667 research outputs found
Differentiation of atypical gastric lymphoid infiltrates from malt lymphoma: Role of paraffin section immunophenotyping.
No full textThe differential diagnosis of early gastric mucosa-associated lymphoma: polymerase chain reaction and paraffin section immunophenotyping.
No full textThe distinction between benign florid lymphoid hyperplasia and low-grade gastric mucosal-associated lymphoid tissue (MALT) lymphoma may be a challenge. The presence of monoclonal B cells in Helicobacter pylori-chronic active gastritis has suggested that polymerase chain reaction (PCR) data should be viewed with caution. We investigated the reliability of PCR versus immunophenotyping in diagnosing early gastric MALT lymphoma. We studied 1511 biopsies from eight patients with high-grade primary gastric lymphoma, 25 with low-grade MALT lymphoma, 32 with atypical lymphoid infiltrates, and 39 with Helicobacter pylori-chronic active gastritis. Paraffin sections from all cases were stained with antibodies to CD20, CD3, AE1/AE3, kappa and lambda. PCR was performed on paraffin sections using the primer set VH-FR3/J(H). Using histopathology as the gold standard in diagnosis, we confirmed monoclonality in 22 of 25 MALT lymphomas (88%); a clonal band was found in 38% (15 of 39) of patients with chronic active gastritis. An immunophenotype pattern with predominance of CD20-positive cells in lymphocytic infiltrates was associated with monoclonality in 92% of cases. The presence of an enlarged irregular mantle zone was found in both monoclonal and polyclonal areas. An equal prevalence of B and T cells in lymphocytic infiltrates was associated with a polyclonal pattern in 24 of 31 cases (77%). Immunostaining of sIg (kappa and lambda) was difficult in paraffin sections and convincing proof of monoclonality was not obtained. Lymphoepithelial lesions were infrequent in gastric biopsies and their presence was highlighted with keratin stains. Because monoclonal B cells are observed in Helicobacter pylori-associated gastritis, the correct interpretation of clonality by PCR remains unclear. Paraffin section IHC using CD20 and CD3 is especially useful to confirm the diagnosis of gastric MALT lymphoma
FAK-mediated mechanotransduction in skeletal regeneration
No full textThe majority of cells are equipped to detect and decipher physical stimuli, and then react to these stimuli in a cell type-specific manner. Ultimately, these cellular behaviors are synchronized to produce a tissue response, but how this is achieved remains enigmatic. Here, we investigated the genetic basis for mechanotransduction using the bone marrow as a model system. We found that physical stimuli produced a pattern of principal strain that precisely corresponded to the site-specific expression of sox9 and runx2, two transcription factors required for the commitment of stem cells to a skeletogenic lineage, and the arrangement and orientation of newly deposited type I collagen fibrils. To gain insights into the genetic basis for skeletal mechanotransduction we conditionally inactivated focal adhesion kinase (FAK), an intracellular component of the integrin signaling pathway. By doing so we abolished the mechanically induced osteogenic response and thus identified a critical genetic component of the molecular machinery required for mechanotransduction. Our data provide a new framework in which to consider how physical forces and molecular signals are synchronized during the program of skeletal regeneration
FAK inhibitors as promising anticancer targets: present and future directions
No full textFAK, a nonreceptor tyrosine kinase, has been recognized as a novel target class for the development of targeted anticancer agents. Overexpression of FAK is a common occurrence in several solid tumors, in which the kinase has been implicated in promoting metastases. Consequently, designing and developing potent FAK inhibitors is becoming an attractive goal, and FAK inhibitors are being recognized as a promising tool in our armamentarium for treating diverse cancers. This review comprehensively summarizes the different classes of synthetically derived compounds that have been reported as potent FAK inhibitors in the last three decades. Finally, the future of FAK-targeting smart drugs that are designed to slow down the emergence of drug resistance is discussed
Effect of FAK knockdown by short-hairpin FAK RNAs on MC3T3-El cells and on their morphology.
