Afadin-nectin forces its way to the front.

Force transmission at cell-cell junctions critically regulates embryogenesis, tissue homeostasis, and diseases including cancer. The cadherin-catenin linkage has been considered the keystone of junctional force transmission, but new findings challenge this paradigm, arguing instead that the nectin-afadin linkage plays the more important role in mature junctions in the intestinal epithelium.

CD112 Supports Lymphatic Migration of Human Dermal Dendritic Cells.

Dendritic cell (DC) migration from peripheral tissues via afferent lymphatic vessels to draining lymph nodes (dLNs) is important for the organism's immune regulation and immune protection. Several lymphatic endothelial cell (LEC)-expressed adhesion molecules have thus far been found to support transmigration and movement within the lymphatic vasculature. In this study, we investigated the contribution of CD112, an adhesion molecule that we recently found to be highly expressed in murine LECs, to this process. Performing in vitro assays in the murine system, we found that transmigration of bone marrow-derived dendritic cells (BM-DCs) across or adhesion to murine LEC monolayers was reduced when CD112 was absent on LECs, DCs, or both cell types, suggesting the involvement of homophilic CD112-CD112 interactions. While CD112 was highly expressed in murine dermal LECs, CD112 levels were low in endogenous murine dermal DCs and BM-DCs. This might explain why we observed no defect in the in vivo lymphatic migration of adoptively transferred BM-DCs or endogenous DCs from the skin to dLNs. Compared to murine DCs, human monocyte-derived DCs expressed higher CD112 levels, and their migration across human CD112-expressing LECs was significantly reduced upon CD112 blockade. CD112 expression was also readily detected in endogenous human dermal DCs and LECs by flow cytometry and immunofluorescence. Upon incubating human skin punch biopsies in the presence of CD112-blocking antibodies, DC emigration from the tissue into the culture medium was significantly reduced, indicating impaired lymphatic migration. Overall, our data reveal a contribution of CD112 to human DC migration.

Single amino acid mutation of nectin-1 provides remarkable resistance against lethal pseudorabies virus infection in mice.

An approach to genetically engineered resistance to pseudorabies virus (PRV) infection was examined by using a mouse model with defined point mutation in primary receptor for alphaherpesviruses, nectin-1, by the CRISPR/Cas9 system. It has become clear that phenylalanine at position 129 of nectin-1 is important for binding to viral glycoprotein D (gD), and mutation of phenylalanine 129 to alanine (F129A) prevents nectin-1 binding to gD and virus entry in vitro. Here, to assess the antiviral potential of the single amino acid mutation of nectin-1, F129A, in vivo, we generated genome-edited mutant mouse lines; F129A and 135 knockout (KO). The latter, 135 KO used as a nectin-1 knockout line for comparison, expresses a carboxy-terminal deleted polypeptide consisting of 135 amino acids without phenylalanine 129. In the challenge with 10 LD50 PRV via intranasal route, perfect protection of disease onset was induced by expression of the mutation of nectin-1, F129A (survival rate: 100% in F129A and 135 KO versus 0% in wild type mice). Neither viral DNA/antigens nor pathological changes were detected in F129A, suggesting that viral entry was prevented at the primary site in natural infection. In the challenge with 50 LD50 PRV, lower but still strong protective effect against disease onset was observed (survival rate: 57% in F129A and 75% in 135 KO versus 0% in wild type mice). The present results indicate that single amino acid mutation of nectin-1 F129A provides significant resistance against lethal pseudorabies.

Sickle cell allele HBB-rs334(T) is associated with decreased risk of childhood Burkitt lymphoma in East Africa.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk.

Expression of PVRL4, a molecular target for cancer treatment, is transcriptionally regulated by FOS.

