Search

Primary Sjögren's syndrome (pSS) is an autoimmune disease triggered by a combination of environmental and host genetic factors, which results in the focal lymphocytic infiltration of exocrine glands causing eye and mouth dryness. Glandular infiltrates include T and B cell subsets positive for CD5 and/or CD6, two surface scavenger receptors involved in the fine-tuning of intracellular signals mediated by the antigen-specific receptor complex of T (TCR) and B (BCR) cells. Moreover, the epithelial cells of inflamed glands overexpress CD166/ALCAM, a CD6 ligand involved in homo and heterotypic cell adhesion interactions. All this, together with the reported association of functionally relevant single nucleotide polymorphisms (SNPs) ofCD5, CD6, andCD166/ALCAMwith the risk or prognosis of some immune-mediated inflammatory disorders, led us to investigate similar associations in a local cohort of patients with pSS. The logistic regression analyses of individual SNPs showed the association ofCD5rs2241002Twith anti-Ro/La positivity,CD6rs17824933Cwith neutropenia, andCD6rs11230563Twith increased leukopenia and neutropenia but decreased peripheral nervous system EULAR Sjögren's syndrome disease activity index (ESSDAI). Further analyses showed the association of haplotypes fromCD5(rs2241002T-rs2229177C) with anemia and thrombocytopenia,CD6(rs17824933G-rs11230563C-rs12360861G) with cutaneous ESSDAI, andCD166/ALCAM(rs6437585C-rs579565A-rs1044243Cand rs6437585C-rs579565G-rs1044243T) with disease susceptibility and several analytical parameters (anti-nuclear antibodies, neurological ESSDAI, and hematologic cytopenias). These results support the relevance of gene variation at loci coding for cell surface receptors involved in the modulation of T and B lymphocyte activation (CD5, CD6) and epithelial-immune cell adhesion (CD166/ALCAM) in modulating the clinical and analytical outcomes in patients with pSS.

VEGFR-2/Notch signalling regulates angiogenesis in part by driving the remodelling of endothelial cell junctions and by inducing cell migration. Here, we show that VEGF-induced polarized cell elongation increases cell perimeter and decreases the relative VE-cadherin concentration at junctions, triggering polarized formation of actin-driven junction-associated intermittent lamellipodia (JAIL) under control of the WASP/WAVE/ARP2/3 complex. JAIL allow formation of new VE-cadherin adhesion sites that are critical for cell migration and monolayer integrity. Whereas at the leading edge of the cell, large JAIL drive cell migration with supportive contraction, lateral junctions show small JAIL that allow relative cell movement. VEGFR-2 activation initiates cell elongation through dephosphorylation of junctional myosin light chain II, which leads to a local loss of tension to induce JAIL-mediated junctional remodelling. These events require both microtubules and polarized Rac activity. Together, we propose a model where polarized JAIL formation drives directed cell migration and junctional remodelling during sprouting angiogenesis., The formation of new blood vessels requires both polarized cell migration and coordinated control of endothelial cell contacts. Here, Cao and colleagues describe at the sub-cellular level the cytoskeletal and cell junction dynamics regulating these processes upon VEGF-induced cell elongation.

Background/Aims: Neointimal formation following vascular injury remains a major mechanism of restenosis, whereas the precise sources of neointimal cells are still uncertain. We tested the hypothesis that both injured arterial cells and non-arterial cells contribute to intimal hyperplasia. Methods: Following allograft transplantation of the balloon-injured carotid common artery (n = 3-6), the cellular composition of the transplant grafts and the origins of neointimal cells were measured by immunohistochemistry and immunofluorescence staining. Results: Smooth muscle actin (SMA)-positive and CD68-positive cells were clearly observed 14 days later in the neointima after allograft transplantation of the balloon-injured carotid common artery, where re-endothelialization was not yet complete. Green fluorescent protein (GFP) and wild-type (WT) allograft transplantation revealed that the majority of the neointima cells were apparently from the recipient (≈85%) versus the donor (≈15%). Both monocyte chemotactic protein-1 (MCP-1)/CCR2 and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling were involved in intimal hyperplasia, with bone marrow-derived cells also playing a role. Conclusion: These data support the hypothesis that intimal hyperplasia could develop in our novel rat allograft transplantation model of arterial injury, where neointima is attributable not only to local arterial cells but also non-arterial cells including the bone marrow.