No full text<p>A, Immunoblot analysis of FAK and pFAKTyr<sup>397</sup> expression in short-hairpin FAK RNA (shFAK #1-#5)-infected MC3T3-El cells. Control, non-infected MC3T3-E1 cells. Shcontrol, control shRNA-infected group. B, Immunofluorescence staining for pFAK Tyr<sup>397</sup> (green) and F-actin (red) and 4’6’-diamidino-2-phenylindole staining (blue) in control, shcontrol and shFAK#5 RNA-infected MC3T3-El cells. Negative control group was treated with antibody dilution buffer minus pFAKTyr<sup>397</sup> antibody. The data from a typical experiment are presented; similar results were obtained in repeated experiments.</p
Effect of SHH on the FAK expression in MC3T3-El cells.
No full text<p>A, RT-PCR analysis of FAK mRNA expression in MC3T3-El cells after treatment with 500 ng/ml SHH. B, Immunoblot analysis of FAK Tyr<sup>397</sup> in MC3T3-El cells after incubation with or without 500 ng/ml SHH. The data from a typical experiment are presented: similar results were obtained in repeated experiments.</p
FAK is a critical regulator of neuroblastoma liver metastasis
No full textCopyright: © Lee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which per-mits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Neuroblastomas express increased levels of gastrin-releasing peptide receptor (GRP-R). However, the exact molecular mechanisms involved in GRP-R-mediated cell signaling in neuroblastoma growth and metastasis are unknown. Here, we report that focal adhesion kinase (FAK), as a critical downstream target of GRP-R, is an important regulator of neuroblastoma tumorigenicity. We found that FAK expression correlates with GRP-R expression in human neuroblastoma sections and cell lines. GRP-R overexpression in SK-N-SH cells increased FAK, integrin α3 and β1 expressions and cell migration. These cells demonstrated flatter cell morphology with broad lamellae, in which intense FAK expression was localized to the leading edges of lamellipodia. Interestingly, FAK activation was, in part, dependent on integrin α3 and β1 expression. Conversely, GRP-R silencing decreased FAK as well as Mycn levels in BE(2)-C cells, which displayed a denser cellular morphology. Importantly, rescu
Combinación de un antiangiogénico y un inhibidor FAK en el tratamiento de melanoma uveal
No full textCombinación de un antiangiogénico y un inhibidor FAK en el tratamiento de melanoma uveal. La presente invención se relaciona con una composición farmacéutica que comprende un agente antiangiogénico, bevacizumab, y un inhibidor de FAK, para su uso en un tipo concreto de cáncer intraocular, melanoma uveal, preferiblemente metastásico. Además, la invención también se relaciona con los usos in vitro de dicha composición farmacéutica, como la inhibición del crecimiento tumoral y mimetismo vasculogénico.Peer reviewedConsejo Superior de Investigaciones Científicas, Delegación AndalucíaA1 Solicitud de patente con informe sobre el estado de la técnic
El papel de la FAK en la acantólisis del Pénfigo vulgar en un modelo murino
No full textPemphigus vulgaris (PV) is an autoimmune blistering skin disease characterized by suprabasal acantholysis, and autoantibodies against desmoglein 3 localized on desmosomes. In addition, caspases also seem to participate in this blistering disease. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in cytoskeleton remodelling and formation and disassembly of cell adhesion structures. We have previously demonstrated that HER (human epidermal growth factor receptor related) isoforms, Src (Rous sarcoma) and mTOR (mammalian target of rapamycin), three molecules implicated in signalling processes, take part in suprabasal acantholysis and apoptosis induced by PV-IgG in a mouse model. Our aim was to investigate if upregulation of FAK is implicated in the development of PV lesions. Herein, using a mouse model, PV-IgG administration showed an increased level of FAK phosphorylated on 397 and 925 tyrosine residues in the basal layer of epidermis. When mice were pretreated with a FAK inhibitor the acantholysis of the basal layer of epidermis was absent. More interestingly, we observed that phosphorylated FAK (Y397/925) decreased when HER isoforms, Src, mTOR, and pan-caspases inhibitors were employed before PV-IgG administration. In addition, pretreatment with the FAK inhibitor before PV-IgG injection avoided the changes of both Bax and Bcl-2 expression and caspases-9 and –3 activities induced by PV-IgG. Finally, FAK inhibitor reduced expression of phosphorylated Src and mTOR in the basal cells of epidermis. In conclusion, our data reveal a novel biochemical mechanism for phosphorylated FAK (Y397/925) in PV development involving HER isoforms, Src and mTOR kinases
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