Expression of Fap amyloids in Pseudomonas aeruginosa, P. fluorescens, and P. putida results in aggregation and increased biofilm formation

PubMed Central

Dueholm, Morten S; Søndergaard, Mads T; Nilsson, Martin; Christiansen, Gunna; Stensballe, Allan; Overgaard, Michael T; Givskov, Michael; Tolker-Nielsen, Tim; Otzen, Daniel E; Nielsen, Per H

2013-01-01

The fap operon, encoding functional amyloids in Pseudomonas (Fap), is present in most pseudomonads, but so far the expression and importance for biofilm formation has only been investigated for P. fluorescens strain UK4. In this study, we demonstrate the capacity of P. aeruginosa PAO1, P. fluorescens Pf-5, and P. putida F1 to express Fap fibrils, and investigated the effect of Fap expression on aggregation and biofilm formation. The fap operon in all three Pseudomonas species conferred the ability to express Fap fibrils as shown using a recombinant approach. This Fap overexpression consistently resulted in highly aggregative phenotypes and in increased biofilm formation. Detailed biophysical investigations of purified fibrils confirmed FapC as the main fibril monomer and supported the role of FapB as a minor, nucleating constituent as also indicated by bioinformatic analysis. Bioinformatics analysis suggested FapF and FapD as a potential β-barrel membrane pore and protease, respectively. Manipulation of the fap operon showed that FapA affects monomer composition of the final amyloid fibril, and that FapB is an amyloid protein, probably a nucleator for FapC polymerization. Our study highlights the fap operon as a molecular machine for functional amyloid formation. PMID:23504942

Expression of Fap amyloids in Pseudomonas aeruginosa, P. fluorescens, and P. putida results in aggregation and increased biofilm formation.

PubMed

Dueholm, Morten S; Søndergaard, Mads T; Nilsson, Martin; Christiansen, Gunna; Stensballe, Allan; Overgaard, Michael T; Givskov, Michael; Tolker-Nielsen, Tim; Otzen, Daniel E; Nielsen, Per H

2013-06-01

The fap operon, encoding functional amyloids in Pseudomonas (Fap), is present in most pseudomonads, but so far the expression and importance for biofilm formation has only been investigated for P. fluorescens strain UK4. In this study, we demonstrate the capacity of P. aeruginosa PAO1, P. fluorescens Pf-5, and P. putida F1 to express Fap fibrils, and investigated the effect of Fap expression on aggregation and biofilm formation. The fap operon in all three Pseudomonas species conferred the ability to express Fap fibrils as shown using a recombinant approach. This Fap overexpression consistently resulted in highly aggregative phenotypes and in increased biofilm formation. Detailed biophysical investigations of purified fibrils confirmed FapC as the main fibril monomer and supported the role of FapB as a minor, nucleating constituent as also indicated by bioinformatic analysis. Bioinformatics analysis suggested FapF and FapD as a potential β-barrel membrane pore and protease, respectively. Manipulation of the fap operon showed that FapA affects monomer composition of the final amyloid fibril, and that FapB is an amyloid protein, probably a nucleator for FapC polymerization. Our study highlights the fap operon as a molecular machine for functional amyloid formation. © 2013 The Authors. Microbiology Open published by John Wiley & Sons Ltd.

The Val30Met familial amyloid polyneuropathy specific Rasch-built overall disability scale (FAP-RODS(©) ).

PubMed

Pruppers, Mariëlle H J; Merkies, Ingemar S J; Faber, Catharina G; Da Silva, Ana M; Costa, Vanessa; Coelho, Teresa

2015-09-01

Familial amyloid polyneuropathy (FAP) is a chronic debilitating multi-organic disorder, mainly assessed using ordinal-based impairment measures. To date, no outcome measure at the activity and participation level has been constructed in FAP. The current study aimed to design an interval activity/participation scale for FAP through Rasch methodology. A preliminary FAP Rasch-built overall disability scale (pre-FAP-RODS) containing 146 activity/participation items was assessed twice (interval: 2-4 week; test-retest reliability) in 248 patients with Val30Met FAP examined in Porto, Portugal, of which 65.7% have received liver transplantation. An ordinal-based 24-item FAP-symptoms inventory questionnaire (FAP-SIQ) was also assessed (validity purposes). The pre-FAP-RODS and FAP-SIQ data were subjected to Rasch analyses. The pre-FAP-RODS did not meet model's expectations. On the basis of requirements such as misfit statistics, differential item functioning, and local dependency, items were systematically removed until a final 34-item FAP-RODS(©) was constructed fulfilling all Rasch requirements. Acceptable reliability/validity scores were demonstrated. In conclusion, the 34-item FAP-RODS(©) is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FAP. The use of the FAP-RODS(©) is recommended for future international clinical trials in patients with Val30Met FAP determining its responsiveness and its cross-cultural validation. Its expansion to other forms of FAP should also be focus of future clinical studies. © 2015 Peripheral Nerve Society.

Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs.

PubMed

Keane, Fiona M; Yao, Tsun-Wen; Seelk, Stefanie; Gall, Margaret G; Chowdhury, Sumaiya; Poplawski, Sarah E; Lai, Jack H; Li, Youhua; Wu, Wengen; Farrell, Penny; Vieira de Ribeiro, Ana Julia; Osborne, Brenna; Yu, Denise M T; Seth, Devanshi; Rahman, Khairunnessa; Haber, Paul; Topaloglu, A Kemal; Wang, Chuanmin; Thomson, Sally; Hennessy, Annemarie; Prins, John; Twigg, Stephen M; McLennan, Susan V; McCaughan, Geoffrey W; Bachovchin, William W; Gorrell, Mark D

2013-01-01

The protease fibroblast activation protein (FAP) is a specific marker of activated mesenchymal cells in tumour stroma and fibrotic liver. A specific, reliable FAP enzyme assay has been lacking. FAP's unique and restricted cleavage of the post proline bond was exploited to generate a new specific substrate to quantify FAP enzyme activity. This sensitive assay detected no FAP activity in any tissue or fluid of FAP gene knockout mice, thus confirming assay specificity. Circulating FAP activity was ∼20- and 1.3-fold less in baboon than in mouse and human plasma, respectively. Serum and plasma contained comparable FAP activity. In mice, the highest levels of FAP activity were in uterus, pancreas, submaxillary gland and skin, whereas the lowest levels were in brain, prostate, leukocytes and testis. Baboon organs high in FAP activity included skin, epididymis, bladder, colon, adipose tissue, nerve and tongue. FAP activity was greatly elevated in tumours and associated lymph nodes and in fungal-infected skin of unhealthy baboons. FAP activity was 14- to 18-fold greater in cirrhotic than in non-diseased human liver, and circulating FAP activity was almost doubled in alcoholic cirrhosis. Parallel DPP4 measurements concorded with the literature, except for the novel finding of high DPP4 activity in bile. The new FAP enzyme assay is the first to be thoroughly characterised and shows that FAP activity is measurable in most organs and at high levels in some. This new assay is a robust tool for specific quantitation of FAP enzyme activity in both preclinical and clinical samples, particularly liver fibrosis.

Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs☆

PubMed Central

Keane, Fiona M.; Yao, Tsun-Wen; Seelk, Stefanie; Gall, Margaret G.; Chowdhury, Sumaiya; Poplawski, Sarah E.; Lai, Jack H.; Li, Youhua; Wu, Wengen; Farrell, Penny; Vieira de Ribeiro, Ana Julia; Osborne, Brenna; Yu, Denise M.T.; Seth, Devanshi; Rahman, Khairunnessa; Haber, Paul; Topaloglu, A. Kemal; Wang, Chuanmin; Thomson, Sally; Hennessy, Annemarie; Prins, John; Twigg, Stephen M.; McLennan, Susan V.; McCaughan, Geoffrey W.; Bachovchin, William W.; Gorrell, Mark D.

2013-01-01

The protease fibroblast activation protein (FAP) is a specific marker of activated mesenchymal cells in tumour stroma and fibrotic liver. A specific, reliable FAP enzyme assay has been lacking. FAP's unique and restricted cleavage of the post proline bond was exploited to generate a new specific substrate to quantify FAP enzyme activity. This sensitive assay detected no FAP activity in any tissue or fluid of FAP gene knockout mice, thus confirming assay specificity. Circulating FAP activity was ∼20- and 1.3-fold less in baboon than in mouse and human plasma, respectively. Serum and plasma contained comparable FAP activity. In mice, the highest levels of FAP activity were in uterus, pancreas, submaxillary gland and skin, whereas the lowest levels were in brain, prostate, leukocytes and testis. Baboon organs high in FAP activity included skin, epididymis, bladder, colon, adipose tissue, nerve and tongue. FAP activity was greatly elevated in tumours and associated lymph nodes and in fungal-infected skin of unhealthy baboons. FAP activity was 14- to 18-fold greater in cirrhotic than in non-diseased human liver, and circulating FAP activity was almost doubled in alcoholic cirrhosis. Parallel DPP4 measurements concorded with the literature, except for the novel finding of high DPP4 activity in bile. The new FAP enzyme assay is the first to be thoroughly characterised and shows that FAP activity is measurable in most organs and at high levels in some. This new assay is a robust tool for specific quantitation of FAP enzyme activity in both preclinical and clinical samples, particularly liver fibrosis. PMID:24371721

Stromal Expression of Fibroblast Activation Protein Alpha (FAP) Predicts Platinum Resistance and Shorter Recurrence in patients with Epithelial Ovarian Cancer.

PubMed

Mhawech-Fauceglia, Paulette; Yan, Li; Sharifian, Maryam; Ren, Xing; Liu, Song; Kim, Grace; Gayther, Simon A; Pejovic, Tanja; Lawrenson, Kate

2015-04-01

The microenvironment plays an important role in tumorigenesis. Fibroblast activation protein alpha (FAP) is overexpressed by fibroblasts present in the microenvironment of many tumors. High FAP expression is a negative prognostic factor in several malignancies, but this has not been investigated in epithelial ovarian cancer (EOC). The aim of this study is to define the value of FAP in EOC. Immunohistochemical staining using an anti-FAP antibody was performed on 338 EOC tissues. mRNA levels in cancer cell lines and FAP silencing using siRNA was also done. FAP immunoexpression by tumor stroma was a significant predictive factor for platinum resistance (p = 0.0154). In survival analysis of days to recurrence, FAP stoma (+) was associated with shorter recurrence than those with FAP (-) stroma (p = 0.0247). In 21.8 % of tumors, FAP protein was expressed by the tumor epithelium, and FAP mRNA was more highly expressed in tumors (n = 489) than in normal tissues (n = 8) (p = 3.88 × 10(-4)). In vitro, addition of FAP to EOC cells induced a 10-12 % increase in cell viability both in the presence and absence of cisplatin. Conversely, siRNA silencing of FAP resulted in ~10 % reduction in EOC cell proliferation. We have shown that FAP expression in EOC is associated with poorer clinical outcomes. FAP may have novel cell-autonomous effects suggesting that targeting FAP could have pleiotropic anti-tumor effects, and anti-FAP therapy could be a highly effective novel treatment for EOC, especially in cisplatinum-resistant cases.

In vivo near-infrared fluorescence imaging of FAP-expressing tumors with activatable FAP-targeted, single-chain Fv-immunoliposomes.

PubMed

Rüger, Ronny; Tansi, Felista L; Rabenhold, Markus; Steiniger, Frank; Kontermann, Roland E; Fahr, Alfred; Hilger, Ingrid

2014-07-28

Molecular and cellular changes that precede the invasive growth of solid tumors include the release of proteolytic enzymes and peptides in the tumor stroma, the recruitment of phagocytic and lymphoid infiltrates and alteration of the extracellular matrix. The reactive tumor stroma consists of a large number of myofibroblasts, characterized by high expression of fibroblast activation protein alpha (FAP). FAP, a type-II transmembrane sialoglycoprotein is an attractive target in diagnosis and therapy of several pathologic disorders especially cancer. In the underlying work, a fluorescence-activatable liposome (fluorescence-quenched during circulation and fluorescence activation upon cellular uptake), bearing specific single-chain Fv fragments directed against FAP (scFv'FAP) was developed, and its potential for use in fluorescence diagnostic imaging of FAP-expressing tumor cells was evaluated by whole body fluorescence imaging. The liposomes termed anti-FAP-IL were prepared via post-insertion of ligand-phospholipid-conjugates into preformed DY-676-COOH-containing liposomes. The anti-FAP-IL revealed a homogeneous size distribution and showed specific interaction and binding with FAP-expressing cells in vitro. The high level of fluorescence quenching of the near-infrared fluorescent dye sequestered in the aqueous interior of the liposomes enables fluorescence imaging exclusively upon uptake and degradation by cells, which results in fluorescence activation. Only FAP-expressing cells were able to take up and activate fluorescence of anti-FAP-IL in vitro. Furthermore, anti-FAP-IL accumulated selectively in FAP-expressing xenograft models in vivo, as demonstrated by blocking experiments using free scFv'FAP. The local tumor fluorescence intensities were in agreement with the intrinsic degree of FAP-expression in different xenograft models. Thus, anti-FAP-IL can serve as a suitable in vivo diagnostic tool for pathological disorders accompanied by high FAP-expression. Copyright © 2014 Elsevier B.V. All rights reserved.

Selective Homogeneous Assay for Circulating Endopeptidase Fibroblast Activation Protein (FAP).

PubMed

Bainbridge, Travis W; Dunshee, Diana Ronai; Kljavin, Noelyn M; Skelton, Nicholas J; Sonoda, Junichiro; Ernst, James A

2017-10-02

Fibroblast Activation Protein (FAP) is a membrane-bound serine protease whose expression is often elevated in activated fibroblasts associated with tissue remodeling in various common diseases such as cancer, arthritis and fibrosis. Like the closely related dipeptidyl peptidase DPPIV, the extracellular domain of FAP can be released into circulation as a functional enzyme, and limited studies suggest that the circulating level of FAP correlates with the degree of tissue fibrosis. Here we describe a novel homogeneous fluorescence intensity assay for circulating FAP activity based on a recently identified natural substrate, FGF21. This assay is unique in that it can effectively distinguish endopeptidase activity of FAP from that of other related enzymes such as prolyl endopeptidase (PREP) and was validated using Fap-deficient mice. Structural modeling was used to elucidate the mechanistic basis for the observed specificity in substrate recognition by FAP, but not by DPPIV or PREP. Finally, the assay was used to detect elevated FAP activity in human patients diagnosed with liver cirrhosis and to determine the effectiveness of a chemical inhibitor for FAP in mice. We propose that the assay presented here could thus be utilized for diagnosis of FAP-related pathologies and for the therapeutic development of FAP inhibitors.

Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer.

PubMed

Feig, Christine; Jones, James O; Kraman, Matthew; Wells, Richard J B; Deonarine, Andrew; Chan, Derek S; Connell, Claire M; Roberts, Edward W; Zhao, Qi; Caballero, Otavia L; Teichmann, Sarah A; Janowitz, Tobias; Jodrell, Duncan I; Tuveson, David A; Fearon, Douglas T

2013-12-10

An autochthonous model of pancreatic ductal adenocarcinoma (PDA) permitted the analysis of why immunotherapy is ineffective in this human disease. Despite finding that PDA-bearing mice had cancer cell-specific CD8(+) T cells, the mice, like human patients with PDA, did not respond to two immunological checkpoint antagonists that promote the function of T cells: anti-cytotoxic T-lymphocyte-associated protein 4 (α-CTLA-4) and α-programmed cell death 1 ligand 1 (α-PD-L1). Immune control of PDA growth was achieved, however, by depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP(+) stromal cell also uncovered the antitumor effects of α-CTLA-4 and α-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T-cell checkpoint antagonists. Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP(+) cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP(+) CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. The residual tumor was composed only of premalignant epithelial cells and inflammatory cells. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP(+) CAF, may direct tumor immune evasion in a model of human PDA.