Purpose BMS-986142 is an oral, small-molecule reversible inhibitor of Bruton’s tyrosine kinase. The main objectives of our phase I studies were to characterize the safety and tolerability, pharmacokinetics, and pharmacodynamics of BMS-986142 in healthy participants, and to investigate the potential for the effect of BMS-986142 on the PK of methotrexate (MTX) in combination. Methods In a combined single ascending dose and multiple ascending dose study, the safety, pharmacokinetics, and pharmacodynamics of BMS-986142 were assessed in healthy non-Japanese participants following administration of a single dose (5–900 mg) or multiple doses (25–350 mg, once daily for 14 days). In a drug–drug interaction study, the effect of BMS-986142 (350 mg, once daily for 5 days) on the single-dose pharmacokinetics of MTX (7.5 mg) was assessed in healthy participants. Results BMS-986142 was generally well tolerated, alone and in combination with MTX. BMS-986142 was rapidly absorbed with peak concentrations occurring within 2 h, and was eliminated with a mean half-life ranging from 7 to 11 h. Exposure of BMS-986142 appeared dose proportional within the dose ranges tested. A dose- and concentration-dependent inhibition of CD69 expression was observed following administration of BMS-986142. BMS-986142 did not affect the pharmacokinetics of MTX. Conclusions BMS-986142 was well tolerated at the doses tested, had pharmacokinetic and pharmacodynamic profiles which support once-daily dosing, and can be coadministered with MTX without the pharmacokinetic interaction of BMS-986142 on MTX. Electronic supplementary material The online version of this article (doi:10.1007/s00228-017-2226-2) contains supplementary material, which is available to authorized users.

© Author(s) (or their employer(s)) 2020., [Background]: CD6 is a lymphocyte surface co-receptor physically associated with the T-cell receptor (TCR)/CD3 complex at the center of the immunological synapse. There, CD6 assists in cell-to-cell contact stabilization and modulation of activation/differentiation events through interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), its main reported ligand. While accumulating evidence is attracting new interest on targeting CD6 for therapeutic purposes in autoimmune disorders, little is known on its potential in cancer. In an attempt to elucidate the in vivo relevance of blocking CD6-mediated interactions in health and disease, we explored the consequences of expressing high circulating levels of a soluble form CD6 (sCD6) as a decoy receptor. [Methods]: High sCD6 serum levels were achieved by using transgenic C57BL/6 mice expressing human sCD6 under the control of lymphoid-specific transcriptional elements (shCD6LckEμTg) or wild type either transduced with hepatotropic adeno-associated virus coding for mouse sCD6 or undergoing repeated infusions of recombinant human sCD6 protein. Characterization of sCD6-induced changes was performed by ex vivo flow cytometry and functional analyses of mouse lymphoid organ cells. The in vivo relevance of those changes was explored by challenging mice with subcutaneous or metastatic tumors induced by syngeneic cancer cells of different lineage origins. [Results]: Through a combination of in vitro and in vivo studies, we show that circulating sCD6 expression induces defective regulatory T cell (Treg) generation and function, decreased CD166/ALCAM-mediated tumor cell proliferation/migration and impaired galectin-induced T-cell apoptosis, supporting the fact that sCD6 modulates antitumor lymphocyte effector function and tumorigenesis. Accordingly, sCD6 expression in vivo resulted in delayed subcutaneous tumor growth and/or reduced metastasis on challenge of mice with syngeneic cancer cells. [Conclusions]: Evidence is provided for the disruption of CD6 receptor-ligand interactions as a feasible immunomodulatory approach in cancer., This work was supported by the Worldwide Cancer Research (14-1275), Fundació La Marató TV3 (201319-30), and Ministerio de Economía y Competitividad (SAF-2016-80535-R) co-financed by European Development Regional Fund 'A way to achieve Europe' ERDF to FL; SAF2016-75195-R to JM, SAF2017-82905-R to RM, and SAF2015-70028-R to GG-A. ITS, MO-M, MV-dA, CC, SC-L and FA are recipients of fellowships from Fundação para a Ciência e a Tecnologia (SFRH/ BD/75738/2011), Ministerio de Economía y Competitividad (BES-2011-048415; BES-2014-069237; BES-2017-082107), Ministerio de Educación Cultura y Deporte (FPU15/02897), and Instituto de Salud Carlos III (Sara Borrell Programme, CD15/00016), respectively.

