Expression of activated integrin ß7 in multiple myeloma patients.

Multiple myeloma (MM) is still extremely difficult to cure, and new therapeutic drugs are needed. We recently found that integrin ß7 is constitutively activated in MM cells, and chimeric antigen receptor (CAR) T cells targeting activated integrin ß7 have a significant anti-MM effect. In this study, we performed flow cytometry analysis of the expression of activated integrin ß7 in bone marrow cells from 137 symptomatic MM patients. In 60/137 (44%) MM patients, activated integrin ß7 was detected in most MM cells (> 80% of MM cells were in the positive gate). Activated integrin ß7 was highly expressed in MM cells even in heavily treated patients. It also showed high expression in many CD38lo/-CD138-CD19+B cells, which reportedly include clonotypic B cells, in the bone marrow of MM patients. Taken together, these results suggest that CAR T-cell therapy targeting activated integrin ß7 has the potential to benefit many patients with relapsed or refractory MM.

Parathyroid Hormone Induces Transition of Myofibroblasts in Arteriovenous Fistula and Increases Maturation Failure.

CONTEXT: Arteriovenous fistula (AVF) maturation failure remains a clinical dilemma, and its pathobiology is largely unclear. Secondary hyperparathyroidism is a complication of chronic renal failure that is associated with cardiovascular disease. While parathyroid hormone (PTH) has a prosclerotic effect on vascular smooth muscle cells (VSMCs), its role in AVF maturation failure remained unknown. OBJECTIVE: This work aimed to investigate the association between plasma PTH and AVF maturation. METHODS: Patients receiving AVF creation were enrolled retrospectively. A mouse model of secondary hyperparathyroidism and aortocaval AVF was used to investigate the effect of PTH on an AVF lesion. A cell model of VSMCs treated with PTH in a pressurized culture system was used to disclose the signaling pathway underlying the effect of PTH on an AVF lesion. RESULTS: In patients receiving AVF creation, higher PTH was associated with an increased risk for maturation failure. In a mouse model, vascular wall thickness and myofibroblasts of AVF significantly increased with higher PTH. When the same mice were treated with cinacalcet, AVF lesions were attenuated by suppression of PTH. A cell model showed that PTH increased the marker of myofibroblasts, integrin ß6 subunit (ITGB6), via the phosphorylated protein kinase B pathway. Finally, in the same model of mice AVF, higher PTH also increased the expression of ITGB6 in the smooth muscle layer of AVF, suggesting the transition to myofibroblast. CONCLUSION: Overall, our results suggest that higher PTH increased the risk of AVF maturation failure through increasing the transition of VSMCs to myofibroblasts. Lowering PTH may be a strategy to enhance AVF maturation.

IL-4 induces the formation of multinucleated giant cells and expression of Beta5 integrin in central giant cell lesion

BACKGROUND: It is now well established that IL-4 has a central role in the development of monocytes to multinucleated giant cells (MGCs) by inducing the expression of integrins on the surface of monocytes. The aim of this study was to investigate the potential role of IL-4 in induction of β5 integrin expression in the peripheral blood samples of patients with giant cell granuloma. MATERIAL AND METHODS: Monocytes were isolated from peripheral blood samples of patients with central giant cell granuloma (CGCG) and healthy controls using human Monocyte Isolation Kit II. Isolated monocytes were then cultured in the absence or presence of IL-4 (10 and 20 ng/mL), and following RNA extraction and cDNA synthesis, Real-time PCR was performed to determine the level of β5 integrin expression. The formation of CGCGs and morphological analyses were done under light microscopy. For confirmation of CGCGs, immunocytochemistry technique was also carried out by anti-RANK (receptor-activator of NF-κB ligand) antibody. RESULTS: In both patient and control groups, β5 levels were significantly enhanced by increasing the IL-4 dose from 10 to 20 ng/mL. In addition, these differences were significant between patient and control groups without IL-4 treatment. On the other hand, the number of cells which expressed RANK and therefore the number of giant cells were significantly higher in the patient group in comparison to controls, as assessed by immunohistochemistry evaluations. CONCLUSIONS: In this study, we showed an elevation in the expression levels of β5 integrin when stimulated by IL-4. It is strongly indicated that this integrin acts as an important mediator during macrophage to macrophage fusion and development of giant cells

Integrin ß6 serves as an immunohistochemical marker for lymph node metastasis and promotes cell invasiveness in cholangiocarcinoma.