Structural insight into the role of Streptococcus parasanguinis Fap1 within oral biofilm formation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garnett, James A.; Simpson, Peter J.; Taylor, Jonathan

2012-01-06

Highlights: Black-Right-Pointing-Pointer Crystal structure of Streptococcus parasanguinis Fap1-NR{sub {alpha}} at pH 5.0. Black-Right-Pointing-Pointer pH-dependent conformational changes mediated through electrostatic potential of Fap1-NR{sub {alpha}}. Black-Right-Pointing-Pointer Fap1 facilitates pH-dependent biofilms. Black-Right-Pointing-Pointer We model inter-Fap1 biofilm interactions. -- Abstract: The fimbriae-associated protein 1 (Fap1) is a major adhesin of Streptococcus parasanguinis, a primary colonizer of the oral cavity that plays an important role in the formation of dental plaque. Fap1 is an extracellular adhesive surface fibre belonging to the serine-rich repeat protein (SRRP) family, which plays a central role in the pathogenesis of streptococci and staphylococci. The N-terminal adhesive region of Fap1 (Fap1-NR)more » is composed of two domains (Fap1-NR{sub {alpha}} and Fap1-NR{sub {beta}}) and is projected away from the bacterial surface via the extensive serine-rich repeat region, for adhesion to the salivary pellicle. The adhesive properties of Fap1 are modulated through a pH switch in which a reduction in pH results in a rearrangement between the Fap1-NR{sub {alpha}} and Fap1-NR{sub {beta}} domains, which assists in the survival of S. parasanguinis in acidic environments. We have solved the structure of Fap1-NR{sub {alpha}} at pH 5.0 at 3.0 A resolution and reveal how subtle rearrangements of the 3-helix bundle combined with a change in electrostatic potential mediates 'opening' and activation of the adhesive region. Further, we show that pH-dependent changes are critical for biofilm formation and present an atomic model for the inter-Fap1-NR interactions which have been assigned an important role in the biofilm formation.« less

[FAP Expression and Its Association with the Prognosis of Gastric Stromal Tumors].

PubMed

Tang, Su-Min; Shen, Chao-Yong; Yin, Yuan; Yin, Xiao-Nan; Cai, Zhao-Lun; Chen, Zhi-Xin; Zhang, Bo

2017-03-01

To determine the association of FAP expression with the prognosis of gastric stromal tumors (GSTs). Paraffin-embedded GSTs samples were collected from January 2010 to December 2013 in the department of pathology of our hospital. FAP expression was examined by immunohistochemistry staining. Its correlations with clinical pathological characteristics and prognosis of GSTs were analyzed. A total of 98 cases were included in this study. FAP was expressed in the cytoplasm of GSTs cells, with a positive rate of 42.9%. No FAP expression was found in normal gastric tissues. No differences of FAP expression were found in patients with different gender, age and tumor mitotic counts ( P >0.05). Tumor diameter and risk classification were associated with FAP expression ( P <0.05). Higher levels of FAP expression were found in larger and higher risk tumors. No significant correlations between FAP expression and routine immunohistochemical markers were found. Log-rank univariate survival analysis showed that mitotic counts, tumor size, postoperative IM and FAP expression were associated with recurrence free survival of GSTs patients with intermediate-high risks ( P <0.05). Cox multivariate survival analysis showed that mitotic counts, tumor size, postoperative IM and FAP were independent predictors for the prognosis of GSTs patients with intermediate-high risks ( P <0.05). FAP is expressed in the cytoplasm of gastric GIST cells, but not in normal gastric tissues. FAP is a predictor for the prognosis of GSTs patients with intermediate-high risks.

FAP-1 and NF-κB expressions in oral squamous cell carcinoma as potential markers for chemo-radio sensitivity and prognosis.

PubMed

Nariai, Y; Mishima, K; Yoshimura, Y; Sekine, J

2011-04-01

This study was designed to investigate the feasibility of using Fas-associated phosphatase-1 (FAP-1), nuclear factor kappa B (NF-κB) and p53 as markers for chemo-radio sensitivity in oral squamous cell carcinoma (OSCC). FAP-1 plays a role as an anti-apoptotic factor through Fas-dependent apoptosis after chemo-radiotherapy. NF-κB and p53 might be involved in modulation of FAP-1 expression. FAP-1, NF-κB and p53 expression were immunohistochemically examined using biopsy specimens in 50 OSCC patients treated with chemotherapy and/or radiotherapy. FAP-1 was expressed in 52%, NF-κB in 52% and p53 in 46% of patients. There was no significant difference in FAP-1, p53 or NF-κB expression according to the clinicopathological features. No correlation was found among FAP-1, p53 or NF-κB expression. FAP-1-positive cases showed a poorer survival rate than FAP-1-negative cases (P = 0.0409) and NF-κB-positive cases showed a poorer survival rate than NF-κB-negative cases (P = 0.0018). Multivariate analysis showed that FAP-1 expression, NF-κB expression, clinical stage and age were significant independent variables for survival (clinical stage: P = 0.0016; age: P = 0.0016; NF-κB: P = 0.0314; FAP-1: P = 0.0366). These results suggest that FAP-1 and NF-κB might play a role as chemo-radioresistant factor during chemo-radiotherapy, and FAP-1 and NF-κB expression in OSCC would be feasible markers for chemo-radio sensitivity and prognosis. Copyright © 2010 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein.

PubMed

Tsai, Ting-Yueh; Yeh, Teng-Kuang; Chen, Xin; Hsu, Tsu; Jao, Yu-Chen; Huang, Chih-Hsiang; Song, Jen-Shin; Huang, Yu-Chen; Chien, Chia-Hui; Chiu, Jing-Huai; Yen, Shih-Chieh; Tang, Hung-Kuan; Chao, Yu-Sheng; Jiaang, Weir-Torn

2010-09-23

Fibroblast activation protein (FAP) belongs to the prolyl peptidase family. FAP inhibition is expected to become a new antitumor target. Most known FAP inhibitors often resemble the dipeptide cleavage products, with a boroproline at the P1 site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAP inhibitor is needed in evaluating that FAP as a therapeutic target. Therefore, it is important to develop selective FAP inhibitors for the use of target validation. To achieve this, optimization of the nonselective DPP-IV inhibitor 8 led to the discovery of a new class of substituted 4-carboxymethylpyroglutamic acid diamides as FAP inhibitors. SAR studies resulted in a number of FAP inhibitors having IC(50) of <100 nM with excellent selectivity over DPP-IV, DPP-II, DPP8, and DPP9 (IC(50) > 100 μM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP.

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice*

PubMed Central

Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua; Ra, Hyun-Jeong; Majumdar, Sonali; Gulick, Dexter L.; Jerome, Jacob A.; Madsen, Daniel H.; Christofidou-Solomidou, Melpo; Speicher, David W.; Bachovchin, William W.; Feghali-Bostwick, Carol; Puré, Ellen

2016-01-01

Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2–4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent with in vitro studies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung. PMID:26663085

A Rare Case of FAP in Kashmir Valley.

PubMed

Sameer, A Syed; Pandith, Arshad A; Syeed, Nidda; Siddiqi, Mushtaq A; Chowdri, Nissar A

2011-06-01

Familial adenomatous polyposis (FAP) is the commonest form of inherited form of CRC. It comprises of about 5% of all the colorectal cancers (CRCs). FAP patients have a family history of CRC that suggests a genetic contribution, common exposures among family members, or a combination of both. This case report gives a glimpse of the phenotypic manifestation of FAP and the underlying molecular mechanism which leads to FAP, in addition it also sheds a light on the management of FAP in early stages of life.

Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma.

PubMed

Wang, H; Wu, Q; Liu, Z; Luo, X; Fan, Y; Liu, Y; Zhang, Y; Hua, S; Fu, Q; Zhao, M; Chen, Y; Fang, W; Lv, X

2014-04-10

It is largely recognized that fibroblast activation protein (FAP) is expressed in cancer-associated fibroblasts (CAFs) of many human carcinomas. Furthermore, FAP was recently also reported to be expressed in carcinoma cells of the breast, stomach, pancreatic ductal adenocarcinoma, colorectum, and uterine cervix. The carcinoma cell expression pattern of FAP has been described in several types of cancers, but the role of FAP in oral squamous cell carcinoma (OSCC) is unknown. The role of endogenous FAP in epithelium-derived tumors and molecular mechanisms has also not been reported. In this study, FAP was found to be expressed in carcinoma cells of OSCC and was upregulated in OSCC tissue samples compared with benign tissue samples using immunohistochemistry. In addition, its expression level was closely correlated with overall survival of patients with OSCC. Silencing FAP inhibited the growth and metastasis of OSCC cells in vitro and in vivo. Mechanistically, knockdown of FAP inactivated PTEN/PI3K/AKT and Ras-ERK and its downstream signaling regulating proliferation, migration, and invasion in OSCC cells, as the inhibitory effects of FAP on the proliferation and metastasis could be rescued by PTEN silencing. Our study suggests that FAP acts as an oncogene and may be a potential therapeutic target for patients with OSCC.

The application of the fibroblast activation protein α-targeted immunotherapy strategy

PubMed Central

Du, Jun; Zhang, Kun-Shui; Zhang, Qiu-Gui; Wang, Xiao-Wei; Liu, Zhi-Gang; Liu, Shuang-Quan; Xie, Wan-Ying; Liu, Hui-Fang; Liu, Jing-Shi; Wu, Bai-Ping

2016-01-01

Cancer immunotherapy has primarily been focused on attacking tumor cells. However, given the close interaction between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), CAF-targeted strategies could also contribute to an integrated cancer immunotherapy. Fibroblast activation protein α (FAP α) is not detectible in normal tissues, but is overexpressed by CAFs and is the predominant component of the stroma in most types of cancer. FAP α has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. When all FAP α-expressing cells (stromal and cancerous) are destroyed, tumors rapidly die. Furthermore, a FAP α antibody, FAP α vaccine, and modified vaccine all inhibit tumor growth and prolong survival in mouse models, suggesting FAP α is an adaptive tumor-associated antigen. This review highlights the role of FAP α in tumor development, explores the relationship between FAP α and immune suppression in the TME, and discusses FAP α as a potential immunotherapeutic target. PMID:26985769

Fibroblast Activation Protein (FAP) Is Essential for the Migration of Bone Marrow Mesenchymal Stem Cells through RhoA Activation

PubMed Central

Chung, Kuei-Min; Hsu, Shu-Ching; Chu, Yue-Ru; Lin, Mei-Yao; Jiaang, Weir-Tong; Chen, Ruey-Hwa; Chen, Xin

2014-01-01

Background The ability of human bone marrow mesenchymal stem cells (BM-MSCs) to migrate and localize specifically to injured tissues is central in developing therapeutic strategies for tissue repair and regeneration. Fibroblast activation protein (FAP) is a cell surface serine protease expressed at sites of tissue remodeling during embryonic development. It is also expressed in BM-MSCs, but not in normal tissues or cells. The function of FAP in BM-MSCs is not known. Principal Findings We found that depletion of FAP proteins significantly inhibited the migration of BM-MSCs in a transwell chemotaxis assay. Such impaired migration ability of BM-MSCs could be rescued by re-expressing FAP in these cells. We then demonstrated that depletion of FAP activated intracellular RhoA GTPase. Consistently, inhibition of RhoA activity using a RhoA inhibitor rescued its migration ability. Inhibition of FAP activity with an FAP-specific inhibitor did not affect the activation of RhoA or the migration of BM-MSCs. Furthermore, the inflammatory cytokines interleukin-1beta (IL-1β) and transforming growth factor-beta (TGF-β) upregulated FAP expression, which coincided with better BM-MSC migration. Conclusions Our results indicate FAP plays an important role in the migration of BM-MSCs through modulation of RhoA GTPase activity. The peptidase activity of FAP is not essential for such migration. Cytokines IL-1β and TGF-β upregulate the expression level of FAP and thus enhance BM-MSC migration. PMID:24551161

Fibroblast activation protein (FAP) is essential for the migration of bone marrow mesenchymal stem cells through RhoA activation.

PubMed

Chung, Kuei-Min; Hsu, Shu-Ching; Chu, Yue-Ru; Lin, Mei-Yao; Jiaang, Weir-Tong; Chen, Ruey-Hwa; Chen, Xin

2014-01-01

The ability of human bone marrow mesenchymal stem cells (BM-MSCs) to migrate and localize specifically to injured tissues is central in developing therapeutic strategies for tissue repair and regeneration. Fibroblast activation protein (FAP) is a cell surface serine protease expressed at sites of tissue remodeling during embryonic development. It is also expressed in BM-MSCs, but not in normal tissues or cells. The function of FAP in BM-MSCs is not known. We found that depletion of FAP proteins significantly inhibited the migration of BM-MSCs in a transwell chemotaxis assay. Such impaired migration ability of BM-MSCs could be rescued by re-expressing FAP in these cells. We then demonstrated that depletion of FAP activated intracellular RhoA GTPase. Consistently, inhibition of RhoA activity using a RhoA inhibitor rescued its migration ability. Inhibition of FAP activity with an FAP-specific inhibitor did not affect the activation of RhoA or the migration of BM-MSCs. Furthermore, the inflammatory cytokines interleukin-1beta (IL-1β) and transforming growth factor-beta (TGF-β) upregulated FAP expression, which coincided with better BM-MSC migration. Our results indicate FAP plays an important role in the migration of BM-MSCs through modulation of RhoA GTPase activity. The peptidase activity of FAP is not essential for such migration. Cytokines IL-1β and TGF-β upregulate the expression level of FAP and thus enhance BM-MSC migration.

Evolutionary insight into the functional amyloids of the pseudomonads.

PubMed

Dueholm, Morten S; Otzen, Daniel; Nielsen, Per Halkjær

2013-01-01

Functional bacterial amyloids (FuBA) are important components in many environmental biofilms where they provide structural integrity to the biofilm, mediate bacterial aggregation and may function as virulence factor by binding specifically to host cell molecules. A novel FuBA system, the Fap system, was previously characterized in the genus Pseudomonas, however, very little is known about the phylogenetic diversity of bacteria with the genetic capacity to apply this system. Studies of genomes and public metagenomes from a diverse range of habitats showed that the Fap system is restricted to only three classes in the phylum Proteobacteria, the Beta-, Gamma- and Deltaproteobacteria. The structural organization of the fap genes into a single fapABCDEF operon is well conserved with minor variations such as a frequent deletion of fapA. A high degree of variation was seen within the primary structure of the major Fap fibril monomers, FapC, whereas the minor monomers, FapB, showed less sequence variation. Comparison of phylogenetic trees based on Fap proteins and the 16S rRNA gene of the corresponding bacteria showed remarkably similar overall topology. This indicates, that horizontal gene transfer is an infrequent event in the evolution of the Fap system.

