorylated MET proteins were also determined by immunofluorescence assay.RESULTS:HGF increased ARPE-19 cells’viability,proliferation and migration,and induced an increase of phosphorylated MET and phosphorylated AKT proteins.SU11274 significantly reduced cell viability,proliferation,and migration and decreased the expression of MET and AKT proteins.SU11274 suppressed HGF-induced increase of viability,proliferation,and migration in ARPE-19 cells.Additionally,SU11274 also blocked HGF-induced phosphorylation of MET and AKT proteins.CONCLUSION:HGF enhances cellular viability,proliferation,and migration in RPE cells through the MET/AKT signaling pathway,whereas this enhancement is suppressed by the MET inhibitor SU11274.HGF-induced MET/AKT signaling might be a vital contributor of RPE cells survival.

Role of savolitinib in advanced gastric adenocarcinoma with meningeal carcinomatosis and cerebellar metastasis:A case report

BACKGROUND Brain metastases(BM)are very rare in gastric adenocarcinoma(GaC),and patients with BMs have a higher mortality rate due to stronger tumor aggressiveness.However,its pathogenesis remains unclear.Genetic testing revealed cellular-mesenchymal epithelial transition factor receptor(MET)amplification.Therefore,treatment with savolitinib,a small molecule inhibitor of c-Met,was selected.CASE SUMMARY A 66-year-old woman was diagnosed with advanced GaC 6 months prior to presentation due to back pain.Cerebellar and meningeal metastases were observed during candonilimab combined with oxaliplatin and capecitabine therapy.The patient experienced frequent generalized seizures and persistent drowsiness in the emergency department.Genetic testing of cerebrospinal fluid and peripheral blood revealed increased MET amplification.After discussing treatment options with the patient,savolitinib tablets were administered.After a month of treatment,the intracranial lesions shrank considerably.CONCLUSION BM is very rare in advanced GaC,especially in meningeal cancer,that is characterized by rapid disease deterioration.There are very few effective treatment options available;however,technological breakthroughs in genomics have provided a basis for personalized treatment.Furthermore,MET amplification may be a key driver of BM in gastric cancer;however,this conclusion requires further investigation.

Mesenchymal-epithelial Transition Factor Regulates Monocyte Function during Mycobacterial Infection via Indoleamine 2,3-dioxygenase

Objective Mycobacterium tuberculosis(Mtb),the causative agent of tuberculosis(TB),causes an estimated 1.6 million human deaths annually,but the pathogenesis of TB remains unclear.Immunity plays a critical role in the onset and outcome of TB.This study aimed to uncover the roles of innate and adaptive immunity in TB.Methods The gene expression profiles generated by RNA sequencing from human peripheral blood mononuclear cells(PBMCs)stimulated with or without Mtb strain H37Rv antigens were analyzed.A total of 973 differentially expressed mRNAs were identified.Results The differentially expressed genes were enriched in innate immunity signaling functions.The mesenchymal-epithelial transition factor(MET)gene was significantly upregulated in CD14^(+)monocytes.A MET inhibitor improved the uptake of the BCG strain by monocytes and macrophages as well as inhibited the expression of indoleamine 2,3-dioxygenase(IDO).The expression of IDO was increased in PBMCs stimulated with Mtb antigens,and the IDO inhibitor promoted the expression of CD40,CD83,and CD86.Conclusion Our results might provide clues regarding the immunomodulatory mechanisms used by Mtb to evade the host defense system.

Transcriptional Factor Snail Mediates Epithelial-Mesenchymal Transition in Human Bronchial Epithelial Cells Induced by Silica

Epithelial-mesenchymal transition （EMT） plays an important role in fibrotic diseases. We have previously showed that silica induces EMT in human bronchial epithelial cells （BECs）; however, the underlying mechanism of silica-induced EMT is poorly understood. In the present study, we investigated the role of Snail in silica-induced EMT in human BECs in vitro. Human BECs were treated with silica at various concentrations and incubation times. Then MTr assay, western blot, electrophoretic mobility shift assay （EMSA）, and small interfering RNA （siRNA） transfection were performed. We found that silica increased the expression and DNA binding activity of Snail in human BECs. SNAI silica-induced expression siRNA upregulated the siRNA inhibited the of Snail. Moreover, SNAI expression of epithelial marker E-cadherin, but attenuated the expression of mesenchymal marker a-smooth muscle actin and vimentin in silica-stimulated cells. These results suggest that Snail mediates the silica-induced EMT in human BECs.

