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Introduction Immunotherapy has an important role in the intervention of breast cancer, but single-agent efficacy of immunotherapy is poor, owing in part to influence of the surrounding tumour microenvironment. Hepatitis A virus cellular receptor-1 (HAVCR1), plays vital roles in immune microenvironment in pancreatic adenocarcinoma, but not clear in breast cancer. The present study aimed to characterize the role of HAVCR1 in immune microenvironment of breast cancer. Methods The Cancer Genome Atlas was used to evaluate functional role of HAVCR1. Kaplan-Meier plotter and Tumor Immune Estimation Resource were applied to illustrate correlation of HAVCR1 with the prognosis and immune infiltration of breast cancer. Results In Pietenpol subtype, high HAVCR1 levels indicated a favourable overall survival (OS) (HR=0.08, 95%CI:0.01-0.61, P=0.0024) in mesenchymal stem–like breast cancer. However, it was connected to worse OS (HR=2.29, 95%CI:1.04-5.04, P=0.035) in immunomodulatory subtype. Significant correlation was found between HAVCR1 expression level and immune infiltration in breast cancer, especially with B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and Dendritic cell (P Conclusion HAVCR1 is closely correlated with immune microenvironment and may serve as a potential tumour immunotherapy target for breast cancer.

Introduction Lymph node metastasis is essential for the outcome of patients with breast cancer. Bone morphogenetic proteins (BMP) and hepatocyte growth factor (HGF), key to angiogenesis and metastasis of cancers, were investigated for their roles in the predication of nodal metastasis from breast cancer. Methods Expression of BMP family ligands, BMP receptors, HGF, its receptor MET and regulatory factors of HGF activation including HGF activator (HGFA), HGFA inhibitor 1 (HAI1), HAI2, Matriptase-1 and Matriptase-2 were determined in breast cancers (n=127) using real time quantitative PCR. Transcript levels of these genes were analysed in the breast cancers for their implication in lymphatic involvement using Mann-Whitney test. Predictive potential of those genes for nodal metastasis of these molecules was evaluated using both binary logistic regression and receiver operating characteristic (ROC) with SPSS (Version 27). Results With median as a cut-off value, logistic regression analyses showed that MET, Matriptase-1 and BMP15 were positively associated with nodal metastasis whereas Matriptase-2, BMP3 and HAI1 were inversely correlated with nodal involvement. After integrating these six prospective factors, ROC model returned with a significant value against nodal status (RUC=0.657, p=0.001). With the optimal ROC cut-off value to dichotomise patients, the integrated expression produced a significant prediction of nodal metastasis (p=0.006, HR=2.929). MET and HAI1 was correlated with the lymphangiogenesis marks of LYVE1, podo, prox1. Matriptase-1 was inversely correlated with podo, whilst Matriptase-2 and BMP15 showed a positive correlation with prox1. Conclusion The MET/Matriptase-1/BMP15 and the inversed Matriptase-2/BMP3/HAI1 are connected significantly with lymph node metastasis in breast cancer.

Introduction MLN70 ([metastatic lymph node gene 70 protein], also known as S100A11 [S100 Calcium-Binding Protein A11] or Calgizzarin), a nucleic and cytosolic protein suspected to have a role in regulation of cellular invasion, migration and tubulin polymerisation in cancer cells and has been implicated in cancer progression. The present study explored how MLN70 might have a value in the clinical outcome of the patients. Methods Expression of MLN70 transcripts was quantified in a clinical cohort of breast cancer and was evaluated against the clinical, pathological, hormonal receptor status and clinical outcome of the patients. Results Breast tumour tissues had higher levels of MLN70 than normal tissues and high levels of MLN70 linked to a shorter overall survival of the patients. MLN70 had a significant correlation with three members of the ERBB family including ERBB1 (EGFR), Her2 (ERBB2) and ERBB4. There were no significant different between node positive and node negative tumours (p=0.237). The most striking finding was that MLN70 showed a significant predictive value in identifying patients who subsequently developed skeletal metastasis (RUC=0.793, p Conclusion The present study reveals MLN70 as a significant and independent predictive factor for skeletal metastasis of patients with breast cancer and a prospective target in this cancer type.

Introduction SIPA1 (Signal-Induced Proliferation-Associated Protein 1) is a mitogen induced GTPase activating protein and known to regulate cycle progression and barrier function of cancer cells. It is reported to influence the disease progression in lung and colorectal cancers. Here, we report the clinical and prognostic value of SIPA1 in gastric cancer. Methods Two independent gastric cancer cohorts were tested for SIPA1 expression. The expression profile of SIPA1 was analysed against the clinical, pathological, outcome and the expression of the ERBB (Her) family members in the same cohorts. Results Gastric tumour tissues had a higher level of SIPA1 transcript than normal stomach tissues. High levels of SIPA1 were seen in high grade, node positive and high TNM tumours. SIPA1 had a significant correlation with the ERBB family members in both normal tissues and in tumour tissues. SIPA1 levels only had a weak relationship with the overall (OS) and disease free (DFS) survival. However, stratification of patients by expression pattern of ERBB3 (Her3), the ERBB family significantly correlated with SIPA1 (p Conclusion SIPA1 expression is frequently seen in gastric cancer and together with members of the ERBB family influences the clinical outcome and responses to chemotherapies of the patients.