Evolutionary Insight into the Functional Amyloids of the Pseudomonads

PubMed Central

Dueholm, Morten S.; Otzen, Daniel; Nielsen, Per Halkjær

2013-01-01

Functional bacterial amyloids (FuBA) are important components in many environmental biofilms where they provide structural integrity to the biofilm, mediate bacterial aggregation and may function as virulence factor by binding specifically to host cell molecules. A novel FuBA system, the Fap system, was previously characterized in the genus Pseudomonas, however, very little is known about the phylogenetic diversity of bacteria with the genetic capacity to apply this system. Studies of genomes and public metagenomes from a diverse range of habitats showed that the Fap system is restricted to only three classes in the phylum Proteobacteria, the Beta-, Gamma- and Deltaproteobacteria. The structural organization of the fap genes into a single fapABCDEF operon is well conserved with minor variations such as a frequent deletion of fapA. A high degree of variation was seen within the primary structure of the major Fap fibril monomers, FapC, whereas the minor monomers, FapB, showed less sequence variation. Comparison of phylogenetic trees based on Fap proteins and the 16S rRNA gene of the corresponding bacteria showed remarkably similar overall topology. This indicates, that horizontal gene transfer is an infrequent event in the evolution of the Fap system. PMID:24116129

Specific inhibition of fibroblast activation protein (FAP)-alpha prevents tumor progression in vitro.

PubMed

Teichgräber, Volker; Monasterio, Carmen; Chaitanya, Krishna; Boger, Regina; Gordon, Katrin; Dieterle, Thomas; Jäger, Dirk; Bauer, Stefan

2015-09-01

Solid tumors modulate their environment to keep non-malignant stromal cells in a tumor-promoting state. The main cells in the stroma of epithelial derived tumors are cancer associated fibroblasts (CAF) that are critical to tumorigenesis and angiogenesis. CAFs also supply the tumor cells with growth factors and extracellular matrix (ECM) degrading enzymes. They are thus essential for tumor initiation as well as tumor progression and metastasis, suggesting that they represent an ideal cellular target of an integrative tumor therapy. Fibroblast activation protein (FAP) is a well-defined marker, expressed at high levels on the cell surface of CAFs. FAP, a constitutively active serine peptidase with both dipeptidyl peptidase IV (DPP IV) and collagenase/gelatinase activity, promotes malignant and invasive behavior of epithelial cancers. High stromal expression levels of FAP correlate with poor prognosis. FAP is difficult to detect in non-diseased adult tissue, but it is generally expressed at sites of tissue remodeling. In our experiments, we aimed for a reduction of the pro-tumorigenic activities of CAFs by depleting FAP from fibroblasts growing in a composite environment with epithelial tumor cells. FAP depletion was achieved by two therapeutically relevant approaches: a novel internalizing anti-FAP IgG1 antibody and FAP gene knock-down by siRNA delivery. The antibody effectively removed FAP from the cell surface and was capable of reversing the FAP mediated migratory and invasive capacity. FAP RNA interference was equally effective when compared to the antibody. Thus, targeting FAP on CAF suppresses pro-tumorigenic activities and may result in a clinically effective reduction of tumor progression and dissemination. Copyright © 2015 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

FAP-α (Fibroblast activation protein-α) is involved in the control of human breast cancer cell line growth and motility via the FAK pathway

PubMed Central

2014-01-01

Background Fibroblast Activation Protein alpha (FAP-α) or seprase is an integral membrane serine peptidase. Previous work has not satisfactorily explained both the suppression and promotion effects that have been observed in cancer. The purpose of this work was to investigate the role of FAP-α in human breast cancer. Expression of FAP-α was characterized in primary tumour samples and in cell lines, along with the effects of FAP-α expression on in vitro growth, invasion, attachment and migration. Furthermore the potential interaction of FAP-α with other signalling pathways was investigated. Results FAP-α was significantly increased in patients with poor outcome and survival. In vitro results showed that breast cancer cells over expressing FAP-α had increased growth ability and impaired migratory ability. The growth of MDA-MB-231 cells and the adhesion and invasion ability of both MCF-7 cells and MDA-MB-231 cells were not dramatically influenced by FAP-α expression. Over-expression of FAP-α resulted in a reduction of phosphorylated focal adhesion kinase (FAK) level in both cells cultured in normal media and serum-free media. An inhibitor to FAK restored the reduced motility ability of both MCF-7exp cells and MDA-MB-231exp cells and prevented the change in phosphorylated FAK levels. However, inhibitors to PI3K, ERK, PLCϒ, NWASP, ARP2/3, and ROCK had no influence this. Conclusions FAP-α in significantly associated with poor outcome in patients with breast cancer. In vitro, FAP-α promotes proliferation and inhibits migration of breast cancer cells, potentially by regulating the FAK pathway. These results suggest FAP-α could be a target for future therapies. PMID:24885257

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice.

PubMed

Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua; Ra, Hyun-Jeong; Majumdar, Sonali; Gulick, Dexter L; Jerome, Jacob A; Madsen, Daniel H; Christofidou-Solomidou, Melpo; Speicher, David W; Bachovchin, William W; Feghali-Bostwick, Carol; Puré, Ellen

2016-04-08

Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent within vitrostudies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

FAP-α (Fibroblast activation protein-α) is involved in the control of human breast cancer cell line growth and motility via the FAK pathway.

PubMed

Jia, Jun; Martin, Tracey Amanda; Ye, Lin; Jiang, Wen Guo

2014-05-21

Fibroblast Activation Protein alpha (FAP-α) or seprase is an integral membrane serine peptidase. Previous work has not satisfactorily explained both the suppression and promotion effects that have been observed in cancer. The purpose of this work was to investigate the role of FAP-α in human breast cancer. Expression of FAP-α was characterized in primary tumour samples and in cell lines, along with the effects of FAP-α expression on in vitro growth, invasion, attachment and migration. Furthermore the potential interaction of FAP-α with other signalling pathways was investigated. FAP-α was significantly increased in patients with poor outcome and survival. In vitro results showed that breast cancer cells over expressing FAP-α had increased growth ability and impaired migratory ability. The growth of MDA-MB-231 cells and the adhesion and invasion ability of both MCF-7 cells and MDA-MB-231 cells were not dramatically influenced by FAP-α expression. Over-expression of FAP-α resulted in a reduction of phosphorylated focal adhesion kinase (FAK) level in both cells cultured in normal media and serum-free media. An inhibitor to FAK restored the reduced motility ability of both MCF-7exp cells and MDA-MB-231exp cells and prevented the change in phosphorylated FAK levels. However, inhibitors to PI3K, ERK, PLCΥ, NWASP, ARP2/3, and ROCK had no influence this. FAP-α in significantly associated with poor outcome in patients with breast cancer. In vitro, FAP-α promotes proliferation and inhibits migration of breast cancer cells, potentially by regulating the FAK pathway. These results suggest FAP-α could be a target for future therapies.

Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells

PubMed Central

2013-01-01

Introduction Malignant pleural mesothelioma (MPM) is an incurable malignant disease, which results from chronic exposition to asbestos in at least 70% of the cases. Fibroblast activation protein (FAP) is predominantly expressed on the surface of reactive tumor-associated fibroblasts as well as on particular cancer types. Because of its expression on the cell surface, FAP is an attractive target for adoptive T cell therapy. T cells can be re-directed by retroviral transfer of chimeric antigen receptors (CAR) against tumor-associated antigens (TAA) and therefore represent a therapeutic strategy of adoptive immunotherapy. Methods To evaluate FAP expression immunohistochemistry was performed in tumor tissue from MPM patients. CD8+ human T cells were retrovirally transduced with an anti-FAP-F19-∆CD28/CD3ζ-CAR. T cell function was evaluated in vitro by cytokine release and cytotoxicity assays. In vivo function was tested with an intraperitoneal xenograft tumor model in immunodeficient mice. Results FAP was found to be expressed in all subtypes of MPM. Additionally, FAP expression was evaluated in healthy adult tissue samples and was only detected in specific areas in the pancreas, the placenta and very weakly for cervix and uterus. Expression of the anti-FAP-F19-∆CD28/CD3ζ-CAR in CD8+ T cells resulted in antigen-specific IFNγ release. Additionally, FAP-specific re-directed T cells lysed FAP positive mesothelioma cells and inflammatory fibroblasts in an antigen-specific manner in vitro. Furthermore, FAP-specific re-directed T cells inhibited the growth of FAP positive human tumor cells in the peritoneal cavity of mice and significantly prolonged survival of mice. Conclusion FAP re-directed CD8+ T cells showed antigen-specific functionality in vitro and in vivo. Furthermore, FAP expression was verified in all MPM histotypes. Therefore, our data support performing a phase I clinical trial in which MPM patients are treated with adoptively transferred FAP-specific re-directed T cells. PMID:23937772

Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma

PubMed Central

Wang, H; Wu, Q; Liu, Z; Luo, X; Fan, Y; Liu, Y; Zhang, Y; Hua, S; Fu, Q; Zhao, M; Chen, Y; Fang, W; Lv, X

2014-01-01

It is largely recognized that fibroblast activation protein (FAP) is expressed in cancer-associated fibroblasts (CAFs) of many human carcinomas. Furthermore, FAP was recently also reported to be expressed in carcinoma cells of the breast, stomach, pancreatic ductal adenocarcinoma, colorectum, and uterine cervix. The carcinoma cell expression pattern of FAP has been described in several types of cancers, but the role of FAP in oral squamous cell carcinoma (OSCC) is unknown. The role of endogenous FAP in epithelium-derived tumors and molecular mechanisms has also not been reported. In this study, FAP was found to be expressed in carcinoma cells of OSCC and was upregulated in OSCC tissue samples compared with benign tissue samples using immunohistochemistry. In addition, its expression level was closely correlated with overall survival of patients with OSCC. Silencing FAP inhibited the growth and metastasis of OSCC cells in vitro and in vivo. Mechanistically, knockdown of FAP inactivated PTEN/PI3K/AKT and Ras-ERK and its downstream signaling regulating proliferation, migration, and invasion in OSCC cells, as the inhibitory effects of FAP on the proliferation and metastasis could be rescued by PTEN silencing. Our study suggests that FAP acts as an oncogene and may be a potential therapeutic target for patients with OSCC. PMID:24722280

Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma

PubMed Central

Li, Chung-Pin; Buza, Elizabeth L.; Blomberg, Rachel; Govindaraju, Priya; Avery, Diana; Monslow, James; Hsiao, Michael

2017-01-01

Pancreatic ductal adenocarcinomas (PDAs) are desmoplastic and can undergo epithelial-to-mesenchymal transition to confer metastasis and chemoresistance. Studies have demonstrated that phenotypically and functionally distinct stromal cell populations exist in PDAs. Fibroblast activation protein–expressing (FAP-expressing) cells act to enhance PDA progression, while α–smooth muscle actin myofibroblasts can restrain PDA. Thus, identification of precise molecular targets that mediate the protumorigenic activity of FAP+ cells will guide development of therapy for PDA. Herein, we demonstrate that FAP overexpression in the tumor microenvironment correlates with poor overall and disease-free survival of PDA patients. Genetic deletion of FAP delayed onset of primary tumor and prolonged survival of mice in the KPC mouse model of PDA. While genetic deletion of FAP did not affect primary tumor weight in advanced disease, FAP deficiency increased tumor necrosis and impeded metastasis to multiple organs. Lineage-tracing studies unexpectedly showed that FAP is not only expressed by stromal cells, but can also be detected in a subset of CD90+ mesenchymal PDA cells, representing up to 20% of total intratumoral FAP+ cells. These data suggest that FAP may regulate PDA progression and metastasis in cell-autonomous and/or non-cell-autonomous fashions. Together, these data support pursuing FAP as a therapeutic target in PDA. PMID:28978805

Expression and role of the cell surface protease seprase/fibroblast activation protein-α (FAP-α) in astroglial tumors.

PubMed

Mentlein, Rolf; Hattermann, Kirsten; Hemion, Charles; Jungbluth, Achim A; Held-Feindt, Janka

2011-03-01

Seprase or fibroblast activation protein-α (FAP-α) is a cell-surface serine protease that was previously described nearly exclusively on reactive and tumor stromal fibroblasts and thought to be involved in tissue remodeling. We investigated the expression and significance of FAP-α in astrocytomas/glioblastomas. As shown by quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, FAP-α was elevated in whole glioblastoma tissues and in particular in most glioma cells in situ and in vitro. In glioma stem-like cells (gliospheres), FAP-α was detected at low levels; however, FAP-α was considerably induced upon differentiation with 10% fetal calf serum. To explore its functional role, FAP-α was silenced by siRNA transfection. In Boyden chamber assays, FAP-α silenced cells migrated similar as control cells through non-coated or Matrigel (basal lamina)-coated porous membranes, but significantly slower through membranes coated with gelatin or brevican, a major component of brain extracellular matrix. Furthermore, FAP-α-silenced glioma cells migrated through murine brain slices much slower under the conditions tested than differentially fluorescent-labeled control cells. Thus, FAP-α is highly expressed on the surface of glioma cells and contributes to diffuse glioma invasion through extracellular matrix components.

[Expression of FAP and alpha-SMA during the incised wound healing in mice skin].

PubMed

Gao, Yang; Peng, Xue; Jin, Zhan-Fen; Fu, Zhi-Jun

2009-12-01

OBJECTIVE To investigate the time-dependent expression of fibroblast activation protein (FAP) and alpha-smooth muscle actin(alpha-SMA) during the incised wound healing of the skin in mice. The expression of FAP and alpha-SMA in incised wound of mice skin was detected by immunohistochemistry and Western blot. By immunohistochemistry, the expression of FAP and alpha-SMA in the normal skin and the skin 1 h after injury maintained at a very low level, but the positive cells expressing FAP and alpha-SMA started to elevate 6 h after injury and reached its peak on 5 d for FAP and on 3 d for alpha-SMA, then gradually decreased to the normal level on 14 d. The expression of FAP and alpha-SMA was observed throughout the wound healing stages 1 d after injuries by Western blot as well with a peak expression occurring on 5 d for FAP and on 3 d for alpha-SMA after injury. FAP may be a potentially useful marker for wound age determination and alpha-SMA may be used as an effective indicator for the mid- and late stage incised wound of mice skin. The combination use of FAP and alpha-SMA may be potentially effective indicators for wound age determination.

Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells

PubMed Central

Scholler, John; Monslow, James; Avery, Diana; Newick, Kheng; O'Brien, Shaun; Evans, Rebecca A.; Bajor, David J.; Clendenin, Cynthia; Durham, Amy C; Buza, Elizabeth L; Vonderheide, Robert H; June, Carl H

2015-01-01

Malignant cells drive the generation of a desmoplastic and immunosuppressive tumor microenvironment. Cancer-associated stromal cells (CASCs) are a heterogeneous population that provides both negative and positive signals for tumor cell growth and metastasis. Fibroblast activation protein (FAP) is a marker of a major subset of CASCs in virtually all carcinomas. Clinically, FAP expression serves as an independent negative prognostic factor for multiple types of human malignancies. Prior studies established that depletion of FAP+ cells inhibits tumor growth by augmenting anti-tumor immunity. However, the potential for immune-independent effects on tumor growth have not been defined. Herein, we demonstrate that FAP+ CASCs are required for maintenance of the provisional tumor stroma since depletion of these cells, by adoptive transfer of FAP-targeted chimeric antigen receptor (CAR) T cells, reduced extracellular matrix proteins and glycosaminoglycans. Adoptive transfer of FAP-CAR T cells also decreased tumor vascular density and restrained growth of desmoplastic human lung cancer xenografts and syngeneic murine pancreatic cancers in an immune-independent fashion. Adoptive transfer of FAP-CAR T cells also restrained autochthonous pancreatic cancer growth. These data distinguish the function of FAP+ CASCs from other CASC subsets and provide support for further development of FAP+ stromal cell-targeted therapies for the treatment of solid tumors. PMID:25979873

Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells.