SUMMARY: The purpose of this study was to examine the expression levels of the dental pulp to elucidate the role of Vascular Endothelial Growth Factor (VEGF) and CD68 on vascular angiogenesis, inflammation and odontoblast differentiation in the pulp tissue of diabetic rats depending on the effect of possible damage induced by diabetes. Wistar rats were used in the study, divided into two groups. Control group was fed with standard rat chow and drinking water ad libitum for 8 weeks. Single dose of streptozotocin (STZ) (55 mg/kg), was disolved in sodium citrate buffer and administered by intraperitoneal injection. Blood glucose concentration of rats exceeding 250 mg/dl were accepted as diabetic. Rats were sacrificed under anesthesia. Tissues were immediately dissected, fixed and embedded in paraffin and cut with a microtome then examined under light microscope. In the cross-sections of pulp tissue of diabetic group; the dilation of blood vessels besides hemorrhage and a significant increase in inflammatory cells were seen. The expression of VEGF in the blood vessel endothelial cells of the pulp was increased. VEGF showed positive reaction for degenerative odontoblast cells in the pulp. In this study, increase in VEGF and CD68 expressions in pulp tissue due to the effect of diabetes was thought to delay pulp treatment by inducing soft tissue damage and hypoxia.

Invariant Vγ9Vδ2 T cells respond to "phosphoantigen" metabolites through binding to the B30.2 domain of butyrophilin BTN3A. Yang et al. (2019) use molecular dynamic simulations based on X-ray structures of distinct B30.2 domain dimers to identify the asymmetric dimer as most active, which has implications for the inside-out signaling mechanism.

Treballs Finals de Grau de Farmàcia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, 2019, Acute Lymphoblastic Leukaemia (ALL) is one of the most prevalent cancers in children and an almost fatal disease for adults. There is an urgent need to develop new drugs because of the lack of good treatments for these patients, especially those with relapsed or refractory clinical disease. Chimeric Antigen Receptor T-cells (CARTs) is a potent cellular cancer therapy consisting of autologous patient’s T lymphocytes, reprogrammed through gene editing to express a surface receptor against a particular tumour antigen. Autologous T cells transduced with anti-CD19 receptors may become a breakthrough for the treatment of B-cell ALL, since they bypass the need for antigen presentation usually affected by tumour immunosuppressive microenvironment. Different CARs have been designed, during the last years, and several institutions have tested its efficacy in clinical studies. Roughly, treated patients presented high remission rates with long-term durations, thus becoming a relevant alternative for those otherwise untreatable patients and granting commercial authorisation by the leading two regulatory agencies: Food and Drug Administration and European Medicines Agency in 2017 and 2018, respectively. This intersection between adoptive cell therapy, bioengineering tools and immunotherapy may have applications beyond cancer such as in autoimmunity and infectious diseases. The primary goal of this review is to present the current evidence of the efficacy of CART treatment and the main problems related to its toxicity and manufacturing, as well as its therapeutic value for ALL., La Leucèmia Limfoblàstica Aguda (LLA) és el tipus de càncer més prevalent en nens i una malaltia pràcticament fatal en adults. L’absència de noves teràpies pel tractament de pacients amb malaltia refractària o en recidiva posa de manifest la necessitat urgent de nous agents amb una eficàcia rellevant. Les cèl·lules T amb receptor d’antigen quimèric són una teràpia immunocel·lular potent que consisteix en la reprogramació dels limfòcits T del pacient a través de l’edició gènica per expressar un receptor a la seva superfície que reconegui un antigen tumoral concret. Les cèl·lules T autòlogues transduides amb receptors anti-CD19 poden arribar a suposar un gran avenç pel tractament de la LLA de cèl·lules B, ja que és capaç d’evitar la necessitat de presentació d’antigen que acostuma a estar inhibida pel microambient immunosupressor del tumor. Al llarg dels anys, diferents dissenys i generacions han sigut estudi de diferents institucions. Pràcticament tots ells presenten taxes de remissió elevades a llarga durada, representant una alternativa rellevant per aquells pacients sense més possibilitats terapèutiques i permetent també l’autorització de comerç per part de les dues agències regulatòries principals: L’Administració d’Aliments i Medicaments dels EEUU al 2017 i l’Agència Europea del Medicament al 2018. Aquesta intersecció entre la teràpia adoptiva de cèl·lules, les eines de bioenginyeria i la immunoteràpia podrien tenir aplicacions més enllà del càncer en autoimmunitat i malalties infecciones. L’exposició de les evidències actuals i les principals característiques pel que fa a toxicitat, eficàcia i fabricació, així com el seu posicionament concret per la LLA, són qüestions tractades en aquesta revisió bibliogràfica.