Cholangiocarcinoma is a devastating malignancy that is notoriously difficult to diagnose and is associated with a high mortality. Despite extensive efforts to improve the diagnosis and treatment of this neoplasm, limited progress has been made. Integrin ß6 is a subtype of integrin that is expressed exclusively on the surfaces of epithelial cells and is associated with a variety of tumors. In the present study, we investigated the expression and roles of integrin ß6 in cholangiocarcinoma. ß6 upregulation in cholangiocarcinoma was correlated with lymph node metastasis and distant metastasis. Moreover, integrin ß6 was identified as a biomarker for the diagnosis of cholangiocarcinoma and an indicator of lymph node metastasis. Integrin ß6 significantly promoted the proliferation, migration and invasion of cholangiocarcinoma cells. Furthermore, integrin ß6 increased Rac1-GTPase, resulting in the upregulation of metalloproteinase-9 (MMP9) and F-actin polymerization. Taken together, our results indicate that integrin ß6 promotes tumor invasiveness in a Rac1-dependent manner and is a potential biomarker for tumor metastasis. Integrin ß6 may help to improve the diagnostic accuracy, and targeting ß6 may be a novel strategy for the treatment of cholangiocarcinoma.

Identification of ß integrin-like- and fibronectin-like proteins in the bivalve mollusk Mytilus trossulus.

Integrins play a key role in the intermediation and coordination between cells and extracellular matrix components. In this study, we first determined the presence of the ß integrin-like protein and its presumptive ligand, fibronectin-like protein, during development and in some adult tissues of the bivalve mollusc Mytilus trossulus. We found that ß integrin-like protein expression correlated with the development and differentiation of the digestive system in larvae. Besides the presence of ß integrin-like protein in the digestive epithelial larval cells, this protein was detected in the hemocytes and some adult tissues of M. trossulus. The fibronectin-like protein was detected firstly at the blastula stage and later, the FN-LP-immunoreactive cells were scattered in the trochophore larvae. The fibronectin-like protein was not expressed in the ß integrin-positive cells of either the veliger stage larvae or the adult mussel tissues and the primary hemocyte cell culture. Despite the ß integrin- and fibronectin-like proteins being expressed in different cell types of mussel larvae, we do not exclude the possibility of direct interaction between these two proteins during M. trossulus development or in adult tissues.

ß Integrin-like protein-mediated adhesion and its disturbances during cell cultivation of the mussel Mytilus trossulus.

In this study, we focus on the specific contribution of ß integrin-like protein to adhesion-mediated events in molluscan larval cells in culture that could not have been investigated within the whole animal. An analysis of disturbances to cell-substratum adhesion, caused by the integrin receptor inhibiting Arg-Gly-Asp-Ser (RGDS)-peptide, the Ca(2+)/Mg(2+)-chelators and the stress influence of freezing-thawing, reveals that all these factors resulted in the partial destruction of the integrin-extracellular matrix (ECM) interaction in culture and, in particular, changes in the distribution and relative abundance of ß integrin-positive cells. The experiments, carried out on selected substrates, found that ß integrin-positive cells demonstrate different affinities for the substrates. This finding further supports the assumption that epithelial differentiation in cultivated cells of larval Mytilus may be mediated by ß integrin-like proteins via binding to laminin; direct binding to other components of the ECM could not be demonstrated. The mussel ß integrin-positive cells are not involved in myogenic or neuronal differentiation on any of the substrates but part of them has tubulin-positive cilia, forming some epithelia-like structures. Our data indicate that ß integrin-positive cells are able to proliferate in vitro which suggests that they could participate in renewing the digestive epithelium in larvae. The findings provide evidence that the distribution pattern of ß integrin-like protein depends on the cell type and the factors influencing the adhesion.

Sophoricoside fails the embryo implantation by compromising the uterine endometrial receptivity at implantation "window" of pregnant mice.