PubMed

Lo, Albert; Wang, Liang-Chuan S; Scholler, John; Monslow, James; Avery, Diana; Newick, Kheng; O'Brien, Shaun; Evans, Rebecca A; Bajor, David J; Clendenin, Cynthia; Durham, Amy C; Buza, Elizabeth L; Vonderheide, Robert H; June, Carl H; Albelda, Steven M; Puré, Ellen

2015-07-15

Malignant cells drive the generation of a desmoplastic and immunosuppressive tumor microenvironment. Cancer-associated stromal cells (CASC) are a heterogeneous population that provides both negative and positive signals for tumor cell growth and metastasis. Fibroblast activation protein (FAP) is a marker of a major subset of CASCs in virtually all carcinomas. Clinically, FAP expression serves as an independent negative prognostic factor for multiple types of human malignancies. Prior studies established that depletion of FAP(+) cells inhibits tumor growth by augmenting antitumor immunity. However, the potential for immune-independent effects on tumor growth have not been defined. Herein, we demonstrate that FAP(+) CASCs are required for maintenance of the provisional tumor stroma because depletion of these cells, by adoptive transfer of FAP-targeted chimeric antigen receptor (CAR) T cells, reduced extracellular matrix proteins and glycosaminoglycans. Adoptive transfer of FAP-CAR T cells also decreased tumor vascular density and restrained growth of desmoplastic human lung cancer xenografts and syngeneic murine pancreatic cancers in an immune-independent fashion. Adoptive transfer of FAP-CAR T cells also restrained autochthonous pancreatic cancer growth. These data distinguish the function of FAP(+) CASCs from other CASC subsets and provide support for further development of FAP(+) stromal cell-targeted therapies for the treatment of solid tumors. ©2015 American Association for Cancer Research.

Fibroblast activation protein is dispensable in the anti-influenza immune response in mice

PubMed Central

Chowdhury, Sumaiya; Polak, Natasa

2017-01-01

Fibroblast activation protein alpha (FAP) is a unique dual peptidase of the S9B serine protease family, being capable of both dipeptidyl peptidase and endopeptidase activities. FAP is expressed at low level in healthy adult organs including the pancreas, cervix, uterus, submaxillary gland and the skin, and highly upregulated in embryogenesis, chronic inflammation and tissue remodelling. It is also expressed by cancer-associated stromal fibroblasts in more than 90% of epithelial tumours. FAP has enzymatic and non-enzymatic functions in the growth, immunosuppression, invasion and cell signalling of tumour cells. FAP deficient mice are fertile and viable with no gross abnormality, but little data exist on the role of FAP in the immune system. FAP is upregulated in association with microbial stimulation and chronic inflammation, but its function in infection remains unknown. We showed that major populations of immune cells including CD4+ and CD8+ T cells, B cells, dendritic cells and neutrophils are generated and maintained normally in FAP knockout mice. Upon intranasal challenge with influenza virus, FAP mRNA was increased in the lungs and lung-draining lymph nodes. Nonetheless, FAP deficient mice showed similar pathologic kinetics to wildtype controls, and were capable of supporting normal anti-influenza T and B cell responses. There was no evidence of compensatory upregulation of other DPP4 family members in influenza-infected FAP-deficient mice. FAP appears to be dispensable in anti-influenza adaptive immunity. PMID:28158223

Expression of the FAP gene in non-fibroblast human cell lines. Development of cancer-associated fibroblast models.

PubMed

Tyulkina, D V; Pleshkan, V V; Alekseenko, I V; Kopantseva, M R; Sverdlov, E D

2016-09-01

The fibroblast activation protein (FAP) is selectively expressed in cancer-associated fibroblasts (CAFs) and facilitates tumor progression, which makes this protein an attractive therapeutic target. There are difficulties in obtaining CAFs for studying the function and suppression of FAP. In this work, the expression level of FAP was determined by PCR assay in 25 human cell lines and 8 surgical samples of tumor stroma. The expression of FAP was observed in all tumor stroma samples and in four cell lines: NGP-127, SJCRH30, SJSA-1, and A375. The level of FAP expression in NGP-127, SJCRH30, and SJSA-1 lines as well as in CAFs of patients was comparable, which makes these cell lines a possible model for studying FAP.

Cribriform-morular variant of papillary thyroid carcinoma: an indication to screen for occult FAP.

PubMed

Levy, Rachel A; Hui, Vanessa W; Sood, Rupa; Fish, Stephanie; Markowitz, Arnold J; Wong, Richard J; Guillem, José G

2014-12-01

Cribriform-morular variant (CMV) is a rare subtype of papillary thyroid carcinoma (PTC) that is associated with familial adenomatous polyposis (FAP). Given the high likelihood for multi-organ malignancies in FAP patients, this study explores the yield of diagnosing occult FAP among CMV-PTC patients. Institutional database was searched in order to identify patients with pathologically-confirmed CMV-PTC from 2000 to 2012. Medical records were reviewed, and clinical and pathological features were analyzed. Eleven cases of CMV were identified from 6,901 patients with PTC, for a prevalence of 0.16 %. All 11 patients were female. The median age at CMV-PTC diagnosis was 36 years (range 18-46). Two patients had pre-existing FAP at the time of PTC diagnosis. The other nine patients were referred for colonoscopy and/or genetic testing. Six patients underwent colonoscopy and one (17 %) was diagnosed with FAP based on polyposis phenotype and genetic testing. The mean age of patients at the time of CMV-PTC diagnosis was younger in the FAP group (23 years, range 18-34) than in the sporadic group (37 years, range 25-46). All three patients with FAP-associated CMV-PTC had multicentric tumors, while all five sporadic patients did not. Our study found that approximately one-sixth of patients with CMV-PTC may have occult FAP. Patients with FAP-associated CMV-PTC appear to be younger and more likely to have multicentric tumors than those with sporadic CMV-PTC. Due to the increased risk of malignancy in patients with FAP, patients with CMV-PTC should be referred for colonoscopy and/or genetic evaluation for FAP.

Dataset on FAP-induced emergence of spontaneous metastases and on the preparation of activatable FAP-targeting immunoliposomes to detect the metastases.

PubMed

Tansi, Felista L; Rüger, Ronny; Böhm, Claudia; Kontermann, Roland E; Teichgraeber, Ulf K; Fahr, Alfred; Hilger, Ingrid

2016-12-01

The underlying data demonstrates that fibroblast activation protein (FAP) paves the way for fibrosarcoma cells, which require the proteolysis of the extracellular matrix (ECM) and basement membranes to intravasate from implanted subcutaneous primary tumors into blood vessels, be transported to distant organs where they extravasate from the blood vessels, reattach and proliferate to metastases. The data additionally shows that FAP, when overexpressed on fibrosarcoma cells induces their invasion and formation of spontaneous metastases in multiple organs, particularly after subcutaneous co-implantation of the FAP-expressing and wildtype fibrosarcoma. The raw and processed data presented herein is related to a research article entitled "Potential of activatable FAP-targeting immunoliposomes in intraoperative imaging of spontaneous metastases" (F.L. Tansi, R. Rüger, C. Böhm, R.E. Kontermann, U.K. Teichgraeber, A. Fahr, I. Hilger, 2016) [1]. Furthermore, evidence for the detection of FAP-expressing tumor cells and cells of the tumor stroma by activatable FAP-targeting liposomes is presented in this dataset.

Evaluation of Illinois Benedictine's Freshman Advising Program via the New Benedictine Advising Survey.

ERIC Educational Resources Information Center

Iaccino, James F.

Many colleges and universities lack a formal evaluation system to assess their advising programs. Illinois Benedictine College, however, has consistently evaluated its Freshman Advising Program (FAP) on an annual basis ever since its inception. In 1986, the college decided to implement the new Benedictine Advising Survey in the exit interview…

Operative risks of domino liver transplantation for the FAP liver donor and the FAP liver recipient.

PubMed

Azoulay, Daniel; Salloum, Chady; Samuel, Didier; Planté-Bordeneuve, Violaine

2012-06-01

This study aimed at evaluating the operative risks of domino liver transplantation (LT). Two retrospective analyses were conducted (comparison of familial amyloid polyneuropathy (FAP) liver donors [61 patients] versus FAP nondonors [39 patients] and FAP liver recipients [61 patients] versus cadaveric liver recipients [61 patients]). First analysis showed a 60-day mortality of 6.6% for FAP donors and 7.7% for FAP nondonors (p = 1.0). Both groups had similar vascular and biliary complication rates. Both groups had similar 1- and 5-year patient and graft survival rates (83.4 % versus 87.2%, and 79.8 % versus 71.8%, p = 0.7) and (83.3% versus 87.2%, and 79.1% versus 71.8%, p = 0.7). The second analysis showed a 1.6% mortality for FAP liver recipients versus 3.2% of the control group (p = 1). Both groups had similar morbidity and technical complication rates (18.0% versus 13.1%, p = 0.45) and (0.18 versus 0.15, p = 0.65). Domino procedure doesn't add any risk to FAP donor or recipient. It increases the organ pool allowing transplantation of marginal recipients who otherwise are denied cadaveric LT.

FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression.

PubMed

Chen, Lingling; Qiu, Xiangting; Wang, Xinhua; He, Jian

2017-05-20

Immune checkpoint blockades that significantly prolonged survival of melanoma patients have been less effective on colorectal cancer (CRC) patients. Growing evidence suggested that fibroblast activation protein-alpha (FAP) on cancer associate fibroblasts (CAFs) has critical roles in regulating antitumor immune response by inducing tumor-promoting inflammation. In this study, we explored the roles of FAP in regulating the tumor immunity and immune checkpoint blockades resistance in CRC experimental systems. We found that CAFs with high FAP expression could induce immune checkpoint blockade resistance in CRC mouse model. Mechanistically, CAFs with high FAP expression promoted immunosuppression in the CRC tumor immune microenvironment by up-regulating CCL2 secretion, recruiting myeloid cells, and decreasing T-cell activity. In human CRC samples, FAP expression was proportional to myeloid cells number, but inversely related to T-cell number. High FAP expression also predicted poor survival of CRC patients. Taken together, our study suggested that high FAP expression in CAFs is one reason leading to immune checkpoint blockades resistance in CRC patients and FAP is an optional target for reversing immune checkpoint blockades resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

The pathway to muscle fibrosis depends on myostatin stimulating the differentiation of fibro/adipogenic progenitor cells in chronic kidney disease

PubMed Central

Dong, Jiangling; Dong, Yanjun; Chen, Zihong; Mitch, William E.; Zhang, Liping

2016-01-01

Fibrosis in skeletal muscle develops after injury or in response to chronic kidney disease (CKD) but the origin of cells becoming fibrous tissue and the initiating and sustaining mechanisms causing muscle fibrosis are unclear. We have identified muscle fibro/adipogenic progenitor cells (FAPs) that potentially differentiate into adipose tissues or fibrosis. We also demonstrated that CKD stimulates myostatin production in muscle. Therefore, we tested whether CKD induces myostatin which stimulates fibrotic differentiation of FAPs leading to fibrosis in skeletal muscles. We isolated FAPs from mouse muscles and found that myostatin stimulates their proliferation and conversion into fibrocytes. In vivo, FAPs isolated from EGFP-transgenic mice (FAPs-EGFP) were transplanted into muscles of mice with CKD or into mouse muscles that were treated with myostatin. CKD or myostatin stimulated FAPs-EGFP proliferation in muscle and increased α-smooth muscle actin expression in FAP-EGFP cells. When myostatin was inhibited with a neutralizing peptibody (a chimeric peptide-Fc fusion protein), the FAP proliferation and muscle fibrosis induced by CKD were both suppressed. Knocking down Smad3 in cultured FAPs interrupted their conversion into fibrocytes indicating that myostatin directly converts FAPs into fibrocytes. Thus, counteracting myostatin may be a strategy for preventing the development of fibrosis in skeletal muscles of patients with CKD. PMID:27653838

The pathway to muscle fibrosis depends on myostatin stimulating the differentiation of fibro/adipogenic progenitor cells in chronic kidney disease.

PubMed

Dong, Jiangling; Dong, Yanjun; Chen, Zihong; Mitch, William E; Zhang, Liping

2017-01-01

Fibrosis in skeletal muscle develops after injury or in response to chronic kidney disease (CKD), but the origin of cells becoming fibrous tissue and the initiating and sustaining mechanisms causing muscle fibrosis are unclear. We identified muscle fibro/adipogenic progenitor cells (FAPs) that potentially differentiate into adipose tissues or fibrosis. We also demonstrated that CKD stimulates myostatin production in muscle. Therefore, we tested whether CKD induces myostatin, which stimulates fibrotic differentiation of FAPs leading to fibrosis in skeletal muscles. We isolated FAPs from mouse muscles and found that myostatin stimulates their proliferation and conversion into fibrocytes. In vivo, FAPs isolated from EGFP-transgenic mice (FAPs-EGFP) were transplanted into muscles of mice with CKD or into mouse muscles that were treated with myostatin. CKD or myostatin stimulated FAPs-EGFP proliferation in muscle and increased α-smooth muscle actin expression in FAP-EGFP cells. When myostatin was inhibited with a neutralizing peptibody (a chimeric peptide-Fc fusion protein), the FAP proliferation and muscle fibrosis induced by CKD were both suppressed. Knocking down Smad3 in cultured FAPs interrupted their conversion into fibrocytes, indicating that myostatin directly converts FAPs into fibrocytes. Thus, counteracting myostatin may be a strategy for preventing the development of fibrosis in skeletal muscles of patients with CKD. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Discovery of Small-Molecule Nonfluorescent Inhibitors of Fluorogen-Fluorogen Activating Protein Binding Pair.

PubMed

Wu, Yang; Stauffer, Shaun R; Stanfield, Robyn L; Tapia, Phillip H; Ursu, Oleg; Fisher, Gregory W; Szent-Gyorgyi, Christopher; Evangelisti, Annette; Waller, Anna; Strouse, J Jacob; Carter, Mark B; Bologa, Cristian; Gouveia, Kristine; Poslusney, Mike; Waggoner, Alan S; Lindsley, Craig W; Jarvik, Jonathan W; Sklar, Larry A

2016-01-01

A new class of biosensors, fluorogen activating proteins (FAPs), has been successfully used to track receptor trafficking in live cells. Unlike the traditional fluorescent proteins (FPs), FAPs do not fluoresce unless bound to their specific small-molecule fluorogens, and thus FAP-based assays are highly sensitive. Application of the FAP-based assay for protein trafficking in high-throughput flow cytometry resulted in the discovery of a new class of compounds that interferes with the binding between fluorogens and FAP, thus blocking the fluorescence signal. These compounds are high-affinity, nonfluorescent analogs of fluorogens with little or no toxicity to the tested cells and no apparent interference with the normal function of FAP-tagged receptors. The most potent compound among these, N,4-dimethyl-N-(2-oxo-2-(4-(pyridin-2-yl)piperazin-1-yl)ethyl)benzenesulfonamide (ML342), has been investigated in detail. X-ray crystallographic analysis revealed that ML342 competes with the fluorogen, sulfonated thiazole orange coupled to diethylene glycol diamine (TO1-2p), for the same binding site on a FAP, AM2.2. Kinetic analysis shows that the FAP-fluorogen interaction is more complex than a homogeneous one-site binding process, with multiple conformational states of the fluorogen and/or the FAP, and possible dimerization of the FAP moiety involved in the process. © 2015 Society for Laboratory Automation and Screening.