Introduction Hepatitis A virus cellular receptor 1 (HAVcR1) has been established to play an important role in tight junction (TJ) in cancer cells and in peripheral endothelial cells. Its role in blood brain barrier (BBB) of cerebral endothelium remains unknown. This study aimed to investigate the association and functionality of HAVcR1 in BBB. Methods HAVcR1 was knocked down by siRNA in human cerebral microvessel endothelial cell/D3 (hCMEC/D3) cell lines. Changes in tight junction (TJ) behaviour were assessed using electric cell impedance sensing (ECIS), transendothelial resistance (TER), and paracellular permeability (PCP). The expression of HAVcR1 and the binding partners of HAVcR1 protein was assessed using quantitative polymerase chain reaction (qPCR). Results The HAVcR1 gene transcript, highly expressed in hCMEC/D3 cells, was successfully knocked down from the cell by anti-HAVcR1 siRNA. HAVcR1 knockdown resulted in an increase in four TJ molecules and a decrease in eight TJ molecules as demonstrated by transcript analysis. HAVcR1 knockdown cells displayed lower electric resistance compared with wild type cells during initial attachment and spreading in hCMEC/D3 cells shown by ECIS. Similarly, TER in HAVcR1 knockdown cells were also reduced. Higher PCP fluorescence signals were detected in HAVcR1 knockdown cell lines compared with wild type. Conclusion HAVcR1 regulates paracellular leakage of cerebral endothelial cells and loss of HAVcR1 renders the cells with weaker tight junction by influencing TJ protein expression. HAVcR1 have a function as part of the regulatory apparatus for TJ in BBB.

Nuclear charge radii are sensitive probes of different aspects of the nucleon-nucleon interaction and the bulk properties of nuclear matter; thus, they provide a stringent test and challenge for nuclear theory. The calcium region has been of particular interest, as experimental evidence has suggested a new magic number at $N = 32$ [1-3], while the unexpectedly large increases in the charge radii [4,5] open new questions about the evolution of nuclear size in neutron-rich systems. By combining the collinear resonance ionization spectroscopy method with $\beta$-decay detection, we were able to extend the charge radii measurement of potassium ($Z =19$) isotopes up to the exotic $^{52}$K ($t_{1/2}$ = 110 ms), produced in minute quantities. Our work provides the first charge radii measurement beyond $N = 32$ in the region, revealing no signature of the magic character at this neutron number. The results are interpreted with two state-of-the-art nuclear theories. For the first time, a long sequence of isotopes could be calculated with coupled-cluster calculations based on newly developed nuclear interactions. The strong increase in the charge radii beyond $N = 28$ is not well captured by these calculations, but is well reproduced by Fayans nuclear density functional theory, which, however, overestimates the odd-even staggering effect. These findings highlight our limited understanding on the nuclear size of neutron-rich systems, and expose pressing problems that are present in some of the best current models of nuclear theory., Comment: submitted version; revision accepted in Nature Physics

To investigate对山东省人感染猪链球菌菌株开展基因组流行病学及病原学分析，为制定合理、精准的猪链球菌预防、控制措施提供依据。本研究对分离的猪链球菌菌株开展分子分型、基因组系统进化树、毒力基因型别、耐药谱、耐药基因及其传播元件等方面的分析，并通过比较菌株刺激宿主细胞产生细胞因子的能力评价不同菌株的致病力。结果显示，血清2型、ST1型是山东患者来源猪链球菌的优势型别，其主要临床表现为脑膜炎。系统进化树分析表明山东菌株主要由5个分枝组成。山东菌株均属高致病型菌株，但细胞因子试验表明分枝2的菌株致病力显著强于其他山东菌株。除分枝3的SD2与SD4菌株外，其余山东菌株均携带不同种类的耐药基因及其传播元件。综上，山东猪链球菌的来源及进化途径存在多样性的特征，且致病能力有显著差异，需要在基因组水平开展菌株监测的工作。.

A resonant state at 3.21-0.04+0.12MeV, located just above the one-neutron separation threshold, was observed for the first time in Be12 from the Be11(d,p)Be12 one-neutron transfer reaction in inverse kinematics. This state is assigned a spin-parity of 0- according to the systematics of the level scheme of the N=8 isotones and decay-width analysis. Gamow coupled-channel and Gamow shell-model calculations show the importance of the continuum coupling, which dramatically influences the excitation energy and ordering of low-lying states. Various exotic structures associated with cross-shell intruding configurations in Be12 and in its isotonic nucleus Li11 are comparably discussed.

We optimize $\mathrm{\ensuremath{\Delta}}$-full nuclear interactions from chiral effective field theory. The low-energy constants of the contact potentials are constrained by two-body scattering phase shifts, and by properties of bound state of $A=2$ to 4 nucleon systems and nuclear matter. The pion-nucleon couplings are taken from a Roy-Steiner analysis. The resulting interactions yield accurate binding energies and radii for a range of nuclei from $A=16$ to $A=132$, and provide accurate equations of state for nuclear matter and realistic symmetry energies. Selected excited states are also in agreement with data.

We report the measurement of reaction cross sections ($\sigma_R^{\rm ex}$) of $^{27,29}$F with a carbon target at RIKEN. The unexpectedly large $\sigma_R^{\rm ex}$ and derived matter radius identify $^{29}$F as the heaviest two-neutron Borromean halo to date. The halo is attributed to neutrons occupying the $2p_{3/2}$ orbital, thereby vanishing the shell closure associated with the neutron number $N = 20$. The results are explained by state-of-the-art shell model calculations. Coupled-cluster computations based on effective field theories of the strong nuclear force describe the matter radius of $^{27}$F but are challenged for $^{29}$F., Comment: 8 pages, 4 figures

A new 11Be( d , p )12Be transfer reaction experiment was carried out in inverse kinematics at 26.9A MeV, with special efforts devoted to the determination of the deuteron target thickness and of the required optical potentials from the present elastic scattering data. In addition a direct measurement of the cross section for the 0 2 + state was realized by applying an isomer-tagging technique. The s-wave spectroscopic factors of 0.20 − 0.04 + 0.03 and 0.41 − 0.11 + 0.11 were extracted for the 0 1 + and 0 2 + states, respectively, in 12Be. Using the ratio of these spectroscopic factors, together with the previously reported results for the p-wave components, the single-particle component intensities in the bound 0 + states of 12Be were deduced, allowing a direct comparison with the theoretical predictions. It is evidenced that the ground-state configuration of 12Be is dominated by the d-wave intruder, exhibiting a dramatic evolution of the intruding mechanism from 11Be to 12Be, with a persistence of the N = 8 magic number broken.