PVRL4 (or nectin­4) is a promising therapeutic target since its upregulated expression is found in a wide range of human cancer types. Enfortumab vedotin, an antibody­drug conjugate targeting PVRL4, is clinically used for the treatment of urothelial bladder cancer. In addition, rMV­SLAMblind, a genetically engineered oncolytic measles virus, can infect cancer cells and induce apoptosis through interaction with PVRL4. Although PVRL4 transcript levels are elevated in breast, lung and ovarian cancer, the mechanisms of its upregulation have not yet been uncovered. To clarify the regulatory mechanisms of elevated PVRL4 expression in breast cancer cells, Assay for Transposase­Accessible Chromatin­sequencing and chromatin immunoprecipitation­sequencing (ChIP­seq) data were used to search for its regulatory regions. Using breast cancer cells, an enhancer region was ultimately identified. Additional analyses, including ChIP and reporter assays, demonstrated that FOS interacted with the PVRL4 enhancer region, and that alterations of the FOS­binding motifs in the enhancer region decreased reporter activity. Consistent with these data, exogenous expression of FOS enhanced the reporter activity and PVRL4 expression in breast cancer cells. Furthermore, RNA­seq analysis using breast cancer cells treated with PVRL4 small interfering RNA revealed its possible involvement in the cytokine response and immune system. These data suggested that FOS was involved, at least partly, in the regulation of PVRL4 expression in breast cancer cells, and that elevated PVRL4 expression may regulate the response of cancer cells to cytokines and the immune system.

Nectin-4 regulates cellular senescence-associated enlargement of cell size.

Cellular senescence is defined as irreversible growth arrest induced by various stress, such as DNA damage and oxidative stress. Senescent cells exhibit various characteristic morphological changes including enlarged morphology. In our recent study, we identified Nectin-4 to be upregulated in cellular senescence by comparative transcriptomic analysis. However, there are few reports on the relationship between Nectin-4 and senescence. Therefore, we analyzed the function of Nectin-4 in senescence and its biological significance. When overexpressed with Nectin-4, the cells exhibited the enlarged cell morphology closely resembling senescent cells. In addition, the cell size enlargement during DNA damage-induced senescence was suppressed by knockdown of Nectin-4, while there were no significant changes in senescence induction. These results suggest that Nectin-4 is not involved in the regulation of senescence itself but contributes to the senescence-associated cell size increase. Furthermore, the Nectin-4-dependent cell size increase was found to be mediated by Src family kinase (SFK)/PI3 kinase (PI3K)/Rac1 pathway. To explore the functional consequences of cell size enlargement, we analyzed cell survival in Nectin-4-depleted senescent cells. Single-cell tracking experiments revealed that Nectin-4 knockdown induced apoptosis in senescent cells, and there is a strong positive correlation between cell size and survival rate. These results collectively indicate that Nectin-4 plays a causative role in the senescence-associated cell size enlargement via SFK/PI3K/Rac1, which can contribute to survival of senescent cells.

Prognostic Potential of Nectin Expressions in Colorectal Cancer: An Exploratory Study.

Colorectal cancer (CRC) is a pressing global health challenge, with an estimated 1.9 million new cases in 2020. Ranking as the third most diagnosed cancer globally, CRC accounts for nearly 930,000 cancer-related deaths annually. Nectins, immunoglobulin-like adhesion molecules, are pivotal in intercellular adhesion formation and cellular function regulation. Altered nectin expression patterns have been identified in various cancers. However, the intricacies of their role in cancer development and progression remain underexplored. This study aimed to evaluate the expression of specific nectins in CRC tumors, explore their association with clinicopathological factors, and ascertain their potential as prognostic indicators for CRC patients post-resection. We retrospectively analyzed the medical records of 92 CRC patients who underwent surgical treatment between 2013 and 2014. Tumor specimens were re-evaluated to determine nectin expression using immunohistochemistry. The study identified heterogeneous expressions of nectin-2, -3, and -4 in 58%, 62.6%, and 87.9% of specimens, respectively. Elevated nectin-4 expression correlated with worse 5-year and overall survival rates, presenting a negative prognostic value (HR = 4, 95% CI: 2.4-6.8, p < 0.001). Conversely, reduced nectin-3 expression was linked to poorer CRC prognosis (HR = 0.54; 95% CI: 0.31-0.96; p = 0.036). Nectin-4 expression positively correlated with elevated carcinoembryonic antigen (CEA) levels and advanced disease stages. In contrast, nectin-3 expression negatively correlated with CEA levels, tumor size, presence of distant metastases, and disease stage. Notably, tumors in the right colon were statistically more likely to express nectin-2 compared to those in the left. This study underscores the potential prognostic significance of nectins in CRC. The high prevalence of nectin-4-expressing cells offers promising avenues for further evaluation in targeted therapeutic interventions with already available agents such as PADCEV.

Anti-tumor activity of a recombinant measles virus against canine lung cancer cells.