Quality of life and consequences for daily life of familial adenomatous polyposis (FAP) family members.

PubMed

Douma, K F L; Bleiker, E M A; Vasen, H F A; Gundy, C M; Aaronson, N K

2011-06-01

The study aimed to document the impact of familial adenomatous polyposis (FAP) on health-related quality of life (HRQOL) and several practical aspects of daily life, and to identify factors significantly associated with HRQOL. This study is the first to compare HRQOL between patients with FAP, at-risk individuals and noncarriers. A total of 525 individuals (response rate 64%) from 145 families at high risk for FAP completed a battery of self-report questionnaires assessing generic- and condition-specific HRQOL and the consequences of FAP for daily life. HRQOL was comparable to that of the general Dutch population. Surgically treated patients with FAP had significantly lower scores on several HRQOL domains compared with at-risk individuals, noncarriers and nonsurgically treated patients with FAP. Type of surgery was not significantly associated with HRQOL. Within the surgically treated group, postsurgical complications and comorbidity significantly affected HRQOL. Forty-one percent of patients reported that FAP had affected their working life. Surgically treated patients with FAP have significantly poorer HRQOL than other groups. The type of surgery and age at time of first surgery were not associated with HRQOL but surgical complications and comorbidity were. Patients should be informed of the consequences of FAP for work and other life domains. © 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.

High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis.

PubMed

Wikberg, Maria L; Edin, Sofia; Lundberg, Ida V; Van Guelpen, Bethany; Dahlin, Anna M; Rutegård, Jörgen; Stenling, Roger; Oberg, Ake; Palmqvist, Richard

2013-04-01

An active stroma is important for cancer cell invasion and metastasis. We investigated the expression of fibroblast activation protein (FAP) in relation to patient prognosis in colorectal cancer. Colorectal cancer specimens from 449 patients were immunohistochemically stained with a FAP antibody and evaluated in the tumor center and tumor front using a semiquantitative four-level scale. FAP was expressed by fibroblasts in 85-90 % of the tumors examined. High versus no/low expression in the tumor center was associated with poor prognosis (multivariate hazard ratio, HR = 1.72; 95 % CI 1.07-2.77, p = 0.025). FAP expression in the tumor front, though more frequent than in the tumor center, was not associated with prognosis. FAP expression in the tumor center was more common in specimens with positive microsatellite instability (MSI) screening status and in patients with high CpG island methylator phenotype (CIMP) status. However, inclusion of MSI screening status and CIMP status in the multivariate analysis strengthened the risk estimates for high FAP expression in the tumor center (HR = 1.89; 95 % CI 1.13-3.14; p = 0.014), emphasizing the role of FAP as an independent prognostic factor. Stromal FAP expression is common in colorectal cancer, and we conclude that high FAP expression in the tumor center, but not the tumor front, is an independent negative prognostic factor.

A specific, transmembrane interface regulates fibroblast activation protein (FAP) homodimerization, trafficking and exopeptidase activity.

PubMed

Wonganu, Benjamaporn; Berger, Bryan W

2016-08-01

Fibroblast activation protein (FAP) is a cell-surface serine protease which promotes invasiveness of certain epithelial cancers and is therefore a potential target for cancer drug development and delivery. Unlike dipeptidyl peptidase IV (DPPIV), FAP exhibits prolyl endopeptidase activity and is active as a homodimer with specificity for type I collagen. The mechanism that regulates FAP homodimerization and its relation to prolyl endopeptidase activity is not completely understood. Here, we investigate key residues in the FAP TM domain that may be significant for FAP homodimerization. Mutations to predicted TM interfacial residues (G10L, S14L, and A18L) comprising a small-X3-small motif reduced FAP TM-CYTO dimerization relative to wild type as measured using the AraTM assay, whereas predicted off-interface residues showed no significant change from wild type. The results implied that the predicted small-X3-small dimer interface affect stabilization of FAP TM-CYTO homodimerization. Compared with FAPwild-type, the interfacial TM residue G10L significantly decreased FAP endopeptidase activity more than 25%, and also reduced cell-surface versus intracellular expression relative to other interfacial residues S14L and A18L. Thus, our results suggest FAP dimerization is important for both trafficking and protease activity, and is dependent on a specific TM interface. Copyright © 2016 Elsevier B.V. All rights reserved.

7 CFR 1753.56 - General.

Code of Federal Regulations, 2011 CFR

2011-01-01

...) The Force Account Proposals (FAPs) are subject to review and approval by RUS. (e) The FAP is approved by RUS on the basis of estimated labor and material costs. The FAP is closed based on the borrower's... by the completed assembly units priced at the unit prices in the approved FAP. (Approved by the...

7 CFR 1753.56 - General.

Code of Federal Regulations, 2013 CFR

2013-01-01

...) The Force Account Proposals (FAPs) are subject to review and approval by RUS. (e) The FAP is approved by RUS on the basis of estimated labor and material costs. The FAP is closed based on the borrower's... by the completed assembly units priced at the unit prices in the approved FAP. (Approved by the...

7 CFR 1753.56 - General.

Code of Federal Regulations, 2010 CFR

2010-01-01

...) The Force Account Proposals (FAPs) are subject to review and approval by RUS. (e) The FAP is approved by RUS on the basis of estimated labor and material costs. The FAP is closed based on the borrower's... by the completed assembly units priced at the unit prices in the approved FAP. (Approved by the...

7 CFR 1753.56 - General.

Code of Federal Regulations, 2012 CFR

2012-01-01

...) The Force Account Proposals (FAPs) are subject to review and approval by RUS. (e) The FAP is approved by RUS on the basis of estimated labor and material costs. The FAP is closed based on the borrower's... by the completed assembly units priced at the unit prices in the approved FAP. (Approved by the...

7 CFR 1753.56 - General.

Code of Federal Regulations, 2014 CFR

2014-01-01

...) The Force Account Proposals (FAPs) are subject to review and approval by RUS. (e) The FAP is approved by RUS on the basis of estimated labor and material costs. The FAP is closed based on the borrower's... by the completed assembly units priced at the unit prices in the approved FAP. (Approved by the...

RANDOM MATRIX DIAGONALIZATION--A COMPUTER PROGRAM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fuchel, K.; Greibach, R.J.; Porter, C.E.

A computer prograra is described which generates random matrices, diagonalizes them and sorts appropriately the resulting eigenvalues and eigenvector components. FAP and FORTRAN listings for the IBM 7090 computer are included. (auth)

[Cloning and sequence analysis of recombinant fusion gene of Escherichia coli heat-liable enterotoxin B subunit and Actinobacillus actinomycetemcomitans fimbria associative protein].

PubMed

Li, Yi; Sun, Hong-chen; Guo, Xue-jun; Feng, Shu-zhang

2005-02-01

To clone the recombinant fusion gene of Escherichia coli heat-liable enterotoxin B subunit (Ltb) and Actinobacillus actinomycetemcomitans fimbria associative protein (Fap). Two couples of primers were designed for PCR according to the known sequence of ltb and fap. The ltb and fap gene were obtained by amplification PCR technique from plasmid EWD299 of Escherichia coli and Actinobacillus actinomycetemcomitans 310 DNA respectively, and fused them by PCR. The fusion gene ltb-fap were cloning into plasmid pET28a(+). The recombined plasmid pET28a ltb-fap was transformed into Escherichia coli DH5alpha. The recombinant was screened and identified by restriction enzyme and PCR. The cloned gene was sequenced. The ltb-fap about 531bp in size was obtained successfully, and identified by PCR, restrictive enzyme and sequence analysis. The vector of pET28a ltb-fap was obtained.

Development and Preliminary Evaluation of a FAP Protocol: Brief Relationship Enhancement

ERIC Educational Resources Information Center

Holman, Gareth; Kohlenberg, Robert J.; Tsai, Mavis

2012-01-01

The purpose of this study was to develop a brief Functional Analytic Psychotherapy (FAP) protocol that will facilitate reliable implementation of FAP interventions, thus supporting research on FAP process and outcome. The treatment was a four-session individual therapy for clients who were interested in improving their relationship with their…

Childbirth after surgery for familial adenomatous polyposis in Japan.

PubMed

Kobayashi, Hirotoshi; Ishida, Hideyuki; Ueno, Hideki; Hinoi, Takao; Inoue, Yasuhiro; Ishida, Fumio; Kanemitsu, Yukihide; Konishi, Tsuyoshi; Yamaguchi, Tatsuro; Tomita, Naohiro; Matsubara, Nagahide; Watanabe, Toshiaki; Sugihara, Kenichi

2017-02-01

Familial adenomatous polyposis (FAP) is a genetic disorder. Some female patients with FAP can become pregnant. However, the current state of childbirth after surgery for FAP is unclear in Japan. The study investigated 303 patients (147 female) who had undergone surgery for FAP at the 23 institutions between 2000 and 2012. Eighty female patients had information available on childbirth after surgery for FAP. Eight patients (10 %) gave birth after surgery. The mean age at surgery for FAP was 27 (range 20-41) years and 37 years in patients with and without childbirth after surgery, respectively (P = 0.044). The rate of childbirth after surgery was 17 % in women ≤30 years of age and 13 % in those ≤40 years of age. Although only one patient with invasive cancer (2.9 %) gave childbirth after surgery, seven patients without cancer (15.6 %) gave birth (P = 0.045). This study clarified the current state of childbirth after surgery for FAP in Japan. It is important to use these data to determine the best therapeutic approach for female FAP patients.

Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis.

PubMed

Obici, Laura; Kuks, Jan B; Buades, Juan; Adams, David; Suhr, Ole B; Coelho, Teresa; Kyriakides, Theodore

2016-02-01

These recommendations highlight recent experience in genetic counselling for the severe autosomal-dominant, late-onset transthyretin familial amyloid polyneuropathy (TTR-FAP) disease, and present a structured approach towards identification and monitoring of asymptomatic carriers of the mutated gene. The effectiveness of current treatment options is still limited in patients with TTR-FAP beyond stage I. Diagnosis in the early stages of TTR-FAP is essential to prevent or delay the progression of disease. Existing legal and cultural issues differ among countries within Europe. Experts of the European Network for TTR-FAP (ATTReuNET) concluded that genetic counselling for diagnosed individuals and at-risk family members is mostly beneficial and should be carried out with care by trained professionals. Systematic and regular monitoring of an asymptomatic carrier is necessary to detect early signs of TTR-FAP and maximize the effectiveness of treatment. This includes five areas of assessment: history/clinical examination, sensorimotor function, autonomic dysfunction, cardiac function, and renal function. At least two related symptoms and positive biopsy findings are required to confirm diagnosis of TTR-FAP. Early detection of TTR-FAP is essential to improve the prognosis of TTR-FAP. ATTReuNET recommends genetic counselling and routine monitoring for asymptomatic carriers of TTR-FAP.

RNA Mimicry by the Fap7 Adenylate Kinase in Ribosome Biogenesis

PubMed Central

Réty, Stéphane; Lebaron, Simon; Deschamps, Patrick; Bareille, Joseph; Jombart, Julie; Robert-Paganin, Julien; Delbos, Lila; Chardon, Florian; Zhang, Elodie; Charenton, Clément; Tollervey, David; Leulliot, Nicolas

2014-01-01

During biogenesis of the 40S and 60S ribosomal subunits, the pre-40S particles are exported to the cytoplasm prior to final cleavage of the 20S pre-rRNA to mature 18S rRNA. Amongst the factors involved in this maturation step, Fap7 is unusual, as it both interacts with ribosomal protein Rps14 and harbors adenylate kinase activity, a function not usually associated with ribonucleoprotein assembly. Human hFap7 also regulates Cajal body assembly and cell cycle progression via the p53–MDM2 pathway. This work presents the functional and structural characterization of the Fap7–Rps14 complex. We report that Fap7 association blocks the RNA binding surface of Rps14 and, conversely, Rps14 binding inhibits adenylate kinase activity of Fap7. In addition, the affinity of Fap7 for Rps14 is higher with bound ADP, whereas ATP hydrolysis dissociates the complex. These results suggest that Fap7 chaperones Rps14 assembly into pre-40S particles via RNA mimicry in an ATP-dependent manner. Incorporation of Rps14 by Fap7 leads to a structural rearrangement of the platform domain necessary for the pre-rRNA to acquire a cleavage competent conformation. PMID:24823650

Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α.

PubMed

Keane, Fiona M; Nadvi, Naveed A; Yao, Tsun-Wen; Gorrell, Mark D

2011-04-01

Fibroblast activation protein-α (FAP) is a cell surface-expressed and soluble enzyme of the prolyl oligopeptidase family, which includes dipeptidyl peptidase 4 (DPP4). FAP is not generally expressed in normal adult tissues, but is found at high levels in activated myofibroblasts and hepatic stellate cells in fibrosis and in stromal fibroblasts of epithelial tumours. FAP possesses a rare catalytic activity, hydrolysis of the post-proline bond two or more residues from the N-terminus of target substrates. α(2)-antiplasmin is an important physiological substrate of FAP endopeptidase activity. This study reports the first natural substrates of FAP dipeptidyl peptidase activity. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY were the most efficiently hydrolysed substrates and the first hormone substrates of FAP to be identified. In addition, FAP slowly hydrolysed other hormone peptides, such as the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are efficient DPP4 substrates. FAP showed negligible or no hydrolysis of eight chemokines that are readily hydrolysed by DPP4. This novel identification of FAP substrates furthers our understanding of this unique protease by indicating potential roles in cardiac function and neurobiology. © 2011 The Authors Journal compilation © 2011 FEBS.

[Therapeutic strategy for familial amyloid polyneuropathy (FAP)].

PubMed

Ikeda, Shu-ichi

2009-11-01

Familial amyloid polyneuropathy (FAP) was long considered to be an incurable disease, but a new therapeutic approach was developed 15 years ago. As the liver produces most of the transthyretin (TTR) in serum, it was assumed that the replacement of a liver expressing an abnormal TTR gene should stop the production of the variant TTR, the serum amyloid precursor in FAP. Until now about 1,500 FAP patients underwent liver transplantation, and the 10-year-survival rate is about 77%. After operation the progression of FAP symptoms certainly stopped, and patients who were in an early stage of the disease and underwent successful operations showed considerable improvement in their quality of life. Electrophysiological study of peripheral nerve function has demonstrated that liver transplantation can halt the progression of peripheral neuropathy in FAP patients, and histopathological regression of amyloid deposits was seen on the patients with long post-transplatation courses. Pharmacological therapies have been considered for FAP patients and among them, diflunisal, one of non-steroidal antiinflammatory drugs, is very promising. TTR tetramer dissociation is an initial step for the process of TTR-derived amyloid fibril formation associated with FAP and diflinisal can inhibit this process by stabilization of the TTR tetramer. Clinical trial of this drug for FAP patients is now going worldwide.

Prevalence of Skin Lesions in Familial Adenomatous Polyposis: A Marker for Presymptomatic Diagnosis?

PubMed Central

Cattani, Nadja; Trueb, Swantje; de Lorenzo, Rosaria; Albertini, Mauro; Bontognali, Emanuele; Itin, Christoph; Schaub, Nathalie; Itin, Peter H.