EDIL3 depletion suppress epithelial-mesenchymal transition of lens epithelial cells via transforming growth factor β pathway

AIM： To study the effect of discoidin I-like domaincontaining protein 3（EDIL3） depletion on the proliferation and epithelial-mesenchymal transition（EMT） in human lens epithelial cells（LECs）. METHODS： RNA interference was used to inhibit the expression of EDIL3 in human LECs in vitro. The morphology of cells was observed using an inverted microscope. Cell proliferation was assessed using Ed U kit. Cell migration was investigated using Transwell chamber and EMT of LECs was assessed using confocal microscope and Western blotting. The transforming growth factor β（TGFβ） pathway was investigated using Western blotting. RESULTS： The data showed that silencing EDIL3 expression changed LECs morphology and suppressed LECs proliferation（P〈0.05） and migration（P〈0.01）. Furthermore, the result of Western blotting showed that EDIL3 depletion reduced the expression of α-smooth muscle actin（α-SMA）（P〈0.001） and vimentin（P〈0.01）, while increased the expression of E-cadherin（P〈0.001）. EDIL3 depletion could suppress the phosphorylation of Smad2（P〈0.01） and Smad3（P〈0.01） and the activation of exracellular signal regulated kinase（ERK）（P〈0.05）. CONCLUSION： The findings indicate that EDIL3 might participate in the proliferation and EMT in LECs via TGFβ pathway and may be a potential therapeutic target for the treatment of posterior capsule opacification.

Theoretical study of spin-forbidden cooling transitions of indium hydride using ab initio methods

The feasibility of spin-forbidden cooling of the In H molecule is investigated based on ab initio quantum chemistry calculations. The potential energy curves for the X^1Σ0^＋^＋, a^3Π0-, a^3Π0^＋, a^3Π1, a-3Π2, A-1Π1, 1-3Σ^0^-＋, and 1-3Σ1-＋states of In H are obtained based on multi-reference configuration interaction plus the Davidson corrections method. The calculated spectroscopic constants are in good agreement with the available experimental data. In addition, the influences of the active space and spin–orbit coupling effects on the potential energy curves and spectroscopic constants are also studied. For Re of a^3Π0^-, a^3Π0^＋, a^3Π1, and a-3Π2 states, the error from large active space is small. The potential energy curve of the A-1Π1state is not smooth for small active space. The spin–orbit coupling effects have great influences on the potential well depth and equilibrium internuclear distance of the A-1Π state. The Franck–Condon factors and radiative lifetimes are obtained on the basis of the transition dipole moments of the a^3Π0^＋）→ X^1Σ0^＋^＋, a-3Π1 → X-1Σ0^＋-＋, and A-1Π1 → X-1Σ0^＋^＋ transitions. Our calculation indicates that the a^3Π1（ ν＇= 0） → X-1Σ0^＋^＋（ν = 0） transition provides a highly diagonally distributed Franck–Condon factor and a short radiative lifetime for the a3Π1 state, which can ensure rapid and efficient laser cooling of In H.The proposed laser drives a-3Π1 → X-1Σ0^＋^＋ transitions by using three wavelengths.

Pion-photon and kaon-photon transition distribution amplitudes in the Nambu–Jona-Lasinio model

The Nambu–Jona-Lasinio model is utilized to investigate the pion-and kaon-photon leading-twist transition distribution amplitudes using proper time regularization.Separately,the properties of the vector and axial vector pion-photon transition distribution amplitudes are examined,and the results meet the desired properties.Our study involves sum rule and polynomiality condition.The vector and axial vector pion-photon transition form factors that are present in theπ^(+)→γe^(+)νprocess are the first Mellin moments of the pion-photon transition distribution amplitudes.The vector transition form factor originates from the internal structure of hadrons,the axial current can be coupled to a pion,this pion is virtual,and its contribution will be present independently of the external hadrons.The kaon transition form factors are similar.The vector form factor's value at zero momentum transfer is determined by the axial anomaly,while this is not the case for the axial one.The vector and axial form factors,as well as the neutral pion vector form factor F_(πγγ)(t),are depicted.According to our findings,the pion axial transition form factor is harder than the vector transition form factor and harder than the electromagnetic form factor.We also discuss the link betweenπ−γandγ−πtransitions distribution amplitudes.