Sophoricoside (SOPH) is an isoflavone glycoside isolated from the fruits of Sophora japonica. Since its first isolation in 1961, there are rare findings about the effects of SOPH on reproductive system. In the present study, the pregnant mice administrated by different doses of SOPH were used to explore the effect of SOPH on embryo implantation, especially on the endometrial receptivity. The statistical results showed that the number of implanted embryos was gradually declining along the increasing dose of SOPH. When the administrated dose of SOPH was 600 mg/kg per day, great changes were observed in the exposed uterine morphology and up-regulated progesterone receptor (PR) and down-regulated estrogen receptor α (ERα), E-cadherin, matrix metalloproteinase-2 (MMP-2) and integrin ß3 were also found in SOPH-exposed uterine. These findings demonstrated that SOPH exposure reduced the number of implanted embryos in a dose-dependent manner and failed the embryo implantation through altering the morphology of uterine and compromising the endometrial receptivity.

The unsaponifiable fraction of extra virgin olive oil promotes apoptosis and attenuates activation and homing properties of T cells from patients with inflammatory bowel disease.

The unsaponifiable fraction (UF) of extra virgin olive oil (EVOO) possesses anti-inflammatory properties and exerts preventative effects in murine models of inflammatory bowel disease (IBD). The present study was designed to determine the in vitro effects of UF on blood and intestinal T cells from IBD patients and healthy subjects. The T cell phenotype was investigated by flow cytometry and cytokine secretion was determined by ELISA. The presence of UF of EVOO promoted apoptosis and attenuated activation of intestinal and blood T cells isolated from IBD patients, decreasing the frequency of CD69(+) and CD25(+) T cells and, also, the secretion of IFN-γ. Moreover, UF reduced the expression of the gut homing receptor integrin ß7 on blood T cells from IBD patients. In conclusion, UF modulates the activity and the gut homing capacity of T cells, and might therefore be considered as a dietary complement with an anti-inflammatory role in IBD patients.

Stability measurements of antibodies stored on paper.

Reagent storage has been a long-standing challenge for diagnostics, especially those designed for low-resource settings and point-of-care applications. In general, the stability of a reagent relies on careful temperature control, often by refrigeration, which is costly and often unavailable in these remote settings. Poor reagent integrity can negatively affect the reproducibility and reliability of an assay. Given the recent interest in paper-based devices designed for quantitative analysis in point-of-care settings, a better understanding of reagent stability on filter paper is critical for proper device use and its longevity. In this article, we present an independent method to examine the stability of reconstituted antibodies that were stored on filter paper using flow cytometry. We validated the method by measuring the activity as measured by the mean fluorescence intensity (MFI) of antibodies stored with known stabilizers. Furthermore, we demonstrated the potential of our method to screen the influence of other paper treatments and storage processes on antibody stability, which may be applicable to the storage of reagents on paper in general.

The majority of HIV type 1 DNA in circulating CD4+ T lymphocytes is present in non-gut-homing resting memory CD4+ T cells.

Memory CD4(+) T lymphocytes in peripheral blood that express integrins α4ß7 preferentially recirculate through gut-associated lymphoid tissue (GALT), a proposed site of significant HIV-1 replication. Tregs and activated CD4(+) T cells in GALT could also be particularly susceptible to infection. We therefore hypothesized that infection of these subsets of memory CD4(+) T cells may contribute disproportionately to the HIV-1 reservoir. A cross-sectional study of CD4(+) T cell subsets of memory CD45RO(+) cells in peripheral blood mononuclear cells (PBMCs) was conducted using leukapheresis from eight subjects with untreated chronic HIV-1 infection. Real-time polymerase chain reaction (PCR) was used to quantify total and integrated HIV-1 DNA levels from memory CD4(+) T cells sorted into integrin ß7(+) vs. ß7(-), CD25(+)CD127(low) Treg vs. CD127(high), and activated CD38(+) vs. CD38(-). More than 80% of total HIV-1 DNA was found to reside in the integrin ß7-negative non-gut-homing subset of CD45RO(+) memory CD4(+) T cells. Less than 10% was found in highly purified Tregs or CD38(+) activated memory cells. Similarly, integrated HIV-1 DNA copies were found to be more abundant in resting non-gut-homing memory CD4(+) T cells (76%) than in their activated counterparts (23%). Our investigations showed that the majority of both total and integrated HIV-1 DNA was found within non-gut-homing resting CD4(+) T cells.