Background: Cystic fibrosis (CF) is the most common autosomal-recessive disorder in western countries. Previous studies have demonstrated an important role of sphingolipids in the pathophysiology of cystic fibrosis. It has been shown that ceramide has a central role in various pulmonary infections, including those with Pseudomonas aeruginosa (P. aeruginosa). Ceramide is accumulated in the airways of CF mice and patients. However, little is known about a potential role of glucosylceramide in cystic fibrosis. Methods: We investigated the expression of glucosylceramide and lactosylceramide in the respiratory tract of murine and human CF samples by immunohistochemistry and analyzed effects of glucosylceramide on P. aeruginosa in vitro. We performed pulmonary infections with P. aeruginosa and tested inhalation with glucosylceramide. Results: We demonstrate that glucosylceramide is down-regulated on the apical surface of bronchial and tracheal epithelial cells in cystic fibrosis mice. Although glucosylceramide did not have a direct bactericidal effect on Pseudomonas aeruginosa in vitro, inhalation of CF mice with glucosylceramide protected these mice from infection with P. aeruginosa, while non-inhaled CF mice developed severe pneumonia. Conclusion: Our data suggest that glucosylceramide acts in vivo in concert with ceramide and sphingosine to determine the pulmonary defense against P. aeruginosa.

Resumen El sarcoma histiocitico es un tumor maligno infrecuente, de patogenia incierta, caracterizado por una proliferacion de celulas neoplasicas con morfologia e inmunofenotipo de los histiocitos tisulares maduros. Aunque existen pocas referencias bibliograficas, afecta a pacientes de ambos sexos, de amplio rango de edad y afectacion nodal y/o extranodal. Se ha senalado la existencia en muchos casos de una estrecha relacion entre esta entidad y varias neoplasias hematolinfoides en un mismo paciente, lo que ha dado lugar a multiples estudios para esclarecer su etiologia y su patogenia. Su curso suele ser rapidamente progresivo y no se conoce una pauta terapeutica eficaz. Actualmente su diagnostico sigue siendo por exclusion. Presentamos el caso de un paciente de 82 anos con perforacion de un asa yeyunal con una tumoracion maligna que infiltra transmuralmente la pared y solo expresa CD68, CD45RO, CD163, lisozima y vimentina, junto con un reordenamiento clonal linfoide B con escasa amplificacion.

Resume Introduction L’histiocytome fibreux angiomatoide (HFA) est une tumeur des tissus mous de differenciation incertaine qui survient chez des enfants et des jeunes adultes, localisee preferentiellement aux extremites. L’HFA est classe parmi les sarcomes de bas grade de malignite. Sa rarete fait qu’il est peu connu ; il en resulte un risque de diagnostic errone de lesion reactionnelle, de tumeur benigne ou de sarcome de haut grade. Nous rapportons six nouveaux cas d’HFA et en reprenons les caracteristiques cliniques, histologiques et genetiques etablies dans la litterature. Observations Il s’agissait de six enfants, âges de 4 a 16 ans, presentant un nodule isole de l’avant-bras (4/6), du tronc ou de la fesse, d’apparition spontanee. En histologie, les lesions apparaissaient comme des nodules bien limites par une pseudo-capsule fibreuse, se composant de cavites pseudo-kystiques hemorragiques et d’une proliferation tumorale polymorphe de cellules fusiformes ou histiocytoides avec des amas lymphoplasmocytaires denses. Les tumeurs exprimaient variablement la desmine, le CD68, le CD99 et l’actine muscle lisse. Un gene de fusion EWSR1-ATF1 etait trouve dans les trois cas ou il etait recherche. Discussion Dans notre serie, le diagnostic d’HFA n’avait jamais ete evoque a l’examen clinique ou a l’imagerie. L’examen histologique de la piece d’exerese chirurgicale a permis de faire le diagnostic dans tous les cas, confirme pour certains d’entre eux par la decouverte de transcrits de fusion. L’exerese elargie a permis une guerison complete dans tous les cas, confirmant le bon pronostic de l’HFA bien qu’un suivi au long cours soit necessaire pour depister au plus tot une recidive locale ou des metastases, qui sont rares mais responsables des cas fatals. Afin de traiter au mieux ces patients et d’eviter les reprises chirurgicales « en deux fois », une biopsie a l’aiguille echo-guidee doit etre proposee comme devant toute tumeur des tissus mous d’aspect non specifique. Les marges d’exerese devraient etre decidees en reunion de concertation pluridisciplinaire (RCP) specialisee dans les tumeurs des tissus mous.