Abnormal expression and activation of tropomyosin-related kinase receptor B (TrkB) are observed in many pathological conditions, including many types of cancer. We try to explore the relationship between ovarian cancer and Brain-derived neurotrophic factor (BDNF), a ligand of TrkB.Human ovarian cancer cell line SKOV-3 was used in this study. qPCR, immunohistochemistry, and immunoblot were used to assay BDNF and TrkB expression level. Scratch assay was used to test the cell motility, and transwell assay was used to test the cell migration ability.We found that BDNF promotes the proliferation and invasion of human ovarian cancer SKOV-3 cells depend on the activation of TrkB. To illuminate the downstream pathway of BDNF/TrkB, we silenced AKT1 and PLCγ1 by siRNA. The functional assay showed that activated PLCγ1 signaling pathway is necessary for the proliferation and invasion of cancer cells other than the AKT pathway. Further study showed that PLCγ1 could inhibit the apoptosis of cancer cells.BDNF triggers TrkB/PLCγ1 signaling pathway to promote proliferation and invasion of ovarian cancer cells through inhibition of apoptosis.

Calculations of nuclei are often carried out in finite model spaces. Thus, finite-size corrections enter, and it is necessary to extrapolate the computed observables to infinite model spaces. In this work, we employ extrapolation methods based on artificial neural networks for observables such as the ground-state energy and the point-proton radius. We extrapolate results from no-core shell model and coupled-cluster calculations to very large model spaces and estimate uncertainties. Training the network on different data typically yields extrapolation results that cluster around distinct values. We show that a preprocessing of input data, and the inclusion of correlations among the input data, reduces the problem of multiple solutions and yields more stable extrapolated results and consistent uncertainty estimates. We perform extrapolations for ground-state energies and radii in $^{4}$He, $^{6}$Li, and $^{16}$O, and compare the predictions from neural networks with results from infrared extrapolations., 9 pages, 8 figures, details added, accepted by Phys. Rev. C

Coherent elastic neutrino scattering on the 40Ar nucleus is computed with coupled-cluster theory based on nuclear Hamiltonians inspired by effective field theories of quantum chromodynamics. Our approach is validated by calculating the charge form factor and comparing it to data from electron scattering. We make predictions for the weak form factor, the neutron radius, and the neutron skin, and estimate systematic uncertainties. The neutron-skin thickness of 40Ar40 is consistent with results from density functional theory. Precision measurements from coherent elastic neutrino-nucleus scattering could potentially be used to extract these observables and help to constrain nuclear models., Comment: 3 figures

The density-dependent finite-range Gogny force has been used to derive the effective Hamiltonian for the shell-model calculations of nuclei. The density dependence simulates an equivalent three-body force, while the finite range gives a Gaussian distribution of the interaction in the momentum space and hence leads to an automatic smooth decoupling between low-momentum and high-momentum components of the interaction, which is important for finite-space shell-model calculations. Two-body interaction matrix elements, single-particle energies and the core energy of the shell model can be determined by the unified Gogny force. The analytical form of the Gogny force is advantageous to treat cross-shell cases, while it is difficult to determine the cross-shell matrix elements and single-particle energies using an empirical Hamiltonian by fitting experimental data with a large number of matrix elements. In this paper, we have applied the Gogny-force effective shell-model Hamiltonian to the ${\it p}$- and ${\it sd}$-shell nuclei. The results show good agreements with experimental data and other calculations using empirical Hamiltonians. The experimentally-known neutron drip line of oxygen isotopes and the ground states of typical nuclei $^{10}$B and $^{18}$N can be reproduced, in which the role of three-body force is non-negligible. The Gogny-force derived effective Hamiltonian has also been applied to the cross-shell calculations of the ${\it sd}$-${\it pf}$ shell., 23 pages, 11 figures

$\beta$-decay properties of $N$=18-22, $Z$=10-14 nuclei are analyzed with a new shell-model Hamiltonian using the Gogny density-dependent interaction. The Gogny force which has been widely and successfully used in mean-field theory can provide reasonable two-body matrix elements for cross-shell calculations. The log$ft$ values and $\beta$-decay level schemes are systematically studied using the D1S-Gogny interaction and compared with the SDPF-M results and experimental data. It is shown that the new Hamiltonian provides reliable results for $\beta$-decay along with subtle level schemes for this region. Shell-model calculations with Gogny interaction can lead to a successful description of nuclei in and around the N =20 island of inversion and supplements experiment where sufficient data are not available.

Recent high-resolution experiments at JLab give the energy spectra of the hypernuclei 7 ΛHe, 9 ΛLi, 10 ΛBe,and 12 ΛB. However, their spins and parities of the excited states have not been known experimentally. In the present paper, we make a systematical theoretical investigation for the p-shell hypernuclei, within the shell model based on the nucleon-nucleon and hyperon-nucleon interactions. The effective nucleon-nucleon interaction takes the finite-range density-dependent Gogny force, and the hyperon-nucleon interaction takes an empirical ΛN interaction which includes the ΛN-ΣN and ΣN-ΣN coupling effects. The shell model with the Gogny force without parameters being refitted can reasonably describe both spectra and binding energies of the p-shell nuclei, which gives a confidence for the further calculations of hypernuclei. We compare our results with experimental data as well as various theoretical calculations, and explain the recent experimental hypernuclear spectra observed at JLab.