Canine primary lung cancer with metastasis has a poor prognosis with no effective treatment. We previously generated a recombinant measles virus (MV) that lost binding affinity to a principal receptor, SLAM, to eliminate its virulence as a new cancer treatment strategy. The virus, rMV-SLAMblind, targets nectin-4, recently listed as a tumor marker, and exerts antitumor activity against nectin-4-positive canine mammary cancer and urinary bladder transitional cell carcinoma cells. However, the effectivity of rMV-SLAMblind for other types of canine cancers is still unknown. Here we evaluated the antitumor effect of rMV-SLAMblind to canine lung cancer. Nectin-4 is expressed on three canine lung cancer cell lines (CLAC, AZACL1, AZACL2) and rMV-SLAMblind was able to infect these cell lines. CLAC cells showed reduced cell viability after virus infection. In the CLAC xenograft nude mouse model, intratumoral administration of rMV-SLAMblind significantly suppressed tumor growth. In rMV-SLAMblind-treated mice, natural killer cells were activated, and Cxcl10 and Il12a levels were significantly increased in comparison with levels in the control group. In addition, the depletion of NK cells reduced the anti-tumor effect. To understand difference in efficacy among canine lung cancer cell lines, we compared virus growth and gene expression pattern after virus treatment in the three canine lung cancer cell lines; virus growth was highest in CLAC cells compared with the other cell lines and the induction of interferon (IFN)-beta and IFN-stimulated genes was at lower levels in CLAC cells. These results suggested that rMV-SLAMblind exhibits oncolytic effect against some canine lung cancer cells and the cellular response after the virus infection may influence its efficacy.

Nectin-3 and shed forms of CSPG4 can serve as epithelial cell receptors for Clostridioides difficile TcdB.

IMPORTANCE: Toxin B (TcdB) is a major virulence factor of Clostridioides difficile, a Gram-positive pathogen that is a leading cause of hospital-acquired diarrhea. While previous studies have established that TcdB can engage multiple cell surface receptors in vitro, little is known about how these interactions promote disease and where these receptors localize on colonic tissue. Here, we used immunofluorescence microscopy to visualize Nectin-3 and CSPG4 on tissue, revealing unexpected localization of both receptors on colonic epithelial cells. We show that Nectin-3, which was previously characterized as an adherens junction protein, is also localized to the brush border of colonocytes. Staining for CSPG4 revealed that it is present along epithelial cell junctions, suggesting that it is shed by fibroblasts along the crypt-surface axis. Collectively, our study provides new insights into how TcdB can gain access to the receptors Nectin-3 and CSPG4 to intoxicate colonic epithelial cells.

Molecular and structural basis of TIGIT: Nectin-4 interaction, a recently discovered pathway crucial for cancer immunotherapy.

TIGIT (T cell immunoglobulin and ITIM domain) is an inhibitory receptor expressed on T and NK cells that interact with cell surface glycoprotein belonging to the nectin and nectin-like family of cell adhesion molecules, particularly nectin-2 and nectin-like 5 (PVR). Nectin-4 has been recently identified as a novel ligand for TIGIT and the interaction among them inhibits NK cell cytotoxicity. In this study, biophysical experiments were conducted to decipher the mechanism of this novel interaction, followed by structure-guided mutagenesis studies to map the nectin-4 binding interface on TIGIT. Using surface plasmon resonance, we deduced that TIGIT recognizes the membrane distal ectodomain of nectin-4 and the interaction is weaker than the well-characterized TIGIT: nectin-2 interaction. Deciphering the molecular basis of this newly identified interaction between TIGIT and nectin-4 will provide us important insight into the manipulation of this inhibitory signaling pathway, especially targeting cancer cells overexpressing nectin-4 that evade the immune surveillance of the body.

Relative Expression of BATF and CD112 in PBMC of Patients with Chronic Lymphocytic Leukemia.

OBJECTIVE: BATF, as a transcription factor, and CD112, as a receptor for TIGIT, are involved in T-cell exhaustion. We investigated BATF and CD112 gene expression in the peripheral blood mononuclear cells from CLL patients and healthy subjects. METHODS: In a case-control study, 33 patients with CLL and 20 sex- and age-matched healthy individual were enrolled. Diagnosis and classification of patients was done according to immunophenotyping via flow cytometry and RAI staging system, respectively. Relative mRNA expression of BATF and CD112 was measured using qRT-PCR. RESULT: Our results showed that the expression of BATF and CD112 in CLL samples were significantly decreased in comparison those of the healthy controls (P = 0.0236 and P = 0.0002, respectively). CONCLUSION: These findings suggest the role of BATF and CD112 not only as a role in T cell exhaustion, but in effector differentiation program in CLL, which warrants further studies in future.