Expression of αvß6 integrin and collagen fibre in oral squamous cell carcinoma: association with clinical outcomes and prognostic implications.

BACKGROUND: This study aims to investigate the expression and significance of the αvß6 integrin, collagen fibres and matrix metalloproteinases (MMP)-3 in oral squamous cell carcinoma (OSCC) and to analyse the possible regulatory relationships between αvß6, collagen fibres and MMP-3. MATERIALS AND METHODS: A series of 80 patients (mean age 56.4 years) diagnosed with OSCC were enrolled. Associations between αvß6, MMP-3, collagen fibre expression levels and clinicopathological parameters were evaluated using the Fisher exact test. Survival analysis was performed with Kaplan-Meier curves. Spearman rank correlation was used to analyse interactions between αvß6, MMP-3 and collagen fibres. RESULTS: αvß6 and MMP-3 were strongly expressed in human OSCC, especially at the peripheral borders of invasive tumour islands, and collagen fibres were generally disrupted and degraded in the same areas. The expression intensity of αvß6 was associated with the differentiation state of cells. ß6 mRNA was expressed in almost all cancer cells. In carcinomas, αvß6 and MMP-3 expression were correlated with the distribution of collagen fibres. CONCLUSIONS: Tumour cells highly expressing αvß6 have a strong capability for invasion and migration, due to concomitant protease production and the destruction and remodelling of collagen fibres. Increased αvß6 integrin and MMP-3 expression and collagen fibre changes in human OSCCs are related to unfavourable clinical prognostic factors and decreased survival.

A laboratory study comparing the effect of ridge exposure using tissue punch versus mucoperiosteal flap on the formation of the implant-epithelial junction.

OBJECTIVE: The objective of the present study was to clarify the influence of the incision design at the time of implant placement on the consolidation of the implanto-epithelial junction. STUDY DESIGN: Twelve minipigs were chosen for the study. Four weeks after premolar extraction in the maxilla, 4 BEGO Semados RI implants were inserted in each quadrant. Using a split-mouth design, the alveolar crest was exposed by a punch ("flapless surgery") on one side and by a crestal incision ("flap surgery") on the other side. Biopsies were obtained from the peri-implant soft tissue at weeks 1, 2, 4, and 12 postinsertion, respectively, and analyzed for the expression of integrin α(6)ß(4) chain ß(4) (ITGB4) and laminin 5 γ(2) chain (lamc2), 2 important marker molecules for the formation of the implanto-epithelial junction. RESULTS: Following exposure of the alveolar crest by the punch technique, a significantly higher expression of ITGB4 was found at the 2- (P = .009), 4- (P = .001), and 12-week (P = .005) follow-up. Furthermore, the expression of lamc2 was significantly higher following punch exposure after 1 (P = .033), 2 (P = .041), 3 (P = .004), and 12 weeks (P = .002) of transmucosal implant healing. CONCLUSIONS: The data of the present study indicate that flapless placement improved the formation of a sufficient implanto-epithelial junction.

[Alterations of cell phenotype in Dupuytren's disease--an in vitro analysis]. / Veränderung des Zell-Phänotyps durch Morbus Dupuytren--eine in-vitro-Analyse.