The residual thermal stresses induced by the high-temperature sintering process in multilayer ceramic capacitors (MLCCs) are investigated by using a finite element unit cell model, in which the strain gradient effect is considered. The numerical results show that the residual thermal stresses depend on the lateral margin length, the thickness ratio of the dielectrics layer to the electrode layer, and the MLCC size. At a given thickness ratio, as the MLCC size is scaled down, the peak shear stress reduces significantly and the normal stresses along the length and thickness directions change slightly with the decrease in the ceramic layer thickness td as td >1 μm, but as td

The elastic scattering and breakup reactions of the halo nucleus $^{11}\mathrm{Be}$ on deuterons at an incident energy of $26.9A$ MeV are reported for the first time. Special attention has been paid to the determination and subtraction of the proton contaminations in the deuterated polyethylene ${({\mathrm{CD}}_{2})}_{n}$ target (where ${\mathrm{D}}_{2}$ denotes $^{2}\mathrm{H}_{2}$). The cross sections for elastic scattering are analyzed with the systematic optical potentials of Daehnick et al. and DA1p, as well as with single-folding potentials, derived from the Jeukenne-Lejeune-Mahaux effective nucleon-nucleon interaction. An extended version of the continuum-discretized coupled-channels (XCDCC) formalism, including dynamic core excitation (DCX) effects, is applied to analyze the elastic scattering and breakup data. Comparisons of the full XCDCC calculation with that omitting DCX effects indicate that the core excitation plays a remarkable role in reproducing breakup reactions of $^{11}\mathrm{Be}+d$.

A microelectromechanical oscillator with a gap of 1.25 μm was immersed in superfluid ^{3}He-B and cooled below 250 μK at various pressures. Mechanical resonances of its shear motion were measured at various levels of driving force. The oscillator enters into a nonlinear regime above a certain threshold velocity. The damping increases rapidly in the nonlinear region and eventually prevents the velocity of the oscillator from increasing beyond the critical velocity which is much lower than the Landau critical velocity. We propose that this peculiar nonlinear behavior stems from the escape of quasiparticles from the surface bound states into the bulk fluid.

The elastic scattering and breakup of the halo nucleus $^{11}\mathrm{Be}$ on protons at an incident energy of $26.9A$ MeV have been measured. The $^{11}\mathrm{Be}+p$ elastic scattering cross sections at various energies, including the present one, are systematically analyzed with the Chapel Hill 89 (CH89) and Koning-Delaroche (KD) global optical model potentials (OMPs), and the corresponding normalization factors are obtained. An extended version of the continuum-discretized coupled-channels (XCDCC) formalism, including dynamic core excitation effects, is applied to analyze the elastic scattering and breakup data. It is found that the core excitation plays a moderate role in the elastic scattering and breakup reaction of the halo nucleus $^{11}\mathrm{Be}$, being consistent with previous results at higher energies.

Chronic wounds represent a significant burden to health services and are associated with patient morbidity. Novel methods to diagnose and/or treat problematic wounds are needed. Interleukin (IL)-15 is a cytokine involved in a number of biological processes and disease states such as inflammation, healing and cancer progression. The current study explores the expression profile of IL-15 and IL-15 receptor α (IL-15Rα) in chronic wounds and its impact on keratinocytes. IL-15 and IL-15Rα expression were examined in healing and non-healing chronic wounds using qPCR and immunohistochemical analysis. The impact of recombinant IL-15 (rhIL-15) on human adult low calcium temperature (HaCaT) keratinocyte growth and migratory potential was further examined. IL-15 transcript expression was slightly, though non-significantly elevated in healing chronic wounds compared with non-healing chronic wounds. IL-15 protein staining was minimal in both subtypes of chronic wounds. By contrast, IL-15Rα transcript and protein expression were both observed to be enhanced in non-healing chronic wounds compared with healing chronic wounds. The treatment of HaCaT cells with rhIL-15 generally enhanced cell growth and promoted migration. Analysis with small molecule inhibitors suggested that the pro-migratory effect of rhIL-15 may be associated with ERK, AKT, PLCγ and FAK signalling. IL-15 may promote healing traits in keratinocytes and the differential expression of IL-15Rα is observed in chronic wounds. Together, this may imply a complex role for this interleukin in wound healing.

To explore the effects of posterior decompression and internal fixation for spinal metastases epidural spinal cord compression (MESCC) and analyze the related factors of postoperative ambulation function.Clinical data of 67 cases with MESCC who received thoracic posterior decompression and internal fixation in our department from January 2006 to December 2014 was retrospectively analyzed. Information about patients' age, gender, pathological type of primary tumor, Karnofsky performance status (KPS) score, pre-operative and postoperative visual analogue scale, preoperative Frankel grade, pre-operative and postoperative imaging characteristics (number of thoracic vertebrae metastases, location, compression fractures of vertebral bodies), time of movement dysfunction and survival was collected.At the end of the follow-up of 67 cases, 57 cases were dead, 10 cases were alive, and the median survival was 8.1 months (1.2-91.9 months).38 cases (67%) died within one year, 50 cases (88%) died within two years. Visual analogue scale of preoperative and postoperative dropped from (5.67±1.67) points to (2.11±1.39) points (P0.001), 38 (53%) patients' Frankel grade improved at least one grade. Among the 34 cases who were unable to walk, 15 cases regained ability of ambulation after surgery. The patients with KPS scores greater than 80 points and/or had preoperative ambulation ability, tended to have better postoperative ambulatory function.Posterior decompression and internal fixation for MESCC is effective, and can effectively relieve pain and spinal cord compression, improve neurological function and the quality of life. The ambulatory functional outcomes after surgery are dependent on KPS scores, the occurrence time of neurological dysfunction, preoperative ambulatory status.