Hereditary hemorrhagic telangiectasia (HHT) is a hereditary condition that results in vascular malfor- mations throughout the body, which have a proclivity to rupture and bleed. HHT has a worldwide incidence of about 1:5000 and approximately 80 % of cases are due to mutations in ENG, ALK1 (aka activin receptor-like kinase 1 or ACVRL1) and SMAD4. Over 200 international clinicians and scientists met at Captiva Island, Florida from June 11-June 14, 2015 to present and discuss the latest research on HHT. 156 abstracts were accepted to the meeting and 60 were selected for oral presentations. The first two sections of this article present summaries of the basic science and clinical talks. Here we have summarized talks covering key themes, focusing on areas of agreement, disagreement, and unanswered questions. The final four sections summarize discussions in the Workshops, which were theme-based topical discussions led by two moderators. We hope this overview will educate as well as inspire those within the field and from outside, who have an interest in the science and treatment of HHT.

Delayed bone healing and non-union occur in approximately 10% of long bone fractures. Despite intense investigations and progress in understanding the processes governing bone healing, the specific pathophysiological characteristics of the local microenvironment leading to non-union remain obscure. The clinical findings and radiographic features remain the two important landmarks of diagnosing non-unions and even when the diagnosis is established there is debate on the ideal timing and mode of intervention. In an attempt to understand better the pathophysiological processes involved in the development of fracture non-union, a number of studies have endeavoured to investigate the biological profile of tissue obtained from the non-union site and analyse any differences or similarities of tissue obtained from different types of non-unions. In the herein study, we present the existing evidence of the biological and molecular profile of fracture non-union tissue.

Effective vaccines induce high-affinity memory B cells and durable antibody responses through accelerated mechanisms of natural selection. Secondary changes in antibody repertoires after vaccine boosts suggest progressive rediversification of B cell receptors (BCRs), but the underlying mechanisms remain unresolved. Here, the integrated specificity and function of individual memory B cell progeny revealed ongoing evolution of polyclonal antibody specificities through germinal center (GC)-specific transcriptional activity. At the clonal and subclonal levels, single-cell expression of the genes encoding the costimulatory molecule CD83 and the DNA polymerase Polη segregated the secondary GC transcriptional program into four stages that regulated divergent mechanisms of memory BCR evolution. Our studies demonstrate that vaccine boosts reactivate a cyclic program of GC function in class-switched memory B cells to remodel existing antibody specificities and enhance durable immunological protection.

Mesenchymal stem cells (MSCs) hold great potential in cell therapy and have attracted increasing interests in a wide range of biomedical sciences. However, the scarcity of MSCs and the prolonged isolation procedure limited the clinical application. To address these 2 issues, we developed a method to isolate MSCs from bone biopsy tissues of euthanized canine body donors. Compared to the traditional method to isolate MSCs from aspirated bone marrow (BMSCs), the isolation procedure for MSCs from harvested epiphyseal cancellous bone (EMSCs) was less time-consuming. The isolated EMSCs had similar plastic-adherence, tri-lineage differentiation and consistent surface marker profiles compared to BMSCs. We harvested BMSCs and EMSCs from 24 euthanized cases from clinics and 42 euthanized donors from a local shelter. The successful rate for EMSC isolation is significantly higher compared to BMSC isolation, while the other properties of the isolated MSCs including the clonogenicity, proliferative potentials and molecular phenotypes were not discernibly different between the MSCs established by the two methods. In conclusion, we demonstrated a new procedure to harvest MSCs by bone biopsy at the epiphyseal region. This method is less time consuming and more reliable, and the resulting MSCs are comparable to those harvested by bone marrow aspiration. The combination of the two methods can greatly improve the efficiency to harvest MSCs.

Background From the simplest bacteria to the highest complex mammals, including humans, every single cell is covered by a dense coat of glycans. Glycans are involved in almost every biological process that takes place in our body, playing a central role in the communication between cells and their environment. Glycans are also involved in infectious diseases, which arise from the specific interaction between glycans of the pathogen cell coat and specific receptors on the host cell or vice versa. Objective The understanding of the mechanisms governing these specific carbohydrateprotein interactions, at atomic and molecular levels, is crucial to develop new drugs able to block the infection and to avoid the disease. Methods Recent advances in biophysical techniques allow for a complete picture of the hostpathogen infection event, unveiling the key aspects of the molecular interaction and, thus, providing an opportunity to interfere with it. Conclusion In this general review, we discuss some recent contributions, providing a summary of what we consider the most innovative and inspiring research lines to the field.