HSV-1 Glycoprotein D and Its Surface Receptors: Evaluation of Protein-Protein Interaction and Targeting by Triazole-Based Compounds through In Silico Approaches.

Protein-protein interactions (PPI) represent attractive targets for drug design. Thus, aiming at a deeper insight into the HSV-1 envelope glycoprotein D (gD), protein-protein docking and dynamic simulations of gD-HVEM and gD-Nectin-1 complexes were performed. The most stable complexes and the pivotal key residues useful for gD to anchor human receptors were identified and used as starting points for a structure-based virtual screening on a library of both synthetic and designed 1,2,3-triazole-based compounds. Their binding properties versus gD interface with HVEM and Nectin-1 along with their structure-activity relationships (SARs) were evaluated. Four [1,2,3]triazolo[4,5-b]pyridines were identified as potential HSV-1 gD inhibitors, for their good theoretical affinity towards all conformations of HSV-1 gD. Overall, this study suggests promising basis for the design of new antiviral agents targeting gD as a valuable strategy to prevent viral attachment and penetration into the host cell.

The prognostic significance of Nectin-2 and Nectin-4 expression in glial tumors.

Glial tumors are the most frequent neoplasms of the central nervous system in adults and despite recent advances in diagnosis and treatment of the disease, the prognosis of glioma is poor. Therefore, there is a great need to identify new prognostic factors and potential immunotherapeutic targets. Members of the Nectin family of proteins are gaining significant attention as possible diagnostic and immunotherapeutic targets in many solid tumors, but they have not been extensively investigated in glial tumors. The aim of the present study was to evaluate the expression of Nectin-2 and Nectin-4 in glial tumors of different grades, and to assess their prognostic value. The results showed heterogeneous expression of Nectin-2 and Nectin-4 in tumor cells and neuropil, with significantly higher Nectin-2 expression compared to Nectin-4, but without differences among tumor grades. In addition, the expression of Nectin-2 and Nectin-4 was associated with shorter survival times in patients with grade II/III gliomas. These results suggest that Nectin-2 and Nectin-4 expression may be used as an independent prognostic indicator for patients with II/III gliomas. This study contributes to the development of personalized care for patients with glioma and provides a basis for further research on nectin-based immunotherapy for brain tumors.

Association of THBS3 with Glycoprotein D Promotes Pseudorabies Virus Attachment, Fusion, and Entry.

Pseudorabies virus (PRV) is a neurotropic virus causing obvious neurological disorders and reproductive failure in pigs. PRV entry into target cells is a complex multistep process initiated by interacting viral envelope glycoproteins with cellular receptors. In the current study, we found that thrombospondin 3 (THBS3) plays an important role in PRV entry into target cells, indicating that THBS3 is a new PRV coreceptor. To confirm this hypothesis, the knockdown of THBS3 in several permissive cells inhibited PRV primary infection, and overexpression of THBS3 in PK15 cells promoted PRV infection. CRISPR-Cas9 knockout markedly reduced PRV infection in PK15 cells. Antibodies against THBS3 blocked PRV infection in naturally permissive target cells. Moreover, soluble THBS3 protein neutralized the infectivity of PRV. Mechanistically, THBS3 interacted with the PRV gD via its N and C termini to facilitate PRV binding in permissive and nonpermissive cells. Also, in the absence of Nectin-1, THBS3 promoted cell-to-cell fusion mediated by virus glycoproteins. While THBS3 alone could not increase virus entry, overexpression of it in the presence of Nectin-1 promoted virus entry into CHO-K1 cells. Our results have identified THBS3 as a critical player in PRV binding and subsequent membrane fusion and entry. IMPORTANCE Herpesvirus entry occurs through a cascade of virus-cell interactions, and multiple surface glycoproteins play a role in virus binding and entry during the virus invasion process. Early studies showed that attachment to cells by PRV, as well as other alphaherpesviruses, is mediated by interactions between the viral glycoprotein gC and cell membrane proteoglycans carrying heparan sulfate chains (HSPGs). However, gD may also be involved in virus binding in an HSPG-independent manner. To date, the respective cellular receptors are still unknown. In this report, we identified a host molecule, THBS3, involved in gD-mediated PRV binding and subsequent membrane fusion and entry, which increases our understanding of the initial events in alpha herpesvirus infections.

CD96 as a Potential Immune Regulator in Cancers.