INTRODUCTION: Despite its potential complications, partial aponeurectomy still is the mainstay of treatment whenever it comes to significant contracture in Dupuytren's disease. With the goal in mind to identify new therapeutic strategies we isolated and characterised cells from healthy palmar aponeurosis (Kon) and compared them to cells isolated from palmar aponeurosis of patients with a primary manifestation of Dupuytren's disease (PrimDup) as well as from patients with recurrent Dupuytren's disease (RezDup). As cells from palmar aponeurosis from patients with Dupuytren's disease share characteristics with stem cells, such as the ability to differentiate into other cell types, we analysed the stemness, morphology and integrin receptor profiles of the cells. MATERIALS AND METHODS: A total of 15 Dupuytren samples were collected from regular partial aponeurectomy procedures. From these, 3 donors without extrinsic risk factors were selected per group (RezDup, PrimDup). Cells were isolated and expanded under standard cell culture conditions. Cells from healthy patients served as control (Kon). Growth curves were produced. Cells were subjected to osteogenic and adipogenic differentiation using standard protocols. Semiquantitative PCR analysis of the integrins α2, ß3, ß5 and fibronectin was performed. RESULTS: PrimDup cells proliferated significantly faster than control cells, which in turn proliferated faster than RezDup cells. Both PrimDup and control cells went into senescence after approximately 40 days whereas RezDup cells proliferated over the entire period of 100 days. Osteogenic and adipogenic differentiation was best in cells derived from Dupuytren patients while Kon cells differentiated poorly. PCR analysis revealed that fibronectin-binding integrins ß3 and ß5 are upregulated in Dupuytren's disease. CONCLUSIONS: PrimDup cells grow faster than the other cell types suggesting that their growth regulation may be altered. The fact that RezDup cells do not reach senescence over 100 days in culture indicates that senescence regulating factors may be altered. As cells from Dupuytren patients differentiate better along the osteogenic and adipogenic lineages, they probably possess a higher level of stemness. Their modified integrin profile may be a key to future therapies.

Retinal pigment epithelial cells use a MerTK-dependent mechanism to limit the phagocytic particle binding activity of αvß5 integrin.

BACKGROUND INFORMATION: αvß5 integrin and Mer tyrosine kinase (MerTK) receptors reside at the apical surface of the retinal pigment epithelium (RPE) in the eye to promote the diurnal, synchronised phagocytosis of shed photoreceptor outer segment fragments (POS) that is critical for vision. Phagocytosis assays studying RPE cells in culture have defined roles for αvß5 in POS surface binding and for MerTK in engulfment of bound POS. Both receptors have thus far only been studied separately. It is therefore unknown if αvß5 integrin activity in POS binding is independent of the engulfment function of RPE cells. This study investigates how increasing αvß5 receptor levels affect POS binding and internalisation by wild-type (wt), αvß5- or MerTK-deficient RPE. RESULTS: ß5 integrin-green fluorescent protein (ß5-GFP) fusion proteins formed heterodimeric receptors with endogenous αv integrin subunits at the apical surface of mouse or rat RPE cells that co-immunoprecipitated focal adhesion kinase and redistributed with bound POS such as endogenous αvß5 receptors. In ß5(-/-) RPE cells, de novo formation of αvß5-GFP receptors restored POS binding and internalisation up to, but not, above wt POS uptake levels. In wt RPE cells, increasing levels of αvß5 surface receptors by over-expressing ß5-GFP only moderately stimulated POS binding, even if POS internalisation was inhibited pharmacologically or by lowering incubation temperatures. In contrast, the same increase in αvß5 receptor levels dramatically enhanced POS binding of RPE cells lacking MerTK. Furthermore, decreasing MerTK expression by RNA interference increased POS binding to endogenous αvß5 receptors of wt RPE cells. CONCLUSIONS: Expressing ß5-GFP is sufficient to reverse phagocytic deficiencies of RPE cells derived from ß5(-/-) mice, indicating that these cells do not irreversibly lose other components of the phagocytic machinery. RPE cells expressing the engulfment receptor MerTK control POS binding by limiting activity of endogenous αvß5 and αvß5-GFP integrins, although they reside at the apical, phagocytic surface. In contrast, RPE cells permanently or transiently losing MerTK expression lack this regulatory mechanism and bind excess POS via surface αvß5 receptors. Taken together, these data reveal a novel feedback mechanism that restricts binding of POS to surface αvß5 integrin receptors in RPE cells.

Cancer stem cell phenotype relates to radio-chemotherapy outcome in locally advanced squamous cell head-neck cancer.