AIM To study the role of semaphorin 4D (Sema4D) expression promoted by tumor-associated macrophages (TAMs) in gastric carcinoma cells and its clinical significance in the invasion and metastasis of gastric carcinoma. METHODS CD68 and Sema4D expression was analyzed in gastric carcinoma and adjacent normal tissues from 290 patients using the immunohistochemical streptavidin-peroxidase method, and their relationships with clinicopathological features were evaluated. Human M2 macrophages were induced in vitro and co-cultured in non-contact with gastric carcinoma SGC-7901 cells. Changes in the secretory Sema4D level in the SGC-7901 cell supernatant were measured using an enzyme-linked immunosorbent assay. The effects of TAMs on SGC-7901 cell invasion and migration were assessed with invasion and migration assays, respectively. RESULTS CD68 and Sema4D protein expression was significantly higher in gastric carcinoma tissues than in adjacent normal tissues (71.7% vs 33.8% and 74.5% vs 42.8%, respectively; P < 0.01). CD68 and Sema4D protein expression was significantly associated with histological differentiation, TNM stage, and lymph node metastasis (P < 0.05), and their expression levels were positively correlated with one another (r = 0.467, P < 0.01). In the in vitro experiment, secretory Sema4D protein expression was significantly increased in the supernatant of SGC-7901 cells co-cultured with TAMs compared with the blank control (1224.13 ± 29.43 vs 637.15 ± 33.84, P < 0.01). Cell invasion and metastasis were enhanced in the Transwell invasion and migration assays (P < 0.01). CONCLUSION TAMs promote the invasion and metastasis of gastric carcinoma cells possibly through upregulated secretory Sema4D protein expression. Combined detection of TAM markers, CD68 and Sema4D, in gastric carcinoma tissue shows potential to predict the trend of gastric carcinoma progression.

Background TREM-1 acts as an amplifier of inflammation expressed on macrophages. The objective of this study was to evaluate the relationship between TREM-1 and macrophage polarization, and association of TREM-1 and M1 macrophage polarization with insulin resistance (IR) in obese population compared to non-obese population.

BACKGROUND: Gallbladder carcinoma presents a dismal prognosis. Choice treatment is surgical resection that is associated a high levels of both morbidity and mortality. Best knowledgement of prognostic factors may result a better selection of patients either for surgical or multimodal treatment. AIM: To evaluate tecidual immunoexpression of P53, E-cadherin, Cox-2, and EGFR proteins and to correlate these findings with resected gallbladder adenocarcinoma survival. METHODS: Clinical, laboratorial, surgical, and anatomopathological reports of a series of gallbladder adenocarcinoma patients were collected by individualized questionary. Total sample was 42 patients. Median of age was 72 years (35-87). There were seven men and 35 women. Lesion distribuition in according TNM state was the following: T1 (n=2), T2 (n=5), T3 (n=31), T4 (n=4). Twenty-three patients underwent radical resection (R0), while 19 palliative surgery (R1-R2). A block of tissue microarray with neoplasic tissue of each patient was confected. It was performed evaluation of P53, E-Caderine, COX-2, and EGFR proteins imunoexpression. These findings were correlated with overall survival. RESULTS: Five-year survival was 28%. The median of global survival was eight months. Only immunoexpression of EGFR protein was considered independent variable at multivariated analysis. CONCLUSION: Final prognosis was influenced by over-expression of EGFR protein in tumoral tissue.

This is a cross-sectional, case-control study analyzing the effect of antiretroviral therapy (ART) including or not maraviroc, on circulating monocytes and natural killer cells. Sixty-eight HIV-positive patients virologically suppressed receiving ART at least 6 months were subdivided as receiving (group 1) or not (group 2) maraviroc in their ART. Frequency of monocytes and natural killer cells, as well as their activation markers, were studied. Modulation of innate immune cells may be differently affected by combined ART.

Discussion on the identification of Langerin+ DC populations in humans.