The discovery of CTLA-4 and PD-1 checkpoints has prompted scientific researchers and the pharmaceutical industry to develop and conduct extensive research on tumor-specific inhibitors. As a result, the list of potential immune checkpoint molecules is growing over time. Receptors for nectin and nectin-like proteins have recently emerged as promising targets for cancer immunotherapy. Potential immune checkpoints, including CD226, TIGIT, and CD96, belong to this receptor class. Among them, CD96 has received little attention. In this mini-review, we aim to discuss the basic biology of CD96 as well as the most recent relevant research on this as a promising candidate for cancer immunotherapy.

Brain matrix metalloproteinase-9 activity is altered in the corticosterone mouse model of depression.

Major depressive disorder is a highly prevalent psychiatric condition. Metalloproteinase 9 (MMP-9), a gelatinase involved in synaptic plasticity, learning and memory processes, is elevated in both chronic stress animal models and human peripheral blood samples of depressed patients. In this study we have evaluated the MMP-9 activity and protein expression in brain areas relevant to depression using the chronic corticosterone mouse model of depression. These mice show a depressive- and anxious-like behaviour. The MMP-9 activity and protein levels are significantly elevated in both the hippocampus and the cortex, and nectin-3 levels are lower in these brain areas in this model. In particular, these mice display an increased gelatinase activity in the CA1 and CA3 subfields of the hippocampus and in the internal layer of the prefrontal cortex. Moreover, the immobility time in the tail suspension test presents a positive correlation with the cortical MMP-9 activity, and a negative correlation with nectin-3 levels. In conclusion, the chronic corticosterone model of depression leads to an increase in the protein expression and activity of MMP-9 and a reduction of its substrate nectin-3 in relevant areas implicated in this disease. The MMP-9 activity correlates with behavioural despair in this model of depression. All these findings support the role of MMP-9 in the pathophysiology of depression, and as a putative target to develop novel antidepressant drugs.

Extracellular CIRP Induces Novel Nectin-2+ (CD112+) Neutrophils to Promote Th1 Differentiation in Sepsis.

Neutrophil heterogeneity represents different subtypes, states, phenotypes, and functionality of neutrophils implicated in sepsis pathobiology. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that promotes inflammation and alters neutrophil phenotype and function through TLR4. Nectin-2 or CD112 is an Ig-like superfamily member. CD112 serves as the ligand for DNAM-1 (CD226), which induces Th1 differentiation in naive CD4+ T cells. Th1 cells produce IFN-γ to fuel inflammation. CD112 is expressed mainly on APCs, but its expression in neutrophils is unknown. We hypothesize that eCIRP induces CD112 expression in neutrophils, promoting Th1 differentiation in sepsis. Incubation of neutrophils with recombinant murine (rm)CIRP significantly increased the gene and protein expression of CD112 in neutrophils. Anti-TLR4 Ab-treated neutrophils significantly decreased CD112+ neutrophils compared with controls upon rmCIRP stimulation. After 4 h of rmCIRP injection in mice, CD112+ neutrophils were significantly increased in the blood and spleen. At 20 h after cecal ligation and puncture-induced sepsis, CD112+ neutrophils were also significantly increased. Blood and splenic CD112+ neutrophils in septic CIRP-/- mice were much lower than in septic wild-type mice. Coculture of naive CD4 T cells with rmCIRP-treated (CD112+) neutrophils significantly increased IFN-γ-producing Th1 cells compared with coculture with PBS-treated neutrophils. CD112 Ab significantly attenuated Th1 differentiation induced by rmCIRP-treated neutrophils. Thus, eCIRP increases CD112 expression in neutrophils via TLR4 to promote Th1 differentiation in sepsis. Targeting eCIRP may attenuate sepsis by reducing Th1-promoting CD112+ neutrophils.