Murine hepatocellular carcinoma derived stem cells reveal epithelial-to-mesenchymal plasticity

AIM To establish a model to enrich and characterize stemlike cells from murine normal liver and hepatocellular carcinoma(HCC) cell lines and to further investigate stem-like cell association with epithelial-to-mesenchymal transition(EMT).METHODS In this study,we utilized a stem cell conditioned serumfree medium to enrich stem-like cells from mouse HCC and normal liver cell lines,Hepa 1-6 and AML12,respectively.We isolated the 3-dimensional spheres and assessed their stemness characteristics by evaluating theRNA levels of stemness genes and a cell surface stem cell marker by quantitative reverse transcriptase-PCR(q RTPCR).Next,we examined the relationship between stem cells and EMT using q RT-PCR.RESULTS Three-dimensional spheres were enriched by culturing murine HCC and normal hepatocyte cell lines in stem cell conditioned serum-free medium supplemented with epidermal growth factor,basic fibroblast growth factor and heparin sulfate.The 3-dimensional spheres had enhanced stemness markers such as Klf4 and Bmi1 and hepatic cancer stem cell(CSC) marker Cd44 compared to parental cells grown as adherent cultures.We report that epithelial markers E-cadherin and ZO-1 were downregulated,while mesenchymal markers Vimentin and Fibronectin were upregulated in 3-dimensional spheres.The 3-dimensional spheres also exhibited changes in expression of Snai,Zeb and Twist family of EMT transcription factors.CONCLUSION Our novel method successfully enriched stem-like cells which possessed an EMT phenotype.The isolation and characterization of murine hepatic CSCs could establish a precise target for the development of more effective therapies for HCC.

Measurements of the γγ＊ → π^0 and γγ＊ → ηc transition form factors at BABAR

We present measurements of the γγ＊ → π^0 transition form factor for the momentum transfer range Q^2=4-40 GeV^2 and the γγ＊ → ηc transition form factor for the range Q^2=2-50 GeV^2. The current status of measurements of the meson-photon transition form factors for the η and η＇ mesons is discussed. The results of the measurement of the ηc mass, total and two-photon widths are also presented.

Pigment epithelium-derived factor protects retinal ganglion cells from hypoxia-induced apoptosis by preventing mitochondrial dysfunction

AIM： To investigate the potential of pigment epitheliumderived factor（PEDF） to protect the immortalized rat retinal ganglion cells-5（RGC-5） exposed to Co Cl2-induced chemical hypoxia. METHODS： After being differentiated with staurosporine（SS）, RGC-5 cells were cultured in four conditions： control group cells cultured in Dulbecco ＇s modified eagle medium（DMEM） supplemented with 10% fetal bovine serum, 100 μmol/m L streptomycin and penicillin（named as normal conditions）; hypoxia group cells cultured in DMEM containing 300 μmol/m L Co Cl2; cells in the group protected by PEDF were first pretreated with 100 ng/m L PEDF for 2h and then cultured in the same condition as hypoxia group cells; and PEDF group cells that were cultured in the presence of 100 ng/m L PEDF under normal conditions. The cell viability was assessed by MTT assay, the percentage of apoptotic cells was quantified using Annexin V-FITC apoptosis kit, and intra-cellar reactive oxygen species（ROS） was measured by dichloro-dihydro-fluorescein diacetate（DCFH-DA） probe. The mitochondria-mediated apoptosis was also examined to further study the underlying mechanism of the protective effect of PEDF. The opening of mitochondrial permeability transition pores（m PTPs） and membrane potential（Δψm） were tested as cellular adenosine triphosphate（ATP） level and glutathione（GSH）. Also, the expression and distribution of Cyt C and apoptosis inducing factor（AIF） were observed.RESULTS： SS induced differentiation of RGC-5 cells resulting in elongation of their neurites and establishing contacts between outgrowths. Exposure to 300 μmol/m L Co Cl2 triggered death of 30% of the total cells in cultures within 24 h. At the same time, pretreatment with 100 ng/m L PEDF significantly suppressed the cell death induced by hypoxia（P〈0.05）. The apoptosis induced by treatment of Co Cl2 was that induced cell death accompanied with increasing intracellar ROS and decreasing GSH and ATP level. PEDF pretreatment suppressed these effects（P〈0.05）. Additionally, PEDF treatment inhibited the opening of m PTPs and suppressed decreasing of Δψm in RGC-5 cells, resulting in blocking of the mitochondrial apoptotic pathway.CONCLUSION： Pretreatment of RGC-5 cells with 100 ng/m L PEDF significantly decreases the extent of apoptosis. PEDF inhibits the opening of m PTPs and suppresses decreasing of Δψm. Moreover, PEDF also reduces ROS production and inhibits cellular ATP level＇s reduction. Cyt C and AIF activation in PEDF-pretreated cultures are also reduced. These results demonstrate the potential for PEDF to protect RGCs against hypoxic damage in vitro by preventing mitochondrial dysfunction.