Experiments investigated maturation of endothelial function in the postnatal period. Carotid arteries isolated from newborn (postnatal day 1, P1) to P21 mice were assessed in myographs at transmural pressure (PTM) of 20 mmHg (P1 blood pressure, BP). Acetylcholine was ineffective in P1 but powerfully dilated P7 arteries, whereas NO-donor DEA-NONOate caused similar dilation at P1 and P7. Dilation to acetylcholine at P7 was abolished by inhibition of NO synthase (NOS) (l-NAME) or of phosphoinositide-3-kinase (PI3K) (wortmannin, LY294002). Endothelial NOS (eNOS) expression decreased in P7 compared with P1 arteries, although acetylcholine increased PO4-eNOS-Ser1177in P7 but not in P1 arteries. Endothelial maturation may therefore reflect increased signaling through PI3K, Akt, and eNOS. Systemic BP increases dramatically in the early postnatal period. After exposing P1 arteries to transient increased PTM(50 mmHg, 60 min), acetylcholine caused powerful dilation and increased PO4-eNOS-Ser1177. Pressure-induced rescue of acetylcholine dilation was abolished by PI3K or NOS inhibition. Transient increased PTMdid not affect dilation at P7, or dilation to NO-donor in P1 arteries. Width of endothelial adherens junctions (VE-cadherin immunofluorescence) increased significantly from P1 to P7, and in P1 arteries exposed to transient increased PTM. A function-blocking antibody to VE-cadherin reduced the pressure-induced rescue of acetylcholine responses at P1, and the dilation to acetylcholine in P7 arteries. Therefore, maturation of newborn endothelium dilator function may be induced by increasing BP in the postnatal period. Furthermore, this may be mediated by VE-cadherin signaling at adherens junctions. Interruption of this maturation pathway may contribute to developmental and adult vascular diseases.

Low frequency clonal mutations recoverable by deep sequencing in patients with aplastic anemia

TITLE: The relation between peripheral levels of CD19+ b cells with the inflammatory activity and the prognosis of multiple sclerosis. A pilot cohort study in patients with multiple sclerosis from Girona. BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system. Globally, it is the first cause of non-traumatic neurological disability in young adults having a great impact in the health system. Although it has been thoroughly investigated, its pathogenesis remains unclear. Recent studies have shown that besides T cells, B cells are also involved in the pathological pathways of the disease. This new finding has led to new fields of investigation as new drugs are being developed and new biomarkers of diagnosis, treatment and prognosis have been proposed. OBJECTIVE: The purpose of this study is to determine whether the levels of CD19+ B cells in peripheral blood of patients who have just been diagnosed with Multiple Sclerosis (MS) are related to the inflammatory activity and prognosis of the disease. DESIGN: The selected study design is a pilot ambispective cohort study. METHOD: Peripheral blood samples from almost 200 patients involved in the BioEM study carried out in the Unitat de Neuroimmunologia i Esclerosi Multiple (UNIEM), will be analysed to determine the levels of CD19+ B cells at the onset of the disease. Then, a minimum follow-up period of 4 years is required to assess the evolution of the disease which will be evaluated measuring the inflammatory activity and the neurological disability. The first one will be assessed using the information from the basal lumbar puncture and the reports from the annual brain MRI and the latter will be described using the Kurtzke EDSS. When all the data is compiled, CD19 levels will be compared with the presence or absence of Gadolinium enhancing lesions; presence or absence of new or enlarged T2 lesions; OCGB index and OCMB in CSF; all of them surrogate markers of inflammatory activity. Plus, the levels will be compared to the presence or absence of progression of the neurological disability

Loose fragments in osteochondritis dissecans (OCD) of the knee require internal fixation. On the other hand, loose fragments derived from spontaneous osteonecrosis of the knee (SONK) are usually removed. However, the difference in healing potential between OCD- and SONK-related loose fragments has not been elucidated. In this study, we investigated proliferative activity and redifferentiation potential of normal cartilage-derived and loose fragment-derived chondrocytes. Cells were prepared from normal articular cartilages and loose fragment cartilages derived from knee OCD and SONK. Cellular proliferation was compared. Redifferentiation ability of pellet-cultured chondrocytes was assessed by real-time PCR analyses. Mesenchymal differentiation potential was investigated by histological analyses. Positive ratio of a stem cell marker CD166 was evaluated in each cartilaginous tissue. Normal and OCD chondrocytes showed a higher proliferative activity than SONK chondrocytes. Chondrogenic pellets derived from normal and OCD chondrocytes produced a larger amount of safranin O-stained proteoglycans compared with SONK-derived pellets. Expression of chondrogenic marker genes was inferior in SONK pellets. The CD166-positive ratio was higher in normal cartilages and OCD loose fragments than in SONK loose fragments. The OCD chondrocytes maintained higher proliferative activity and redifferentiation potential compared with SONK chondrocytes. Our results suggest that chondrogenic properties of loose fragment-derived cells and the amount of CD166-positive cells may affect the repair process of osteochondral defects.