Wuzi-Yanzong-Wan prevents oligoasthenospermia due to TAp73 suppression by affecting cellular junction remodeling in testicular tissue in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Wuzi-Yanzong-Wan (WZYZW) is a classic Chinese herbal preparation, which has a significant clinical efficacy in tonifying the kidney and benefiting the sperm, and is widely used in the treatment of oligoasthenospermia with a long history. TAp73 inhibition results in the decrease of sperm quality, but the therapeutic mechanism of WZYZW on oligoasthenospermia caused by TAp73 gene inhibition remains elusive. AIMS OF STUDY: The purpose of this study is to investigate whether TAp73 suppression leads to oligoasthenospermia and the application of WZYZW treatment in condition of TAp73 suppression. METHODOLOGY: C57BL/6 male mice were injected with Pifithrin-α (2.5 mg/kg) intraperitoneally for 30 days to induce TAp73 suppression model, with WZYZW at 1.0, 2.0 and 4.0 g/kg were administrated in parallel. The blood, testis and epididymis were collected, with organ coefficient calculated. Makler sperm counter was used to analyze the density, motility, survival and malformation rate of sperm. Apoptosis of sperm was analyzed by flow cytometry. Serum hormone levels were determined using ELISA. HE staining and transmission electron microscopy (TEM) were used to observe histopathological changes of testis in blood-testis barrier (BTB), ectoplasmic specialization (ES) and other cell junctions. Expressions of cell adhesion factors including TAp73, Integrin-α6, N-cadherin, Nectin-2 and Occludin were determined by RT-PCR and western blotting. RESULTS: Compared to control mice, TAp73 inhibition dramatically decreased the epididymal coefficient, sperm quality, and serum testosterone (T) level, while increasing apoptosis in sperm in mice. HE staining and TEM showed that the tight junction (TJ) and apical ES structure were seriously abnormal in the testis in mice with TAp73 inhibition. Additionally, the expression of Occludin protein was elevated, while that of TAp73, Integrin-α6, N-cadherin, and Nectin-2 reduced in model mice. WZYZW treatment ameliorated testicular spermatogenic dysfunctions in TAp73 suppressed mice, restoring the decreased sperm quality, serum T level and testicular histopathological changes of TJ and ES, as well as decreasing sperm malformation rate and apoptosis. Moreover, WZYZW reversed the expressions of Occludin, TAp73, Integrin-α6, N-cadherin and Nectin-2 in TAp73 suppressed mice. CONCLUSIONS: By impairing spermatogenesis and maturation, TAp73 inhibition led to oligoasthenospermia in mice. WZYZW could rescue the oligoasthenospermia associated with TAp73 inhibition via affecting the dynamic remodeling of cellular junctions in testicular tissues in mice.

Immunohistochemical Analysis of HER2, EGFR, and Nectin-4 Expression in Upper Urinary Tract Urothelial Carcinoma.

BACKGROUND/AIM: Upper urinary tract urothelial carcinoma (UTUC) is a rare disease, often discovered at an advanced stage at diagnosis. Nectin-4 is expressed in a broad range of patients with UTUC and is associated with poor progression-free survival. The receptors of the erythroblastosis oncogene B (ErbB) family are potential therapeutic targets for urothelial carcinoma. Herein, we aimed to investigate the relationship of nectin-4 and ErbB family receptors, namely epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in patients with UTUC. Targeted therapies for these receptors could be used in sequence or in combination for increasing treatment efficiency. PATIENTS AND METHODS: We performed immunohisto-chemical analysis for HER2, EGFR, and nectin-4 using tissue microarrays. A total of 98 UTUC patients were included in the study. We investigated the impact of EGFR and HER2 expression status on recurrence-free survival (RFS) and cancer-specific survival (CSS) of all patients. RESULTS: The percentages of patients positive for HER2, EGFR, and nectin-4 were 97%, 70%, and 65%, respectively. The co-expression rates of HER2-EGFR, HER2-nectin-4, and EGFR-nectin-4 were 69%, 64%, and 47%, respectively. The number of patients positive for all three receptors was 47%. Higher HER2 levels were significantly associated with worse CSS and RFS. Higher EGFR levels were associated with a worse CSS. CONCLUSION: HER2, EGFR, and nectin-4 were highly expressed in UTUC. Combination of HER2-, EGFR-, and nectin-4-targeted therapy may be an effective option for the treatment of patients with UTUC.

Cell adhesion molecules in the pathogenesis of the schizophrenia.

The causes of schizophrenia remain obscure and complex to identify. Alterations in dopaminergic and serotonergic neurotransmission are, to date, the primary pharmacological targets in treatment. Underlying abnormalities in neural networks have been identified as cell adhesion molecules (CAMs) involved in synaptic remodeling and interplay between neurons-neurons and neurons-glial cells. Among the CAMs, several families have been identified, such as integrins, selectins, cadherins, immunoglobulins, nectins, and the neuroligin-neurexin complex. In this paper, cell adhesion molecules involved in the pathogenesis of schizophrenia will be described.