2011-01-01

Background and Aims. Benign skin tumors such as lipomas, fibromas, and epidermal cysts are among the extracolonic manifestations of familial adenomatous polyposis (FAP). Readily detectable by inspection, they could serve as presymptomatic diagnostic markers to identify FAP patients. We therefore prospectively determined the prevalence of cutaneous lesions in genetically confirmed adenomatous polyposis coli (APC) mutation carriers and assessed their potential usefulness in the identification of FAP patients. Methods. Whole-skin examination was performed in 56 adult APC mutation carriers, compared with a control group (n = 116). In addition, FAP patients were investigated for the presence of congenital hypertrophy of the retinal pigment epithelium (CHRPE), an established clinical marker for FAP, and a detailed review of medical records was performed. Results. Nearly half of all FAP patients (48.2%) had at least one FAP-associated skin lesion, compared with one third (34.5%) of controls. Only multiple lipomas and combined skin lesions were significantly more prevalent in APC mutation carriers. CHRPE was observed in 22 (43.1%) of 51 FAP patients, including 14 (37.8%) of 37 individuals with APC mutations outside the CHRPE-associated region between codons 311 and 1465. Conclusions. Despite a significantly higher prevalence of multiple lipomas, occurring at younger age, and combined skin lesions in APC mutation carriers, the low diagnostic sensitivity of FAP-associated skin lesions precludes their use as markers for FAP in clinical practice. Based on our findings, the common CHRPE-associated region should be extended to APC codons 148-2043. PMID:22135120

Comparison of sporadic and FAP-associated desmoid-type fibromatoses.

PubMed

Koskenvuo, Laura; Ristimäki, Ari; Lepistö, Anna

2017-11-01

Desmoid-type fibromatosis is a rare disease of which 7.5-16% have been reported to be related to familial adenomatous polyposis (FAP). We sought to compare the characteristics and treatment of sporadic and FAP-related desmoid-type fibromatoses. Altogether 220 patients were included in the study after receiving a diagnosis of desmoid-type fibromatosis by the Pathology Department of Helsinki University Hospital, with adequate follow-up. Patients were included from January 1, 1980 until April 30, 2015. FAP-related tumors were found in 22 (10%) patients. FAP-related desmoid-type fibromatoses were larger, more commonly multiple, and more often intra-abdominally situated. Surgery was the treatment of choice for 179 (90%) of the sporadic patients and for 18 (82%) of FAP-related patients. Resections with non-involved margins (R0) were more common in sporadic desmoid-type fibromatoses (55% vs. 23%, P = 0.048). The risk of recurrence was 25% in sporadic- and 44% in the FAP-related group. Three (14%) patients with FAP-related desmoid-type fibromatoses died from the disease. The predictors for FAP occurrence among desmoid tumor patients are large tumor size, intra-abdominal location, multiple tumors, and patient's young age. Desmoid-type fibromatosis patients suffer a high recurrence rate, also among those experiencing sporadic tumors, but the risk of death due to the tumor is low. Conversely, desmoid disease represents a substantial cause of death among FAP patients. © 2017 Wiley Periodicals, Inc.

Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice.

PubMed

Duperret, Elizabeth K; Trautz, Aspen; Ammons, Dylan; Perales-Puchalt, Alfredo; Wise, Megan C; Yan, Jian; Reed, Charles; Weiner, David B

2018-03-01

Purpose: Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts and is an interesting target for cancer immune therapy, with prior studies indicating a potential to affect the tumor stroma. Our aim was to extend this earlier work through the development of a novel FAP immunogen with improved capacity to break tolerance for use in combination with tumor antigen vaccines. Experimental Design: We used a synthetic consensus (SynCon) sequence approach to provide MHC class II help to support breaking of tolerance. We evaluated immune responses and antitumor activity of this novel FAP vaccine in preclinical studies, and correlated these findings to patient data. Results: This SynCon FAP DNA vaccine was capable of breaking tolerance and inducing both CD8 + and CD4 + immune responses. In genetically diverse, outbred mice, the SynCon FAP DNA vaccine was superior at breaking tolerance compared with a native mouse FAP immunogen. In several tumor models, the SynCon FAP DNA vaccine synergized with other tumor antigen-specific DNA vaccines to enhance antitumor immunity. Evaluation of the tumor microenvironment showed increased CD8 + T-cell infiltration and a decreased macrophage infiltration driven by FAP immunization. We extended this to patient data from The Cancer Genome Atlas, where we find high FAP expression correlates with high macrophage and low CD8 + T-cell infiltration. Conclusions: These results suggest that immune therapy targeting tumor antigens in combination with a microconsensus FAP vaccine provides two-fisted punch-inducing responses that target both the tumor microenvironment and tumor cells directly. Clin Cancer Res; 24(5); 1190-201. ©2018 AACR . ©2018 American Association for Cancer Research.

Congenital Hypertrophy of Retinal Pigment Epithelium for Diagnosis of Familial Adenomatous Polyposis - the First FAP registry in Iran

PubMed

Mirinezhad, Seyed Kazem; Mousavi, Farideh; Baghri, Masood; Sepehri, Bita; Ghavidel, Ali; Ghojazadeh, Morteza; Somi, Mohammad Hossein

2018-01-27

Objective: Familial adenomatous polyposis (FAP), an autosomal dominant inherited disorder is characterized by the presence of multiple adenomatous colorectal polyps, which can develop into cancer during early adulthood. Therefore, early diagnosis is essential. Most FAP patients have several extracolonic manifestations, including congenital hypertrophy of the retinal pigment epithelium (CHRPE). Whereas genetic markers may provide the main route to detection of ‘‘at risk’’ subjects , at present this approach is clearly limited and searches for a noninvasive phenotypic marker continue to be high priority.The aim of this study was to describe the pattern of distribution of CHRPE lesions and evaluate their diagnostic value in FAP patients and their family members in a local population. Methods: A total of 23 FAP patients and 26 relatives belonging to 12 families at high risk of developing FAP were subjected to colonoscopic and ophthalmological examination. Result: Retinal examinations demonstrated prevalences of CHRPE in FAP patents and their siblings of 78% and 38%, respectively. We were able to illustrate a significant correlation between FAP disease and the presence of retinal lesions. Sensitivity and specificity of CHRPE as a screening test to detect the presence of FAP are 78.3% and 61.5%, respectively, with a positive predictive value of 64.3% and a negative predictive value of 76.2 %. A “lesion form” significant difference was found between FAP and normal participants.Spearman nonparametric analysis revealed no correlation between age and number or size of lesions. Conclusion: Multiple CHRPE lesions are a diagnostic feature of FAP patients They are specific and sensitive clinical markers of this disease (specificity 60% and sensitivity 77%). Creative Commons Attribution License

Clinical features of familial adenomas polyps in Chinese and establishment of its immortal lymphocyte cell lines.

PubMed

Cai, Shan-Rong; Zhang, Su-Zhang; Zheng, Shu

2007-05-28

To reserve the rare Chinese familial adenomas polyp (FAP) family resource and to investigate the clinical features of FAP in Chinese for its diagnosis. Clinical features of patients with FAP were investigated. If there is any question, their medical records were verified. Blood sample was taken and lymphocyte immortal cell lines were established with modified EB-transformation methods. Congenital hypertrophy of retinal pigment epithelium (CHRPE) was checked by an experienced ophthalmologist. Twenty seven families including 21 classical FAP (CFAP) families, 3 attenuated FAP (AFAP) families, and 3 suspected AFAP families were investigated. A total of 116 lymphocyte immortal cell lines were established from 26 families. In all the FAP families, colorectal cancer occurred at the mean age of 42.84 years. Of the 16 families checked, 15 (93.75%) had CHRPE. The mean number of patients suffering from colorectal neoplasm was 3.14 in CFAP families and 2.0 in AFAP families (P<0.01). The mean oldest age at diagnosis of FAP was 41.75 years in CFAP families, and 58.67 years in AFAP families, respectively (P<0.01). Mean age of development of colorectal cancer was 42.23 in CFAP and 57.33 years old in AFAP (P<0.01). Mean of the earliest age at diagnosis of FAP was 29.95 years in the FAP families with a positive family history and 46.80 years in the FAP families with a negative family history (P < 0.01). The ratio of extra-intestinal tumors to colorectal neoplasms was different in the two kinds of families with positive and negative family history (P<0.01). Additional use of ciclosporin will effectively improve to establish lymphocyte immortal cell lines with modified EB- transformation methods. In Chinese FAP, there was a high frequency of CHRPE , and a later age at diagnosis and a later age of development of colorectal cancer in AFAP. And earlier age at diagnosis in FAP with positive family history was also found that will help to diagnose various kinds of FAP in Chinese.

FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells.

PubMed

Lee, Hyung-Ok; Mullins, Stefanie R; Franco-Barraza, Janusz; Valianou, Matthildi; Cukierman, Edna; Cheng, Jonathan D

2011-06-13

Alterations towards a permissive stromal microenvironment provide important cues for tumor growth, invasion, and metastasis. In this study, Fibroblast activation protein (FAP), a serine protease selectively produced by tumor-associated fibroblasts in over 90% of epithelial tumors, was used as a platform for studying tumor-stromal interactions. We tested the hypothesis that FAP enzymatic activity locally modifies stromal ECM (extracellular matrix) components thus facilitating the formation of a permissive microenvironment promoting tumor invasion in human pancreatic cancer. We generated a tetracycline-inducible FAP overexpressing fibroblastic cell line to synthesize an in vivo-like 3-dimensional (3D) matrix system which was utilized as a stromal landscape for studying matrix-induced cancer cell behaviors. A FAP-dependent topographical and compositional alteration of the ECM was characterized by measuring the relative orientation angles of fibronectin fibers and by Western blot analyses. The role of FAP in the matrix-induced permissive tumor behavior was assessed in Panc-1 cells in assorted matrices by time-lapse acquisition assays. Also, FAP+ matrix-induced regulatory molecules in cancer cells were determined by Western blot analyses. We observed that FAP remodels the ECM through modulating protein levels, as well as through increasing levels of fibronectin and collagen fiber organization. FAP-dependent architectural/compositional alterations of the ECM promote tumor invasion along characteristic parallel fiber orientations, as demonstrated by enhanced directionality and velocity of pancreatic cancer cells on FAP+ matrices. This phenotype can be reversed by inhibition of FAP enzymatic activity during matrix production resulting in the disorganization of the ECM and impeded tumor invasion. We also report that the FAP+ matrix-induced tumor invasion phenotype is β1-integrin/FAK mediated. Cancer cell invasiveness can be affected by alterations in the tumor microenvironment. Disruption of FAP activity and β1-integrins may abrogate the invasive capabilities of pancreatic and other tumors by disrupting the FAP-directed organization of stromal ECM and blocking β1-integrin dependent cell-matrix interactions. This provides a novel preclinical rationale for therapeutics aimed at interfering with the architectural organization of tumor-associated ECM. Better understanding of the stromal influences that fuel progressive tumorigenic behaviors may allow the effective future use of targeted therapeutics aimed at disrupting specific tumor-stromal interactions. © 2011 Lee et al; licensee BioMed Central Ltd.

FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells

PubMed Central

2011-01-01

Background Alterations towards a permissive stromal microenvironment provide important cues for tumor growth, invasion, and metastasis. In this study, Fibroblast activation protein (FAP), a serine protease selectively produced by tumor-associated fibroblasts in over 90% of epithelial tumors, was used as a platform for studying tumor-stromal interactions. We tested the hypothesis that FAP enzymatic activity locally modifies stromal ECM (extracellular matrix) components thus facilitating the formation of a permissive microenvironment promoting tumor invasion in human pancreatic cancer. Methods We generated a tetracycline-inducible FAP overexpressing fibroblastic cell line to synthesize an in vivo-like 3-dimensional (3D) matrix system which was utilized as a stromal landscape for studying matrix-induced cancer cell behaviors. A FAP-dependent topographical and compositional alteration of the ECM was characterized by measuring the relative orientation angles of fibronectin fibers and by Western blot analyses. The role of FAP in the matrix-induced permissive tumor behavior was assessed in Panc-1 cells in assorted matrices by time-lapse acquisition assays. Also, FAP+ matrix-induced regulatory molecules in cancer cells were determined by Western blot analyses. Results We observed that FAP remodels the ECM through modulating protein levels, as well as through increasing levels of fibronectin and collagen fiber organization. FAP-dependent architectural/compositional alterations of the ECM promote tumor invasion along characteristic parallel fiber orientations, as demonstrated by enhanced directionality and velocity of pancreatic cancer cells on FAP+ matrices. This phenotype can be reversed by inhibition of FAP enzymatic activity during matrix production resulting in the disorganization of the ECM and impeded tumor invasion. We also report that the FAP+ matrix-induced tumor invasion phenotype is β1-integrin/FAK mediated. Conclusion Cancer cell invasiveness can be affected by alterations in the tumor microenvironment. Disruption of FAP activity and β1-integrins may abrogate the invasive capabilities of pancreatic and other tumors by disrupting the FAP-directed organization of stromal ECM and blocking β1-integrin dependent cell-matrix interactions. This provides a novel preclinical rationale for therapeutics aimed at interfering with the architectural organization of tumor-associated ECM. Better understanding of the stromal influences that fuel progressive tumorigenic behaviors may allow the effective future use of targeted therapeutics aimed at disrupting specific tumor-stromal interactions. PMID:21668992

Functional Analytic Psychotherapy (FAP) in Ibero-America: Review of Current Status and Some Proposals

ERIC Educational Resources Information Center

Munoz-Martinez, Amanda; Novoa-Gomez, Monica; Gutierrez, Rochy Vargas

2012-01-01

Functional Analytic Psychotherapy (FAP) has been making an important rise in Ibero-America in recent years. This paper presents a review of different contributions, problems and some proposals. Three principal topics are reviewed: (a) general characteristics and theoretical bases of FAP, (b) the uses of FAP and its relationship with other…

The role of illness perceptions in adherence to surveillance in patients with familial adenomatous polyposis (FAP).

PubMed

Eriksson, Lars E; Fritzell, Kaisa; Rixon, Lorna; Björk, Jan; Wettergren, Lena

2016-06-01

The aim of the study was to examine patients' beliefs about having familial adenomatous polyposis (FAP), a hereditary colorectal cancer syndrome, and how these beliefs are associated with adherence to endoscopic surveillance. Adult patients diagnosed with FAP on the national Swedish polyposis register who had undergone prophylactic colorectal surgery (n 209, response rate 76%) completed the Illness Perception Questionnaire (IPQ). Logistic regression analysis was used to investigate the relationships between illness perceptions and adherence, when controlling for demographic and clinical factors. FAP was less distressing in men and those with fewer symptoms, reporting less serious consequences and more coherent understanding of FAP. Non-adherence (14%) to surveillance was associated with being older, having undergone surgery less recently and no history of malignancy. Patients' beliefs about their FAP were able to explain unique variance in non-adherence, in particular those who believed FAP was less distressing. Patients who were non-adherent to endoscopic surveillance had more positive perceptions about their FAP and, in particular, were less emotionally affected compared to those who adhered. As non-adherence implies a greater risk of future malignancies, special efforts are required to effectively prevent cancer in all patients with FAP. Those who have lived with the condition for a long time, and are not troubled by gastrointestinal symptoms or worried about their FAP, may be in need of specific information and support. Further prospective research is required to examine emotional predictors and consequences of non-adherence. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Predictive values of FAP and HGF for tumor angiogenesis and metastasis in colorectal cancer.