Background: Gastric cancer is the fifth most frequent cancer and the third most common cause of cancer-related deaths worldwide.It has been reported that Wnt/ betacatenin pathway is activated in 30-50% of these tumors. However,the deregulation of this pathway has not been fully elucidated. Aim: To determine the expression of E-cadherin, betacatenin, APC, TCF-4 and survivin proteins in gastric adenocarcinoma tissues and correlate with clinical and pathological parameters. Method: Seventy-one patients with gastric adenocarcinoma undergoing gastrectomy were enrolled. The expression of E-cadherin, betacatenin, APC, TCF-4 and survivin proteins was detected by immunohistochemistryand related to the clinical and pathological parameters. Results: The expression rates of E-cadherin in the membrane was 3%; betacatenin in the cytoplasm and nucleus were 23,4% and 3,1% respectively; APC in the cytoplasm was 94,6%; TCF-4 in the nucleus was 19,4%; and survivin in the nucleus 93,9%. The expression rate of E-cadherin was correlated with older patients (p=0,007), while betacatenin with tumors

The Human Leucocyte Differentiation Antigens Workshops (HLDA) have since 1984 provided a forum for the characterization and study of leucocyte surface molecules and antibodies against them. HLDA devised the CD nomenclature, which is sanctioned by IUIS. The HLDA Council reviewed and modified the objectives of HLDA in 2004, and changed the name of the organization to Human Cell Differentiation Molecules (HCDM) to reflect the broader objectives. Workshop studies under the HCDM banner proceeded during 2005 and early 2006, culminating in a meeting in May 2006. At that meeting the Council, acting as Nomenclature Committee, approved a number of new CD designations and changes to some pre-existing CD designations, which are summarized in this report.

There are many routes to exploiting tolerance processes to ensure long–term graft survival. Complete tolerance although attractive as a goal, may not be the most practical in the clinic. Instead simple and low–impact procedures that harness tolerance processes used in conjunction with low doses of immunosuppressive drugs may prove the most reliable and user–friendly of approaches.

To review the epidemiology, pathophysiology, clinical features, and management of type B insulin resistance syndrome.Type B insulin resistance syndrome is a rare disorder caused by autoantibodies to the insulin receptor. This disorder is most frequently reported in middle-aged black women and is invariably associated with other autoimmune diseases. Typically, refractory transient hyperglycemia and extreme insulin resistance are the cardinal features, but hypoglycemia may also occur. Traditionally, the high reported mortality rate was typically attributed to the hypoglycemia. There is no well standardized treatment regimen. However, recent therapeutic advances with combination immunomodulatory therapy have led to significant reported improvements in hypoglycemia-associated mortality and durability of remission.We review the literature on the pathophysiology and clinical features of type B insulin resistance syndrome and highlight the complexities and recent advances in the management of this disorder.

Several naturally occuring mutations in the human insulin gene are associated with diabetes mellitus. The three known mutant molecules, Wakayama, Los Angeles and Chicago were evaluated using molecular docking and molecular dynamics (MD) to analyse mechanisms of deprived binding affinity for insulin receptor (IR). Insulin Wakayama, is a variant in which valine at position A3 is substituted by leucine, while in insulin Los Angeles and Chicago, phenylalanine at positions B24 and B25 is replaced by serine and leucine, respectively. These mutations show radical changes in binding affinity for IR. The ZDOCK server was used for molecular docking, while AMBER 14 was used for the MD study. The published crystal structure of IR bound to natural insulin was also used for MD. The binding interactions and MD trajectories clearly explained the critical factors for deprived binding to the IR. The surface area around position A3 was increased when valine was substituted by leucine, while at positions B24 and B25 aromatic amino acid phenylalanine replaced by non-aromatic serine and leucine might be responsible for fewer binding interactions at the binding site of IR that leads to instability of the complex. In the MD simulation, the normal mode analysis, rmsd trajectories and prediction of fluctuation indicated instability of complexes with mutant insulin in order of insulin native insulin insulin Chicago insulin Los Angeles insulin Wakayama molecules which corresponds to the biological evidence of the differing affinities of the mutant insulins for the IR.