Textile composites consist of interlaced tows, which are impregnated with a matrix material and then cured. The interlacing of the tows offers the potential for increased through-thickness strength compared to conventional laminated composites. However, one disadvantage of textile composites is the difficulty in predicting their performance due to the complex geometry of their internal architectures. Finite element analysis (FEA) has become an effective means to predict the response of complex textile composite structures. When an attempt is made to perform a conventional FEA, one of the tough issues faced is how to deal with the topologically complex internal geometries. To overcome this difficult issue, a domain superposition technique (DST) has been proposed to implement free vibration analysis of woven composite structures. The significant advantage of the DST over traditional FEA is that it does not need to directly deal with the likely degenerated resin-rich region, thus the DST model is much easier to establish. Numerical results show that DST predictions correlate excellently with traditional FEAs., Tekstilni kompoziti načinjeni su od isprepletenih vlakana koja se impregniraju matričnim materijalom i zatim očvršćuju. Preplitanjem vlakana može se povećati poprečna čvrstoća u usporedbi s konvencionalnim laminarnim kompozitima. Međutim, nedostatak tekstilnih kompozita je teško predviđanje osobina zbog složene geometrije unutarnje građe. Analiza konačnih elemenata (FEA) postala je učinkovito sredstvo za predviđanje ponašanja složenih tekstilnih kompozitnih struktura. Jedan od problema koji se javljaju u primjeni konvencionalne metode konačnih elemenata je topološki kompleksna unutarnja geometrija. Za prevladavanje te poteškoće predlaže se primjena metode superpozicije domena (DST) radi analize vibracija tkanih kompozitnih struktura. Važna prednost DST-a pred tradicionalnim FEA-om jest u tome da nije potrebno izravno se baviti područjem bogatim smolom koje je vjerojatno degenerirano. Numerički rezultati pokazuju da predviđanja DST-a izvrsno koreliraju s tradicionalnim FEA-om.

DLEC1 (deleted in lung and oesophageal cancer), located on 3p22.3, is a candidate tumour suppressor gene in lung, esophageal, and renal cancer. The aim of this study was determine whether the mRNA expression levels of DLEC1 were consistent with a tumour suppressive function.A total of 153 samples were analysed. The levels of transcription of DLEC1 were determined using quantitative PCR and normalised against (CK19). Transcript levels within breast cancer specimens were compared to normal background tissues.Levels of transcription were lower [corrected] in tumour samples compared to adjacent non cancerous tissue (ANCT) samples but this was not statistically significant (median 0.167 vs. 0.03; p=0.138). DLEC1 expression levels were significantly lower in samples from patients who developed metastasis, local recurrence, or died of breast cancer when compared to those who were disease free for10 years (p=0.041).These findings are consistent with a possible tumour suppressor function of DLEC1 in breast cancer.

The role of the insulin like growth factor (IGF) system in various human malignancies has been well established. The aim of this study was to determine the levels of mRNA expression of insulin-like growth factor-binding protein (IGFBP)-1, -3 and -7 genes in benign and malignant breast tissue and explore their relationship with various prognostic parameters.Breast cancer tissue (n=127) and normal background tissue (n-33) were prospectively collected and analysed for levels of IGFBP-1, -3 and -7 mRNA using real-time Q-PCR. mRNA levels were then analysed against tumour grade, nodal status, Nottingham prognostic index (NPI)/TNM stage and tumour type.For IGFBP-1 and -3, mRNA expression was higher in normal tissue. This was significant for IGFBP-1 when comparing NPI 3 with NPI 1 (p=0.050) and the normal group (p=0.040). With respect to TNM analysis, there was less IGFBP-1 mRNA when comparing TNM 3 with normal (p=0.017), TNM 1 (p=0.047) and TNM 2 (p=0.019) tumours. This was also found when comparing TNM 4 samples with normal tissue (p=0.017), TNM 1 (p=0.046) and TNM 2 (p=0.019). For IGFBP-3 mRNA, there was less mRNA when comparing TNM 3 with TNM 1 (p= 0.017) and TNM 2 (p=0.050), and also less mRNA expression when comparing TNM 4 with TNM 1 (p=0.030). For IGFBP-7 mRNA, both TNM 1 (p=0.0077) and TNM 2 (p=0.015) had significantly more expression than TNM 3 samples.This study supports the role of IGFBP-1, -3 and -7 as potential tumour suppressor genes in human breast cancer.

Bone morphogenetic proteins (BMPs) belong to the TGF-Beta superfamily and are vital bone inductive factors. BMPs also play important roles during embryonic development and the postnatal homeostasis of various organs and tissues, by controlling cellular differentiation, proliferation and apoptosis. Prostate cancer is the most common cancer in men in Western countries, with a high incidence of bone metastasis. Once bony metastasis developed, the condition is incurable, and contributes significant disease specific morbidity and mortality. However, the mechanisms underlying the development of bone metastasis remain unclear. BMPs have been implicated in the development of both primary and secondary tumors, particularly skeletal metastasis. Aberrations in BMPs signaling have also been identified in various neoplasms. Recently studies have also suggested a pivotal role in bone metastasis for Noggin, which is a BMP antagonist. In this review, we discuss the current knowledge of BMPs signaling, abnormalities which have been identified and their involvement in tumour progression, and particularly in the development of bone metastasis in prostate cancer.

Steroid sulfatase (STS) is the enzyme responsible for hydrolysing biologically inactive estrogen sulfates to active estrogens. Therefore it plays a significant role in supporting the growth of hormone-dependent tumours of the breast, endometrium and prostate. OATP-B is a member of a family of membrane transporter proteins that regulates the uptake of steroid sulfates through cell membranes. Our objective was to determine, using quantitative PCRA whether the mRNA expression levels from these genes were positively correlated with clinical outcome in human breast cancer. This is the first study in the literature to examine the relationship between STS and OATP-B in human breast cancer and to investigate the potential prognostic value of OATP-B.A total of 153 samples (120 tumour tissues and 33 normal breast tissues) were analysed. The levels of transcription of STS and OATP-B were determined using real-time quantitative PCR and normalized against cytokeratin 19. The levels of expression were analysed against tumour's stage, grade, nodal status, local relapse, distant metastasis, ERalpha, ERbeta and HER1-4 receptor status and survival over a 10 year follow up period.The levels of STS mRNA were significantly higher in malignant samples (p=0.031) and in node positive disease (p=0.0222). STS mRNA expression increased with increasing tumour grade but this did not reach statistical significance. A significant increase was also noted in levels correlating with tumour stage when stages TNM1 and TNM2, TNM2 and TNM3, and TNM3 and TNM4 (p=0.00001, 0.0017 and 0.02, respectively) were compared. Furthermore, STS expression levels positively correlated with progression of disease, as levels were significantly higher in samples from patients who developed metastasis, local recurrence, or died of breast cancer when compared to those who were disease free for10 years (p=0.0036). No significant correlation was found between the levels of STS expression and ERalpha/ERbeta/ status. The levels positively correlated with HER1 and HER3 receptors. The levels of mRNA expression of OATP-B were higher in malignant tissue compared to normal tissue; this, however, did not reach statistical significance (p=0.4045). Levels were also higher in node positive disease (p=0.0672). Expression levels increased with increasing tumour grade and this became statistically significant when comparing grade 1 to 2, and grade 2 to 3 (p=0.0271 and 0.0289, respectively). An increase in levels correlating with TNM tumour staging was also observed; this, however, did not reach statistical significance. There was no significant correlation between OATP-B expression levels and clinical progression of breast cancer. No correlation was found between STS and OATP-B expression levels.This study demonstrates a compelling trend for STS transcription levels to be higher in cancer tissues and in patients who developed progressive disease. OATP-B expression levels correlated with the grade and stage of the disease, but not with the clinical outcome. These results suggest that STS mRNA has a significant potential as an important predictor of clinical outcome in patients with breast cancer.

Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal length and stability thus leading to cellular immortalisation. hTERT (human telomerase reverse transcriptase) gene is the rate-limiting determinant of telomerase reactivation. The present study aims to quantitatively measure the expression of hTERT mRNA in human breast cancer, examine the association between hTERT and the clinicopathological characteristics of the cancer specimens including the Nottingham Prognostic Index (NPI) and to explore the relationship between hTERT expression and clinical outcome.RNA was extracted from 116 breast carcinomas and 31 matched adjacent non-cancerous tissue (ANCT). hTERT mRNA expression was estimated by reverse transcriptase-PCR (RT-PCR) and Taqman methodology.hTERT mRNA was present in all of the cancerous specimens (mean=0.1701, median=0.0205) and most ANCT specimens with levels being 2.6 times higher in the cancerous tissue than in ANCT (mean=0.156 vs. 0.68, p=0.18). The mean mRNA levels increased with NPI scores (0.0816 for NPI 1, 0.1186 for NPI 2 and 0.68 for NPI 3), however this failed to reach statistical significance (P-values= 0.33 for NPI 1 vs. 2, 0.27for NPI2 vs. 3 and 0.24 for NPI 1 vs. 3). hTERT levels also increased with increasing tumour's grade (mean= 0.0459 for grade 1, 0.111for grade 2, and 0.27 for grade 3) but this trend did not reach a statistical significance. Low levels of hTERT were associated with mucinous carcinoma compared with ductal (p=0.023) and lobular (p=0.021) types. hTERT mRNA levels were higher in patients who had recurrent disease or died from breast cancer compared with those who remained alive without disease after a median follow up of 6 years (p=0.0026).High hTERT mRNA levels are associated with a poor clinical outcome in human breast cancer and should be included as a prognostic marker in future validation studies.

The expression of certain CD44 variants has been linked with metastasis and tumour progression. In particular, high molecular weight forms of CD44 show restricted expression in tumours and may correlate with tumour development and metastasis. In this study, we examined the expression of CD44 variants in prostate cancer cell lines: the invasive PC-3 and DU-145, low invasive LNCaP, and two non-invasive prostate epithelial cell lines. PC-3 prostate cancer cells were transfected with a high molecular weight CD44 variant isoform, CD44v3-v10, isolated from non-invasive prostate epithelial cell lines. These transfected cells (PC-NIVO) were assessed using in vitro invasion, tumour-endothelial, growth, and migration assays. The expression of MMP-14 was examined using SDS-PAGE and Western blot analysis. Transfected PC-3 cells (PC-NIVO) were found to be less adherent to endothelial cells and had significantly reduced invasiveness compared to wild-type PC-3 or control cells. In addition, tumour cell adhesion to endothelial cells and invasiveness was increased after exposure to HGF/SF, and can be blocked by the presence of anti-CD44 antibodies. Further investigation revealed a reduction in the expression of MMP-14 in PC-NIVO cells, but not in PC-3 or control cells. In conclusion, non-invasive prostate epithelial cells express a high molecular weight CD44 isoform, CD44v3-v10, which may counteract the standard isoform function of CD44 by reducing adhesion and invasion of endothelium by prostate tumour cells through negation of the MMP-14 function.

Men who die from prostate cancer do so from uncontrolled metastatic disease. A better understanding of the mechanisms involved in the progression and metastasis of prostate cancer may lead to novel therapeutic approaches to prevent its natural progression. Hepatocyte Growth Factor / Scatter factor (HGF/SF) has been demonstrated to elicit a number of key functions in numerous tissues that are important in the progression, invasion and metastasis of cancer. Studies have demonstrated that the activity of HGF/SF and its receptor c-Met are linked to disease progression in numerous cancers. However, research into these functions, which include activities as a mitogen, a motogen and an anti-apoptotic and angiogenic factor in prostate cancer are limited. This article reviews the published evidence of the roles HGF/SF plays in prostate cancer progression and highlights the clinical and therapeutic potential of research into this pleiomorphic cytokine.

The Wnt family encodes secreted signaling molecules involved in cell adhesion and, by implication, cell growth. Wnt5a has been shown to behave as a putative oncogene and also as a tumour suppressor gene. This is a reflection of its role within a multi-step pathway and in the variety of ways in which its production can be stimulated or switched off. Wnt genes can be functionally separated into two classes; those that activate the canonical Wnt/beta-catenin pathway and those that activate the Wnt/Ca++ pathway. Wnt5a signals through frizzled receptors and, depending upon which frizzled receptor is present, may activate either pathway. Therefore the observed function of Wnt5a is entirely dependent upon its context, hence the confusion over its role in tumorigenesis. This study examines Wnt5a mRNA expression using RT-PCR in human breast cancer.One hundred and twenty malignant breast tumours and 33 normal breast tissues were analysed. The levels of transcription of Wnt5a were determined using real-time quantitative PCR. Levels of expression were analysed against staging, nodal involvement, grade, distant metastasis and survival over a 6-year follow-up period.Levels of Wnt5a mRNA were lower in tumours than in normal tissue (mean values: 107 vs. 62.7). They fell further with increasing stage using the Nottingham Prognostic Index. This became statistically significant when NPI3 was compared to normal tissue (p=0.043, t-test). There was a trend towards lower levels of Wnt5a in those with progressive disease, however, this did not reach statistical significance. In patients with ER-negative disease, lower levels of Wnt5a were significantly associated with a worse clinical outcome (p=0.016).There is a trend for mRNA levels to be lower in cancerous tissue and lower still in those showing more aggressive behaviour. This is consistent with the hypothesis that Wnt5a is a tumour suppressor gene with potential clinical applications.