PubMed

Ma, T H; Gao, C C; Xie, R; Yang, X Z; Dai, W J; Zhang, J L; Yan, W; Wu, S N

2017-01-01

This study aims to explore the correlation of hepatocyte growth factor (HGF) and fibroblast activation protein (FAP) expressions with the angiogenesis and metastasis in colorectal cancer (CRC). The immunohistochemical SABC method was used to detect HGF and FAP expressions in 127 CRC tissues, 51 colorectal polyp tissues and 28 normal tissues. HGF and FAP expressions in liver metastasis were detected using western blot to analyze the correlation of their expressions with lymph node metastasis and liver metastasis. Micro-vessel density (MVD) and clinic-pathologic information of CRC patients were recorded and analyzed. In CRC group, HGF and FAP expressions were greatly higher than those in normal group and colorectal polyps group (P < 0.05). Moreover, the positive rates of HGF and FAP expressions in lymph node metastasis were evidently higher than those in non-lymph node metastasis (P < 0.05). In liver metastasis group, HGF and FAP expressions were obviously higher than non-liver metastasis group (P < 0.05). CRC group had much more MVD in comparison with normal group and colorectal polyps group (P < 0.05).When compared with negative group, MVD was significantly higher than that in CRC tissue with positive HGF and FAP (P < 0.05). Spearman rank correlation analysis showed that HGF and FAP were in positive correlation with MVD (r = 0.542, P < 0.001; r = 0.753, P < 0.001). These results indicate that FAP and HGF play an important role in CRC angiogenesis, and their expression levels are valuable to predict CRC liver metastasis and lymph node metastasis.

Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity Without Severe Toxicity

PubMed Central

Wang, Liang-Chuan S; Lo, Albert; Scholler, John; Sun, Jing; Majumdar, Rajrupa S; Kapoor, Veena; Antzis, Michael; Cotner, Cody E.; Johnson, Laura A; Durham, Amy C; Solomides, Charalambos C.; June, Carl H; Puré, Ellen; Albelda, Steven M

2013-01-01

The majority of chimeric antigen receptor (CAR) T cell research has focused on attacking cancer cells. Here we show that targeting the tumor-promoting, non-transformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single chain Fv FAP (mAb 73.3) with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFNγ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAPhi stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8+ T cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective suggesting that further clinical development of anti-human FAP-CAR is warranted. PMID:24778279

Targeting Inhibition of Fibroblast Activation Protein-α and Prolyl Oligopeptidase Activities on Cells Common to Metastatic Tumor Microenvironments1

PubMed Central

Christiansen, Victoria J; Jackson, Kenneth W; Lee, Kyung N; Downs, Tamyra D; McKee, Patrick A

2013-01-01

Fibroblast activation protein (FAP), a membrane prolyl-specific proteinase with both dipeptidase and endopeptidase activities, is overexpressed by reactive stromal fibroblasts during epithelial-derived cancer growth. FAP digests extracellular matrix as tissue is remodeled during cancer expansion and may also promote an immunotolerant tumor microenvironment. Recent studies suggest that nonspecific FAP inhibitors suppress human cancer xenografts in mouse models. Prolyl oligopeptidase (POP), another prolyl-specific serine proteinase, is also elevated in many cancers and may have a regulatory role in angiogenesis promotion. FAP and POP cell-associated activities may be targets for diagnosis and treatment of various cancers, but their accessibilities to highly effective specific inhibitors have not been shown for cells important to cancer growth. Despite their frequent simultaneous expression in many cancers and their overlapping activities toward commonly used substrates, precise, separate measurement of FAP or POP activity has largely been ignored. To distinguish each of the two activities, we synthesized highly specific substrates and inhibitors for FAP or POP based on amino acid sequences surrounding the scissile bonds of their respective putative substrates. We found varying amounts of FAP and POP protein and activities on activated fibroblasts, mesenchymal cells, normal breast cells, and one breast cancer cell line, with some cells exhibiting more POP than FAP activity. Replicating endothelial cells (ECs) expressed POP but not FAP until tubulogenesis began. Targeting FAP-positive cells, especially mesenchymal stem cells and cancer-associated fibroblasts for inactivation or destruction, and inhibiting POP-producing EC may abrogate stromal invasion and angiogenesis simultaneously and thereby diminish cancer growth. PMID:23555181

Our experience of treatment of cribriform morular variant of papillary thyroid carcinoma; difference in clinicopathological features of FAP-associated and sporadic patients.

PubMed

Ito, Yasuhiro; Miyauchi, Akira; Ishikawa, Hideki; Hirokawa, Mitsuhiro; Kudo, Takumi; Tomoda, Chisato; Miya, Akihiro

2011-01-01

Cribriform-morular variant (CMV) is a comparably rare histological subtype of papillary thyroid carcinoma (PTC). This can be associated with familial adenomatous polyposis (FAP) due to APC gene mutations. In this study, we investigated the difference in the biological characteristics between FAP-associated and sporadic CMV. Between 1991 and 2010, 32 patients with CMV were treated in Kuma Hospital. Thirty-one of these underwent initial surgery for CMV in Kuma Hospital. Twelve patients were FAP-associated and the remaining 19 were sporadic CMV. All patients were female. Tumors of FAP-associated CMV were more frequently multiple than those of sporadic CMV. Patient age and tumor size did not differ between the two groups. Of 12 FAP-associated CMV, 5 were detected by thyroid nodule (thyroid precedent group) and 7 were detected by FAP (polyposis precedent group) as an initial manifestation. Patient age was younger and tumor size was smaller in the polyposis group than in the thyroid nodule group. All patients lacked extrathyroid extension on intraoperative finding and were node-negative on pathological examination. To date, two patients with FAP-associated CMV who initially underwent hemithyroidectomy (one in Kuma Hospital and one in another hospital) showed recurrence to the remnant thyroid during follow-up. None of the patients showed recurrence to other regions or died of carcinoma. Taken together, CMV is considered an indolent disease in our series. FAP-associated CMV showed multiple tumors more frequently than sporadic CMV. Total thyroidectomy is recommended for FAP-associated CMV, but extensive lymph node dissection is not necessary.

Psychiatric disorders and family functioning in children and adolescents with functional abdominal pain syndrome.

PubMed

Ghanizadeh, Ahmad; Moaiedy, Farah; Imanieh, Mohammad Hadi; Askani, Hamid; Haghighat, Mahmood; Dehbozorgi, Gholamreza; Dehghani, Seyed Mohsen

2008-07-01

Functional abdominal pain syndrome (FAPS) is a functional gastrointestinal disorder. There is a heightened risk when conducting potentially dangerous and unnecessary medical investigations and procedures in children with FAPS. The aim of this study was to survey the rate of the psychiatric disorders and family functioning in children and adolescents with FAPS. The subjects were a consecutive new sample of 45 children and adolescents with FAPS, 45 with an organic abdominal pain, and 45 pain-free comparison subjects aged 5-18 years that were interviewed using the Farsi version of K-SADS. Family functioning and the severity of pain were also studied. About 51.1% of patients with FAPS suffered from at least one psychiatric disorder. Psychiatric disorders in the FAPS patients studied included general anxiety disorder (8.9%), obsessive-compulsive disorder (11.1%), attention deficit hyperactivity disorder (15.6%), separation anxiety disorder (24.4%), and major depressive disorder (15.6%). Except for generalized anxiety disorder and tic disorder, the other disorders were significantly more common in the FAPS group than in the two other control groups. Family functioning scores were not significantly different between groups. There is a high rate of psychiatric disorders in children and adolescents with FAPS in Iran, but our study found fewer incidences of disorders than previous reports have indicated. Family dysfunction difficulties in FAPS children are not more common than those in the control groups.

Fibronectin Attachment Protein (FAP) From Bacillus Calmette-Guerin As Targeting Agent For Bladder Tumor Cells

PubMed Central

Coon, Brian G.; Crist, Scott; González-Bonet, Andrés M.; Kim, Hee-Kwon; Sowa, Jennifer; Thompson, David H.; Ratliff, Timothy L.; Aguilar, R. Claudio

2011-01-01

The adjuvant therapy of choice for superficial bladder cancer is the intravesical instillation of live Mycobacterium bovis Bacillus Calmette-Guerin (BCG). In spite of the fact that this therapy is the most effective treatment for superficial bladder cancer, intravesical administration of BCG is associated with high local morbidity and the potential for systemic infection. Therefore, there is a need for the development of safer, less toxic approaches to fight this disease. Since fibronectin attachment protein (FAP) is a key element in BCG retention and targeting to cells, we hypothesize that this protein can be used as targeting agent to deliver cytotoxic cargo for the treatment of bladder tumors. Here we evaluated the ability of bladder tumor cells to bind and endocytose FAP via fibronectin-integrin complexes. We found that microaggregation induced by an anti-FAP polyclonal antibody accelerated FAP uptake by T24 bladder tumor cells. FAP was determined to be internalized via a clathrin-independent, caveolae-dependent mechanism. Further, once within the endosomal compartment, FAP was targeted to the lysosomal compartment with negligible recycling to the plasma membrane. Importantly, we demonstrated that FAP microaggregation and internalization could also be triggered by multivalent Ni2+NTA-bearing liposomes. Overall, our studies validate the use of FAP as a targeting vector and provide the foundation for the design of more effective, less toxic bladder cancer therapeutics. PMID:21901746

Cleavage-site specificity of prolyl endopeptidase FAP investigated with a full-length protein substrate.

PubMed

Huang, Chih-Hsiang; Suen, Ching-Shu; Lin, Ching-Ting; Chien, Chia-Hui; Lee, Hsin-Ying; Chung, Kuei-Min; Tsai, Ting-Yueh; Jiaang, Weir-Tong; Hwang, Ming-Jing; Chen, Xin

2011-06-01

Fibroblast activation protein (FAP) is a prolyl-cleaving endopeptidase proposed as an anti-cancer drug target. It is necessary to define its cleavage-site specificity to facilitate the identification of its in vivo substrates and to understand its biological functions. We found that the previously identified substrate of FAP, α(2)-anti-plasmin, is not a robust substrate in vitro. Instead, an intracellular protein, SPRY2, is cleavable by FAP and more suitable for investigation of its substrate specificity in the context of the full-length globular protein. FAP prefers uncharged residues, including small or bulky hydrophobic amino acids, but not charged amino acids, especially acidic residue at P1', P3 and P4 sites. Molecular modelling analysis shows that the substrate-binding site of FAP is surrounded by multiple tyrosine residues and some negatively charged residues, which may exert least preference for substrates with acidic residues. This provides an explanation why FAP cannot cleave interleukins, which have a glutamate at either P4 or P2', despite their P3-P2-P1 sites being identical to SPRY2 or α-AP. Our study provided new information on FAP cleavage-site specificity, which differs from the data obtained by profiling with a peptide library or with the denatured protein, gelatin, as the substrate. Furthermore, our study suggests that negatively charged residues should be avoided when designing FAP inhibitors.

Gastrointestinal permeability (GIPerm) is increased in family members of children with functional abdominal pain (FAP) and irritable bowel syndrome (IBS)

USDA-ARS?s Scientific Manuscript database

Increased GIPerm has been described in children with FAP/IBS and adults with IBS. We sought to determine if baseline GIPerm is increased and if ibuprofen induces a greater increase in GIPerm in parents and siblings of children with FAP/IBS vs. control families without children with FAP/IBS. Site spe...

WD60/FAP163 is a dynein intermediate chain required for retrograde intraflagellar transport in cilia

PubMed Central

Patel-King, Ramila S.; Gilberti, Renée M.; Hom, Erik F. Y.; King, Stephen M.

2013-01-01

Retrograde intraflagellar transport (IFT) is required for assembly of cilia. We identify a Chlamydomonas flagellar protein (flagellar-associated protein 163 [FAP163]) as being closely related to the D1bIC(FAP133) intermediate chain (IC) of the dynein that powers this movement. Biochemical analysis revealed that FAP163 is present in the flagellar matrix and is actively trafficked by IFT. Furthermore, FAP163 copurified with D1bIC(FAP133) and the LC8 dynein light chain, indicating that it is an integral component of the retrograde IFT dynein. To assess the functional role of FAP163, we generated an RNA interference knockdown of the orthologous protein (WD60) in planaria. The Smed-wd60(RNAi) animals had a severe ciliary assembly defect that dramatically compromised whole-organism motility. Most cilia were present as short stubs that had accumulated large quantities of IFT particle–like material between the doublet microtubules and the membrane. The few remaining approximately full-length cilia had a chaotic beat with a frequency reduced from 24 to ∼10 Hz. Thus WD60/FAP163 is a dynein IC that is absolutely required for retrograde IFT and ciliary assembly. PMID:23864713

Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma

PubMed Central

Kakarla, Sunitha; Chow, Kevin KH; Mata, Melinda; Shaffer, Donald R; Song, Xiao-Tong; Wu, Meng-Fen; Liu, Hao; Wang, Lisa L; Rowley, David R; Pfizenmaier, Klaus; Gottschalk, Stephen

2013-01-01

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors. PMID:23732988

Focus on autonomic dysfunction in familial amyloidotic polyneuropathy (FAP).

PubMed

Obayashi, Konen; Ando, Yukio

2012-06-01

It is well known that autonomic dysfunction in familial amyloidotic polyneuropathy (FAP) is the most serious problem, because it restricts the daily life of these patients. The detail mechanisms of the onset are not well understood in FAP and domino liver transplantation-induced amyloid neuropathy. As autonomic disturbances play an important role in the symptomatology of FAP, further studies of autonomic dysfunction in these patients may lead the pathogenesis of FAP. Autonomic dysfunction is often observed before sensory and motor nerve dysfunction in FAP. This can be attributed to the morphological characteristics of the nerves. Unmyelinated, small myelinated, and large myelinated fibers tend to become impaired in that order. Although the reasons of susceptibility to amyloid infiltration and injury are not known, studies of autopsied FAP patients have revealed heavy infiltration of amyloid in autonomic ganglions. Moreover, spinal ganglion and posterior loot of the spine had severe amyloid deposits than did the anterior root of the spine or the motor nerves. It is well known that autonomic dysfunction is the most serious problem, because it restricts the daily life of FAP patients. However, we have four major questions about autonomic dysfunction in clinical. In this manuscript, we discuss about the answers of these questions.

Fibro/Adipogenic Progenitors (FAPs): Isolation by FACS and Culture.

PubMed

Low, Marcela; Eisner, Christine; Rossi, Fabio

2017-01-01

Fibro/adipogenic progenitors (FAPs ) are tissue-resident mesenchymal stromal cells (MSCs). Current literature supports a role for these cells in the homeostasis and repair of multiple tissues suggesting that FAPs may have extensive therapeutic potential in the treatment of numerous diseases. In this context, it is crucial to establish efficient and reproducible procedures to purify FAP populations from various tissues. Here, we describe a protocol for the isolation and cell culture of FAPs from murine skeletal muscle using fluorescence -activated cell sorting (FACS), which is particularly useful for experiments where high cell purity is an essential requirement. Identification, isolation, and cell culture of FAPs represent powerful tools that will help us to understand the role of these cells in different conditions and facilitate the development of safe and effective new treatments for diseases.