B_s → f_0 (980) Transition Form Factors Within the k_T Factorization Approach

In the paper, we apply the kT factorization approach to deal with the B8 → fofo（980） transition form factors in the large recoil regions, i.e. the small q2 regions. For the purpose, we adopt the B-meson wave-functions ЖB, ЖB and that include the three-Fock states contributions to do our discussion. Although the scalar meson fo（980） is widely perceived as the 4-quark bound state （scenario 2）, but the distribution amplitudes of 4-quark states are still unknown to us, so we adopt 2-quark model （scenario 1） for scalar meson fo（980） in our discussion. By varying the B-meson wave-function parameters within their reasonable regions, we obtain Fo（0） = F＋（0） = 0.20 ± 0.02, FT（O） = 0.24 4± 0.02. Our present results for these form factors are consistent with the light-cone sum rule results obtained in the literature.

Effective response to crizotinib of concurrent KIF5B-MET and MET-CDR2-rearranged non-small cell lung cancer:A case report

BACKGROUND Due to the rarity of mesenchymal-epithelial transition factor(MET)fusions,the clinical efficacy of crizotinib has only been described in a few patients with MET fusions involving various fusion partners.Herein,we report the clinical response to crizotinib of a patient with advanced poorly differentiated non-small cell carcinoma(NSCLC)having concurrent MET fusions.CASE SUMMARY A 46-year-old woman was diagnosed with poorly differentiated NSCLC(T4 N3 M1).With no classic driver mutations,she was treated with two cycles of gemcitabine and cisplatin without clinical benefit.Targeted sequencing revealed the detection of two concurrent MET fusions,KIF5 B-MET and novel MET-CDR2.Crizotinib was initiated at a dose of 250 mg twice daily.Within 4 wk of crizotinib therapy,repeat computed chromatography revealed a dramatic reduction in primary and metastatic lesions,assessed as partial response.She continued to benefit from crizotinib for 3 mo until disease progression and died within 1 mo despite receiving nivolumab therapy.CONCLUSION Crizotinib sensitivity was observed in an advanced poorly differentiated NSCLC patient with concurrent MET fusions KIF5 B-MET and MET-CDR2.Crizotinib can serve as a therapeutic option for patients with MET fusions.In addition,our case also highlights the importance of comprehensive genomic profiling particularly in patients with no classic driver mutation for guiding alternative therapeutic decisions.

D^(+)→π^(+)v■decay process within the QCDSR approach

In this paper,we investigate the charmed meson rare decay process D^(+)→π^(+)v■using an approach based on QCD sum rules.First,the pion twist-2,3 distribution amplitude(DA)moments<ξ_(2)^(n);|μand<ξ3;π(p,σ),n>|μ,are calculated up to the tenth and fourth orders,respectively,in the QCD sum rules according to the background field theory.After constructing the light-cone harmonic oscillator model for the pion twist-2,3 D As,we obtain their behaviors by matching the calculatedξ-moments.Then,the D→πtransition form factors(TFFs)are calculated using an approach based on QCD light-cone sum rules.The vector form factor at the large recoil region is f_(+)^(D)→^(π)(0)=0.627_(-0.080)^(+0.120).Using the rapidly converging simplified series expansion of z(q^(2),t),we present the TFFs and corresponding angular coefficients in the whole squared momentum transfer physical region.Based on nonstandard neutrino interactions,the■^(0)→π^(+)e■_(e)decay can be related to the■^(0)→π^(+)e■_(e)decay indirectly.Thus,we first describe the semileptonic decay process■^(0)→π^(+)e■_(e),differential decay widths,and branching fraction with B(■^(0)→π^(+)e■_(e))=0.308_(-0.066)^(+0.155)×10^(2).The■^(0)→π^(+)e■_(e)differential/total predictions for forward-backward asymmetry,q^(2)-differential flat terms,and lepton polarization asymmetry are also reported.The prediction for the D^(+)→π^(+)v■branching fraction isB(D^(+)→π^(+)v■)=1.85_(-0.46)+^(0.93)×10^(-8).