In many tumour types, lymphatic vasculature serves as a major route for tumour metastasis. The dissemination of malignant cells to the regional lymph nodes is an early step in the progression of many solid tumours and is an important determinant of prognosis. Lymphangiogenesis (formation of new lymphatic vessels) is thought to be crucial for cancer cells to metastasise to the regional lymph nodes. However research in this important process has been neglected largely due to the lack of molecular markers specific to the lymphatic endothelium. Recently, several specific markers have been identified including LYVE-1, podoplanin and prox-1. Although the biology of lymphangiogeneis, particularly its regulation, is still far from clear, it is now well established that tumours are lymphangiogenic i.e. they could induce the generation of their own lymphatics and metastasise to the regional lymph nodes. It is thought that the interruption of the main signalling pathways involved in this process could help to prevent lymphatic spread of many tumours. Furthermore, understanding the molecular mechanisms in lymphangiogenesis might help to develop new therapeutic strategies against cancer lymphatic spread. Here, we reviewed the literature in regards to the biology of lymphangiogenesis, its molecular regulation, lymphatic markers and the significance in human solid tumours.

This study sought to examine the effect of matrix-bound fibroblasts on angiogenesis and endothelial cell motility. Promotion of angiogenesis by matrix-bound fibroblasts was assessed using rat aortic ring and endothelial tube formation assays. Enhancement of human endothelial cell motility by matrix-bound fibroblasts was assessed using cytodex-2 bead and colloidal gold phagokinetic motility assays. Antibody to hepatocyte growth factor/scatter factor (HGF/SF) but not vascular endothelial growth factor (VEGf) decreased fibroblast-enhanced motility of endothelial cells. The promotion of tube formation by matrix-bound fibroblasts was neutralised with antibodies to HGF/SF and VEGf, both known promoters of angiogenesis. HGF/SF presence was detected by ELISA; whilst the presence of VEGf was detected by Western blotting. These data show that matrix-embedded fibroblasts regulate the motility of vascular endothelial cells and enhance angiogenesis, an effect partly attributed to production of angiogenesis-promoting cytokines HGF/SF and/or VEGf.

Interleukin-7 (IL-7) plays an important role in the normal development and maintenance of the human immune system. Its effects are mediated via its receptor, IL-7R. Ligand-receptor engagement results in a cascade of phosphorylation events mediated by various molecules including the Janus kinases (Jak1 and Jak3), PI3-kinase, Stats (signal transducers and activators of transcription) and other molecules. The activation of IL-7 signalling pathway results in survival, proliferation, differentiation and maturation of haematopoietic cells including B and T lymphocytes. Although the relationship of IL-7 with the development and differentiation of some haematological cancers like leukaemias and lymphomas is well recognised, little is known about it involvement with solid tumours. There are several studies that have revealed IL-7/IL-7R expression in epithelial systems and some human solid epithelial tumours. Furthermore, IL-7 can be produced by some human tumour cells and involved in tumour development and progression. In this review article we have summarised the main biological activities of IL-7 and its downstream signalling complex in relation to some human solid malignancies.

Breast cancer is one of the commonest malignancies in women in the western world. It spreads predominantly via the lymphatic system. However, the understanding of the formation of lymphatics, lymphangiogenesis, has been limited. This has been largely due to the previous lack of lymphatic specific markers. The most specific marker used in humans has been the vascular endothelial growth factor receptor 3 (VEGFR-3). However, this is also found on blood vessel endothelium. The other vascular endothelial factor receptors (VEGFR-1 and -2) are primarily blood vessel receptors. More recently, novel, specific markers for lymphatics have been discovered, such as LYVE-1, prox I and podoplanin, enabling further research into this new field. Each of these new markers is described in detail. The article also outlines the current understanding in breast cancer metastasis, with an emphasis on the more recent research into lymphangiogenesis. Since these specific markers are now available, quantitation of lymphangiogenesis is now possible by using either immunohistochemistry or quantitative PCR approaches. In addition, to breast cancer, research into many other cancers is now possible using these methods and new markers. With this in mind, possible therapeutic strategies for the future are discussed.

Vascular endothelial cadherin (VE-cadherin/cadherin-5) has previously been described as playing a specific role in angiogenesis due to its localisation at areas of intercellular contact, where it functions in maintenance of tubular architecture. Matrix-bound fibroblasts have been show to produce a number of factors that are important in inducing angiogenesis and to promote tubule-formation by human endothelial cells, an indicator of angiogenic potential.Tubule formation stimulated by fibroblast-derived growth factors can be prevented by the addition of monoclonal antibody to VE-cadherin. In addition, fibroblasts-derived growth factors are able to modulate the expression and hence the regulation of this endothelial cell specific cadherin.The change in VE-cadherin expression of human endothelial cells by fibroblast-derived growth factors may contribute to the regulation of angiogenesis.

Tight Junctions govern the permeability of endothelial and epithelial cells and are the most topical structures of these cell types. Tight junctions create an intercellular barrier and intramembrane diffusion fence. An important step in the formation of cancer metastases interaction and penetration of the vascular endothelium by dissociated cancer cells. Early studies demonstrated a correlation between the reduction of tight junctions and tumour differentiation and experimental evidence has emerged to place tight junctions in the frontline as the structure that cancer cells must overcome in order to metastasise. Changes in tight junction function are thus an early and key aspect in cancer metastasis. Further work is required to fully realise the potential that this structure has in cancer invasion and metastasis in order to develop new and novel therapies in the prevention of tumour metastasis.