BACKGROUND: Cancer stem cells (CSCs) tend to repopulate malignant tumours during radiotherapy and, therefore, prolongation of the overall treatment time may result in radiotherapy failure. Thus, an estimate of the number of CSCs in tumour biopsies may prove most useful in predicting resistance to radiotherapy and a guide for development therapies aimed to eradicate a cancer cell population with effects on radiotherapy-related cancer regrowth. METHODS: The CSC population was investigated semi-quantitatively in 74 locally advanced squamous cell head-neck cancers (HNSCC) from an equal number of patients, treated with accelerated platinum-based radiotherapy. A standard immunohistochemical technique and the CSC markers CD44, CD24, Oct4, integrin-ß1 and aldehyde dehydrogenase isoform 1A1 (ALDHA1) was used, in parallel with the proliferation marker MIB-1. The results were correlated with the site of the tumour, the MIB-1 index, the tumour grade and stage, and prognosis. RESULTS: The expression of CD44, CD24 and Oct4 were significantly associated with the MIB-1 proliferation index. In addition, the CD44 was linked with the better differentiated HNSCC. The CD44, Oct4 and integrin-ß1 were all associated with poor prognosis but, in a multivariate analysis, the integrin-ß1 had an independent statistical significance in terms of local relapse, distant metastases and overall survival. Interestingly, ALDH1 was associated with favourable prognosis. CONCLUSION: CSC markers are linked with poor radiotherapy outcome in HNSCC, with integrin-ß1 being the strongest and independent prognostic factor. Targeting CSC molecules with monoclonal antibodies or pharmaceutical agents may prove important for the treatment of HNSCC.

PET-radioimmunodetection of integrins: imaging acute colitis using a 64Cu-labeled anti-ß7 integrin antibody.

Integrins are involved in a wide range of cell interactions. Imaging their distribution using high-resolution noninvasive techniques that are directly translatable to the clinic can provide new insights into disease processes and presents the opportunity to directly monitor new therapies. In this chapter, we describe a protocol to image, the in vivo distribution of the integrin ß(7), expressed by lymphocytes recruited to and retained by the inflamed gut, using a radiolabeled whole antibody. The antibody is purified, conjugated with a bifunctional chelator for labeling with a radiometal, labeled with the positron-emitting radionuclide (64)Cu, and injected into mice for microPET studies. Mice with DSS-induced colitis were found to have higher uptake of the (64)Cu-labeled antibody in the gut than control groups.

Insights into the local pathogenesis induced by fish toxins: Role ofnatterins and nattectin in the disruption of cell–cell and cell–extracellularmatrix interactions and modulation of cell migration

Combined proteomic and transcriptomic approaches to study the composition of the venom of Thalassophryne nattereri venomous fish revealed the primary structures of the major toxins as a family of proteases natterins, never described on venoms and a C-type lectin nattectin. To gain new insights into the mechanisms of venom pathogenesis and to further elucidate the role of its major toxins, the natterins and nattectin, we undertookin vitro investigations using these isolated toxins. Here we demonstrated the specific ability of the nattectin to bind types I and V collagen and natterins to bind and cleave type I collagen as well as type IV collagen, disrupting cell attachment and HeLa cells survival. Natterins have cytotoxic effect on both adherent cells or at in suspension, showing direct induction of necrosis that is followed by cell detachment. Nattectin improves integrinmediated HeLa cell adhesion and resistance to apoptosis by its binding to RGD dependent integrins, especially the b1 subunit. Based on our studies we now report that extracellular matrix (ECM) components as well as the integrin b1 subunit are targets for the natterins and nattectin. The ECM degradation or remodeling activities exerted by these toxins affect cell–cell and cell–ECM adhesion and survival and impair inflammatory cell migration into inflamed tissues.

Tubulointerstitial nephritis antigen-like 1 is expressed in the uterus and binds with integrins in decidualized endometrium during postimplantation in mice.