Analytical investigation of γN→N^*,Δ^* transition helicity amplitudes

We study the structure of nonstrange baryons by analytically calculating the electromagnetic transition helicity amplitudes of the nucleon andΔresonances.We employ an improved hypercentral constituent quark model and obtain the corresponding eigenenergies and eigenfunctions in closed forms.Then,we calculate the transverse and longitudinal helicity amplitudes for nucleon andΔresonances.The comparison of evaluated observables and experimental data indicates good agreement between the proposed model and available data.

Collective Perspective on Advances in Dyson–Schwinger Equation QCD

We survey contemporary studies of hadrons and strongly interacting quarks using QCD's Dyson-Schwinger equations, addressing the following aspects: confinement and dynamical chiral symmetry breaking; the hadron spectrum; hadron elastic and transition form factors, from small-to large-Q2; parton distribution functions; the physics of hadrons containing one or more heavy quarks; and properties of the quark gluon plasma.

Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met

Verticillin A is a diketopiperazine compound which was previously isolated from Amanita flavorubescens Aik(containing parasitic fungi Hypomyces hyalines(Schw.)Tul.).Here,we initially found,by wound healing assay and Tran swell assay in vitro,that verticilli n A possesses an inhibitory effect agai nst the migrati on and in vasion of the human colon cancer cell.Subsequently,c-mesenchymal,epithelial transition factor(c-Met)was identified as a molecular target of verticillin A by screening key genes related to cell migration.Verticillin A-mediated c-Met suppress!on is at the transcriptio nal level.Further study dem on strated that verticilli n A suppressed c-MET phosphorylation and decreased c-MET protein level.In addition,verticillin A inhibited the phosphorylation of c-MET downstream molecules including rat sarcoma(Ras)-associated factor(Raf),extracellular signal-regulated kinase(ERK),and protein kinase B(AKT).Overexpression of Erk partially reversed the verticillin A-mediated anti-metastasis action in the human colon cancer cell.More importantly,verticillin A also inhibited cancer cell metastasis in vivo.Thus,verticillin A can significantly inhibit the migration and invasion of colon cancer cells by targeting c-Met and inhibiting Ras/Raf/mitogen-activated extracellular signal-regulated kinase(MEK)/ERK signaling pathways.Therefore,we determined that verticillin A is a natural compound that can be further developed as an anti-metastatic drug in human cancers.

A data-driven approach to π^0,η and η＇ single and double Dalitz decays

The dilepton invariant mass spectra and integrated branching ratios of the single and double Dalitz decays P→l^＋l^-γ and P→l^＋l^-l^＋l^-（P=π^0,η,η＇;l=e or μ） are predicted by means of a data-driven approach based on the use of rational approximants applied to π^0,η and η＇ transition form factor experimental data in the space-like region.

Analysis of the electrical characteristics of GaInP/GaAs HBTs including the recombination effect

An analytical model is used to predict the effects of surface recombination current on the gain and transit time of GalnP/GaAs heterojunction bipolar transistors（HBTs）.The present analysis shows that consideration of the recombination current gives current gain values that are comparable to those of the experimental results.The dependence of current gain on temperature,base doping and emitter area are also analyzed,and the variation in collector current with emitter-base voltage,temperature and doping is considered.

The N* physics program at Jefferson Lab

Recent measurements of nucleon resonance transition form factors with CLAS at Jefferson Lab are discussed. The new data confirm the assertion of the symmetric constituent quark model of the Roper as the first radial excitation of the nucleon. The data on high Q2 nπ＋ production better constrain the branching ratios liNK and [3Nn. For the first time, the longitudinal transition amplitude to the S11（1535） was extracted from the nπ＋ data. Also, new results on the transition amplitudes for the D13（1520） resonance are presented showing a rapid transition from helicity 3/2 dominance seen at the real photon point to helicty 1/2 dominance at higher Q2. I also discuss the status of the search for new excited nucleon states.

Single π0electro-production in the resonance region with CLAS＊

We report the analysis status of single π0electroproduction in the resonance region to study the electromagnetic excitation of the nucleon resonances. The study is aimed at understanding of the internal structure and dynamics of the nucleon. The experiment was performed using an unpolarized cryogenic hydrogen target and 2.0 and 5.8 GeV polarized electron beam during the ele and e1-6 run periods with CLAS at Jefferson Lab. The new measurements will produce a data base with high statistics and large kinematic coverage for the hadronic invariant mass （W） up to 2.0 CeV in the momentum transfer （Q2） range of 0.3--6.0 GeV2. Preliminary results will be presented and compared with the various model calculations.