The current study examined the effects of hepatocyte growth factor/scatter factor (HGF/SF) on cell-cell dissociation, invasion, and its association with the mediated release of matrix metalloproteinase-7 (Matrilysin) on the extracellular cleavage of E-cadherin in prostate cancer cells.The effects of HGF/SF on cell-cell dissociation, in vitro invasion, and on the expression of E-cadherin at both protein and mRNA levels were assessed in cells whose expression of Matrilysin was altered by treatment with antisense oligonucleotide.Incubation with HGF/SF mediated the release of active Matrilysin (M(r) 19,000), resulting in extracellular cleavage of E-cadherin from prostate cancer cells. This resultant soluble M(r) 80,000 fragment of E-cadherin was subsequently recognized upon immunoprobing with an anti-E-cadherin antibody. Both recombinant human Matrilysin (rh-Matrilysin) and/or HGF/SF increased the level of soluble E-cadherin and decreased the level of full-length (M(r) 120,000) E-cadherin as detected by Western blotting. The effects of rh-Matrilysin and HGF/SF were inhibited by an antisense oligonucleotide specifically directed toward human Matrilysin. In addition, stimulation with either rh-Matrilysin or HGF/SF resulted in disruption to the E-cadherin/beta-catenin complex, as shown by a significant increase (P0.05) in both cell scattering and invasion index.Treatment with HGF/SF induced Matrilysin-mediated cleavage to the extracellular domain of E-cadherin, resulting in its dissociation from the cadherin/catenin complex. This provides a new mechanism in HGF/SF-induced cell scattering, resulting in a switch to a more invasive phenotype in LNCapFGC cells, as demonstrated by in vitro invasion.

Hepatocyte growth factor/scatter factor (HGF/SF), a cytokine associated with cancer cell migration and invasion, is synthesised as pro-HGF/SF and requires activation by factors such as the HGF activator (HGFA). The present study examined the expression of HGF/SF, HGFA, the two inhibitors to HGFA action known as hepatocyte growth factor activator inhibitors type 1 and 2 (HAI-1 and HAI-2), and the HGF/SF receptor, c-Met. We examined a variety of normal and cancer cells, which included breast, prostate, colon, bladder, liver, lung, and pancreatic cancer cell lines. The cell lines all displayed different patterns of expression, and in some of the cancer cell lines the concomitant expression of the HGF/SF, c-Met, HGFA and HAI genes was observed. The only cell line to produce a significant amount of HGF/SF was the human fibroblasts (MRC-5) which also co-expressed the c-Met and HGFA genes to allow autocrine regulation of HGF/SF stimulation, and importantly displayed little or no inhibitor presence to suppress the biological function of HGF/SF. The highly invasive breast cancer cells (MDA MB-231) expressed large amounts of both c-Met and HGFA, to enable maximum influence from HGF/SF and did not express the HAI-1 gene at all, which suggests a shift in the activation-inhibition balance to enhance metastatic potential. In contrast, the breast cancer cells of low invasive nature (MCF-7) displayed a low level of c-Met and HGFA expression, while expressing the HAI genes to a high degree. However, there was no correlation between HAI-1 and HAI-2 expression. Interestingly, there appeared to be an inverse correlation between the degree of HGFA and HAI-1 expression, which may influence the metastatic ability of the cancer cells. This study has shown that c-Met, HGF/SF and its activator and inhibitors are expressed in different patterns in cancer cells and in normal cells. The balance between HGF/SF activation and HGFA inhibition is critical to the metastatic potential of the tumour cells, and the invasive nature of the cancer cell lines correlated to the degree of c-Met and/or HGFA presence along with HAI-1 expression.

Hepatocyte growth factor/scatter factor (HGF/SF), via its receptor c-MET, has been implicated to play a pivotal role in breast cancer development and progression. This study examined a transgene-consisting of a combination of U1snRNA, hammerhead ribozyme, and antisense, designed to inhibit c-met expression-and its impact on the migration and in vitro invasion of breast cancer cells.A hammerhead ribozyme targeting human c-MET was cloned into a modified pZeoU1EcoSpe vector and transfected into breast cancer cells MDA MB 231 and MCF-7 by electroporation. Expression of MET mRNA and protein was determined. Migration and in vitro invasiveness of transfected cells were also analyzed.Breast cancer cells were transfected with the ribozyme-containing plasmids. Stable transfectants manifested an almost complete loss of MET mRNA and protein, as shown by reverse transcription-PCR, Northern blotting, and Western blotting, respectively, whereas the wild-type plasmid had no effects. Met-ribozyme transfected cells exhibited reduced migration and in vitro invasiveness through extracellular matrix (Matrigel), compared with the wild-type cells and cells transfected with empty plasmid.These data show that targeting c-MET by way of a hammerhead ribozyme encoding antisense to c-MET is an effective approach in reducing the invasiveness of breast cancer cells.

Hepatocyte growth factor (HGF)/scatter factor (SF) is a cytokine exerting a wide range of biological functions on many cell types, including vascular endothelial cells. HGF/SF increases migration, motility, and dissociation of human umbilical vascular endothelial cells (HUVECs). This study demonstrated that such action of HGF/SF on HUVECs was achieved by regulation of the endothelial cell-specific cadherin, vascular endothelial (VE)-cadherin. HGF/SF induced a time-dependent reduction of VE-cadherin protein from HUVECs as shown by Western blotting and immunocytochemistry, accompanied by an increase in the migration of HUVECs. The change of VE-cadherin appeared at the mRNA level, as demonstrated by reverse transcription-PCR, with a decrease in the VE-cadherin signal. These results show, for the first time, that HGF/SF targets the endothelial cell-specific adhesion molecule VE-cadherin.