Extracellular matrix substrates contribute to both uterine and blastocyst functions during the peri-implantation period. Tubulointerstitial nephritis antigen-like 1 (TINAGL1, also known as adrenocortical zonation factor 1 [AZ-1] or lipocalin 7) is a novel matricellular protein that promotes cell adhesion and spreading. However, the physiological roles of TINAGL1 are still not clearly understood. We examined the expression and localization of TINAGL1 in peri-implantation mouse uteri. During the preimplantation period, TINAGL1 was expressed in the basement membranes of uterine luminal epithelial cells on Days 1 and 2 of pregnancy, while its expression levels declined after Day 3. In the whole uteri, the expression levels of Tinagl1 mRNA and TINAGL1 protein were similar on Days 1-4 of pregnancy. In contrast, the expression of Tinagl1 mRNA and TINAGL1 protein increased in postimplantation uteri. From Days 6 to 8, TINAGL1 was markedly expressed in the decidual endometrium. TINAGL1 is a ligand for integrins and promotes cell adhesion in cultured cells. Therefore, to address whether TINAGL1 interacts with integrins in the uterus, immunohistochemical analysis and immunoprecipitation were performed. Immunohistochemical analysis showed that ITGA2, ITGA5, and ITGB1 were expressed in stromal cells around the implanted embryos on Days 7 and 8. Biacore and immunoprecipitation analysis determined that TINAGL1 linked with ITGA5 and ITGB1 in the decidual endometrium. These results suggest that Tinagl1 functions during the postimplantation period; in particular, it associates with ITGA5B1 in the decidualized uterine endometrium.

[Expression pattern of invasion-related molecules in brain tumors of different origin]. / Különbözo eredetu malignus agydaganatok invazivitásának panelszeru vizsgálata.

Tumor cell invasion into the surrounding brain tissue is mainly responsible for the failure of radical surgical resection and successful treatment, with tumor recurrence as microdisseminated disease. Epidermal growth factor receptors (EGFRs), integrins and their ligands in the extracellular matrix (ECM) predominantly participate in the invasion process, including the cell adhesion to the surrounding microenvironment and cell migration. The extent of infiltration of the surrounding brain tissue by malignant tumors strongly depends on the tumor cell type. Malignant gliomas show much more intensive peritumoral invasion than do metastatic tumors. In this study, the mRNA expression of 29 invasion-related molecules (18 cell membrane receptors or receptor subunits (EGFRs and integrins) and 11 ECM components: collagens, laminins and fibronectin) was investigated by quantitative reverse transcriptase-polymerase chain reaction. Fresh frozen human tissue samples from glioblastoma (GBM) and intracerebral bronchial adenocarcinoma metastases (five pieces from each) were evaluated. Significant differences were established in six of the 29 molecules (ErbB1, 2, 3, integrins alpha3, 7 and beta1). To confirm our results at the protein level, immunohistochemical analysis of nine molecules was performed. The staining intensity differed definitely in the case of ErbB1, 2 and integrins alpha3 and beta1. Determining the differences in invasion-related molecules in tumors of different origin can help identify the exact molecular mechanisms that facilitate peritumoral infiltration by glioblastoma cells. These results should allow the selection of target molecules for potential chemotherapeutic agents directed against highly invasive malignant gliomas.

IL-10 regulates movement of intestinally derived CD4+ T cells to the liver.

Diseases that affect the intestine may have hepatic manifestations, but the mechanisms involved in establishing hepatic disease secondarily remain poorly understood. We previously reported that IL-10 knockout (KO) mice developed severe necrotizing hepatitis following oral infection with Trichinella spiralis. In this study, we used this model of intestinal inflammation to further examine the role of IL-10 in regulating hepatic injury. Hepatic damage was induced by migrating newborn larvae. By delivering the parasite directly into the portal vein, we demonstrated that an ongoing intestinal immune response was necessary for the development of hepatitis. Intestinally derived CD4+ cells increased in the livers of IL-10 KO mice, and Ab-mediated blockade of MAdCAM-1 inhibited the accumulation of CD4+alpha(4)beta(7)+ cells in the liver. Moreover, adoptive transfer of intestinally primed CD4+ T cells from IL-10 KO mice caused hepatitis in infected immunodeficient animals. Conversely, transfer of wild-type donor cells reduced the severity of hepatic inflammation in IL-10 KO recipients, demonstrating regulatory activity. Our results revealed that IL-10 prevented migration of intestinal T cells to the liver and inhibited the development of hepatitis.