Eu/Tb codoped spindle-shaped fluorinated hydroxyapatite nanoparticles for dual-color cell imaging

NASA Astrophysics Data System (ADS)

Ma, Baojin; Zhang, Shan; Qiu, Jichuan; Li, Jianhua; Sang, Yuanhua; Xia, Haibing; Jiang, Huaidong; Claverie, Jerome; Liu, Hong

2016-06-01

Lanthanide doped fluorinated hydroxyapatite (FAp) nanoparticles are promising cell imaging nanomaterials but they are excited at wavelengths which do not match the light sources usually found in a commercial confocal laser scanning microscope (CLSM). In this work, we have successfully prepared spindle-shaped Eu/Tb codoped FAp nanoparticles by a hydrothermal method. Compared with single Eu doped FAp, Eu/Tb codoped FAp can be excited by a 488 nm laser, and exhibit both green and red light emission. By changing the amounts of Eu and Tb peaks, the emission in the green region (500-580 nm) can be decreased to the benefit of the emission in the red region (580-720 nm), thus reaching a balanced dual color emission. Using MC3T3-E1 cells co-cultured with Eu/Tb codoped FAp nanoparticles, it is observed that the nanoparticles are cytocompatible even at a concentration as high as 800 μg ml-1. The Eu/Tb codoped FAp nanoparticles are located in the cytoplasm and can be monitored by dual color--green and red imaging with a single excitation light at 488 nm. At a concentration of 200 μg ml-1, the cytoplasm is saturated in 8 hours, and Eu/Tb codoped FAp nanoparticles retain their fluorescence for at least 3 days. The cytocompatible Eu/Tb codoped FAp nanoparticles with unique dual color emission will be of great use for cell and tissue imaging.Lanthanide doped fluorinated hydroxyapatite (FAp) nanoparticles are promising cell imaging nanomaterials but they are excited at wavelengths which do not match the light sources usually found in a commercial confocal laser scanning microscope (CLSM). In this work, we have successfully prepared spindle-shaped Eu/Tb codoped FAp nanoparticles by a hydrothermal method. Compared with single Eu doped FAp, Eu/Tb codoped FAp can be excited by a 488 nm laser, and exhibit both green and red light emission. By changing the amounts of Eu and Tb peaks, the emission in the green region (500-580 nm) can be decreased to the benefit of the emission in the red region (580-720 nm), thus reaching a balanced dual color emission. Using MC3T3-E1 cells co-cultured with Eu/Tb codoped FAp nanoparticles, it is observed that the nanoparticles are cytocompatible even at a concentration as high as 800 μg ml-1. The Eu/Tb codoped FAp nanoparticles are located in the cytoplasm and can be monitored by dual color--green and red imaging with a single excitation light at 488 nm. At a concentration of 200 μg ml-1, the cytoplasm is saturated in 8 hours, and Eu/Tb codoped FAp nanoparticles retain their fluorescence for at least 3 days. The cytocompatible Eu/Tb codoped FAp nanoparticles with unique dual color emission will be of great use for cell and tissue imaging. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr02137a

7 CFR 1753.57 - Procedures.

Code of Federal Regulations, 2011 CFR

2011-01-01

... equipment needed for normal operation and maintenance. (2) [Reserved] (b) Force Account Proposal (FAP). Upon... the purchase of materials or equipment, shall submit to RUS two copies of its FAP. The FAP shall...

7 CFR 1753.57 - Procedures.

Code of Federal Regulations, 2013 CFR

2013-01-01

... equipment needed for normal operation and maintenance. (2) [Reserved] (b) Force Account Proposal (FAP). Upon... the purchase of materials or equipment, shall submit to RUS two copies of its FAP. The FAP shall...

7 CFR 1753.57 - Procedures.

Code of Federal Regulations, 2010 CFR

2010-01-01

... equipment needed for normal operation and maintenance. (2) [Reserved] (b) Force Account Proposal (FAP). Upon... the purchase of materials or equipment, shall submit to RUS two copies of its FAP. The FAP shall...

7 CFR 1753.57 - Procedures.

Code of Federal Regulations, 2012 CFR

2012-01-01

... equipment needed for normal operation and maintenance. (2) [Reserved] (b) Force Account Proposal (FAP). Upon... the purchase of materials or equipment, shall submit to RUS two copies of its FAP. The FAP shall...

7 CFR 1753.57 - Procedures.

Code of Federal Regulations, 2014 CFR

2014-01-01

... equipment needed for normal operation and maintenance. (2) [Reserved] (b) Force Account Proposal (FAP). Upon... the purchase of materials or equipment, shall submit to RUS two copies of its FAP. The FAP shall...

Mapping the low palmitate fap1 mutation and validation of its effects in soybean oil and agronomic traits in three soybean populations.

PubMed

Cardinal, Andrea J; Whetten, Rebecca; Wang, Sanbao; Auclair, Jérôme; Hyten, David; Cregan, Perry; Bachlava, Eleni; Gillman, Jason; Ramirez, Martha; Dewey, Ralph; Upchurch, Greg; Miranda, Lilian; Burton, Joseph W

2014-01-01

fap 1 mutation is caused by a G174A change in GmKASIIIA that disrupts a donor splice site recognition and creates a GATCTG motif that enhanced its expression. Soybean oil with reduced palmitic acid content is desirable to reduce the health risks associated with consumption of this fatty acid. The objectives of this study were: to identify the genomic location of the reduced palmitate fap1 mutation, determine its molecular basis, estimate the amount of phenotypic variation in fatty acid composition explained by this locus, determine if there are epistatic interactions between the fap1 and fap nc loci and, determine if the fap1 mutation has pleiotropic effects on seed yield, oil and protein content in three soybean populations. This study detected two major QTL for 16:0 content located in chromosome 5 (GmFATB1a, fap nc) and chromosome 9 near BARCSOYSSR_09_1707 that explained, with their interaction, 66-94 % of the variation in 16:0 content in the three populations. Sequencing results of a putative candidate gene, GmKASIIIA, revealed a single unique polymorphism in the germplasm line C1726, which was predicted to disrupt the donor splice site recognition between exon one and intron one and produce a truncated KASIIIA protein. This G to A change also created the GATCTG motif that enhanced gene expression of the mutated GmKASIIIA gene. Lines homozygous for the GmKASIIIA mutation (fap1) had a significant reduction in 16:0, 18:0, and oil content; and an increase in unsaturated fatty acids content. There were significant epistatic interactions between GmKASIIIA (fap1) and fap nc for 16:0 and oil contents, and seed yield in two populations. In conclusion, the fap1 phenotype is caused by a single unique SNP in the GmKASIIIA gene.

RG7386, a Novel Tetravalent FAP-DR5 Antibody, Effectively Triggers FAP-Dependent, Avidity-Driven DR5 Hyperclustering and Tumor Cell Apoptosis.

PubMed

Brünker, Peter; Wartha, Katharina; Friess, Thomas; Grau-Richards, Sandra; Waldhauer, Inja; Koller, Claudia Ferrara; Weiser, Barbara; Majety, Meher; Runza, Valeria; Niu, Huifeng; Packman, Kathryn; Feng, Ningping; Daouti, Sherif; Hosse, Ralf J; Mössner, Ekkehard; Weber, Thomas G; Herting, Frank; Scheuer, Werner; Sade, Hadassah; Shao, Cuiying; Liu, Bin; Wang, Peng; Xu, Gary; Vega-Harring, Suzana; Klein, Christian; Bosslet, Klaus; Umaña, Pablo

2016-05-01

Dysregulated cellular apoptosis and resistance to cell death are hallmarks of neoplastic initiation and disease progression. Therefore, the development of agents that overcome apoptosis dysregulation in tumor cells is an attractive therapeutic approach. Activation of the extrinsic apoptotic pathway is strongly dependent on death receptor (DR) hyperclustering on the cell surface. However, strategies to activate DR5 or DR4 through agonistic antibodies have had only limited clinical success. To pursue an alternative approach for tumor-targeted induction of apoptosis, we engineered a bispecific antibody (BsAb), which simultaneously targets fibroblast-activation protein (FAP) on cancer-associated fibroblasts in tumor stroma and DR5 on tumor cells. We hypothesized that bivalent binding to both FAP and DR5 leads to avidity-driven hyperclustering of DR5 and subsequently strong induction of apoptosis in tumor cells but not in normal cells. Here, we show that RG7386, an optimized FAP-DR5 BsAb, triggers potent tumor cell apoptosis in vitro and in vivo in preclinical tumor models with FAP-positive stroma. RG7386 antitumor efficacy was strictly FAP dependent, was independent of FcR cross-linking, and was superior to conventional DR5 antibodies. In combination with irinotecan or doxorubicin, FAP-DR5 treatment resulted in substantial tumor regression in patient-derived xenograft models. FAP-DR5 also demonstrated single-agent activity against FAP-expressing malignant cells, due to cross-binding of FAP and DR5 across tumor cells. Taken together, these data demonstrate that RG7386, a novel and potent antitumor agent in both mono- and combination therapies, overcomes limitations of previous DR5 antibodies and represents a promising approach to conquer tumor-associated resistance to apoptosis. Mol Cancer Ther; 15(5); 946-57. ©2016 AACR. ©2016 American Association for Cancer Research.

Mutation analysis of the APC gene in Taiwanese FAP families: low incidence of APC germline mutation in a distinct subgroup of FAP families.

PubMed

Chiang, J M; Chen, H W; Tang, R P; Chen, J S; Changchien, C R; Hsieh, P S; Wang, J Y

2010-06-01

Familial adenomatous polyposis (FAP) is an autosomal-dominant disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. The affected individuals develop colorectal polyposis and show various extra-colonic manifestations. In this study, we aimed to investigate the genetic and clinical characteristics of FAP in Taiwanese families and analyze the genotype-phenotype correlations. Blood samples were obtained from 66 FAP patients registered in the hereditary colorectal cancer database. Then, germline mutations in the APC genes of these 66 polyposis patients from 47 unrelated FAP families were analyzed. The germline-mutation-negative cases were analyzed by performing multiplex ligation-dependent probe amplification (MLPA) and single-strand conformation polymorphism (SSCP) analysis of the MUTYH gene. Among the analyzed families, 79% (37/47) of the families showed 28 APC mutations, including 19 frameshift mutations, 4 nonsense mutations, 3 genomic deletion mutations, 1 missense mutation, and 1 splice-site mutation. In addition, we identified 15 novel mutations in 32% (15/47) of the families. The cases in which APC mutations were not identified showed significantly lower incidence of profuse polyposis (P = 0.034) and gastroduodenal polyps (P = 0.027). Furthermore, FAP families in which some affected individuals had less than 100 polyps showed significant association with low incidence of APC germline mutations (P = 0.002). We have added the APC germline-mutation data for Taiwanese FAP patients and indicated the presence of an FAP subgroup comprising affected individuals with nonadenomatous polyps or less than 100 adenomatous polyps; this form of FAP is less frequently caused by germline mutations of the APC gene.

Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens

PubMed Central

Zhang, Jiping; Valianou, Matthildi; Simmons, Heidi; Robinson, Matthew K.; Lee, Hyung-Ok; Mullins, Stefanie R.; Marasco, Wayne A.; Adams, Gregory P.; Weiner, Louis M.; Cheng, Jonathan D.

2013-01-01

Fibroblast activation protein (FAP) is a serine protease selectively expressed on tumor stromal fibroblasts in epithelial carcinomas and is important in cancer growth, adhesion, and metastases. As FAP enzymatic activity is a potent therapeutic target, we aimed to identify inhibitory antibodies. Using a competitive inhibition strategy, we used phage display techniques to identify 53 single-chain variable fragments (scFvs) after three rounds of panning against FAP. These scFvs were expressed and characterized for binding to FAP by surface plasmon resonance and flow cytometry. Functional assessment of these antibodies yielded an inhibitory scFv antibody, named E3, which could attenuate 35% of FAP cleavage of the fluorescent substrate Ala-Pro-7-amido-4-trifluoromethylcoumarin compared with nonfunctional scFv control. Furthermore, a mutant E3 scFv was identified by yeast affinity maturation. It had higher affinity (4-fold) and enhanced inhibitory effect on FAP enzyme activity (3-fold) than E3. The application of both inhibitory anti-FAP scFvs significantly affected the formation of 3-dimensional FAP-positive cell matrix, as demonstrated by reducing the fibronectin fiber orientation from 41.18% (negative antibody control) to 34.06% (E3) and 36.15% (mutant E3), respectively. Thus, we have identified and affinity-maturated the first scFv antibody capable of inhibiting FAP function. This scFv antibody has the potential to disrupt the role of FAP in tumor invasion and metastasis.—Zhang, J., Valianou, M., Simmons, H., Robinson, M. K., Lee, H.-O., Mullins, S. R., Marasco, W. A., Adams, G. P., Weiner, L. M., Cheng, J. D. Identification of inhibitory ScFv antibodies targeting fibroblast activation protein utilizing phage display functional screens. PMID:23104982

A novel pathogenic splice acceptor site germline mutation in intron 14 of the APC gene in a Chinese family with familial adenomatous polyposis.

PubMed

Wang, Dan; Liang, Shengyun; Zhang, Zhao; Zhao, Guoru; Hu, Yuan; Liang, Shengran; Zhang, Xipeng; Banerjee, Santasree

2017-03-28

Familial adenomatous polyposis (FAP) is an autosomal dominant precancerous condition, clinically characterized by the presence of multiple colorectal adenomas or polyps. Patients with FAP has a high risk of developing colorectal cancer (CRC) from these colorectal adenomatous polyps by the mean age of diagnosis at 40 years. Germline mutations of the APC gene cause familial adenomatous polyposis (FAP). Colectomy has recommended for the FAP patients with significant polyposis. Here, we present a clinical molecular study of a four generation Chinese family with FAP. Clinical diagnosis of FAP has been done according to the phenotype, family history and medical records. Patient's blood samples were collected and genomic DNA was extracted. In order to identify the pathogenic mutation underlying the disease phenotype targeted next-generation sequencing and confirmatory sanger sequencing has undertaken. Targeted next generation sequencing identified a novel heterozygous splice-acceptor site mutation [c.1744-1G>A] in intron 14 of APC gene, which is co-segregated with the FAP phenotypes in the proband and amongst all the affected family members. This mutation is not present in unaffected family members and in normal healthy controls of same ethnic origin. According to the LOVD database for Chinese colorectal cancer patients, in Chinese population, 60% of the previously reported APC gene mutations causes FAP, are missense mutations. This novel splice-acceptor site mutation causing FAP in this Chinese family expands the germline mutation spectrum of the APC gene in the Chinese population.

Cleavage of Type I Collagen by Fibroblast Activation Protein-α Enhances Class A Scavenger Receptor Mediated Macrophage Adhesion

PubMed Central

Mazur, Anna; Holthoff, Emily; Vadali, Shanthi; Kelly, Thomas; Post, Steven R.

2016-01-01

Pathophysiological conditions such as fibrosis, inflammation, and tumor progression are associated with modification of the extracellular matrix (ECM). These modifications create ligands that differentially interact with cells to promote responses that drive pathological processes. Within the tumor stroma, fibroblasts are activated and increase the expression of type I collagen. In addition, activated fibroblasts specifically express fibroblast activation protein-α (FAP), a post-prolyl peptidase. Although FAP reportedly cleaves type I collagen and contributes to tumor progression, the specific pathophysiologic role of FAP is not clear. In this study, the possibility that FAP-mediated cleavage of type I collagen modulates macrophage interaction with collagen was examined using macrophage adhesion assays. Our results demonstrate that FAP selectively cleaves type I collagen resulting in increased macrophage adhesion. Increased macrophage adhesion to FAP-cleaved collagen was not affected by inhibiting integrin-mediated interactions, but was abolished in macrophages lacking the class A scavenger receptor (SR-A/CD204). Further, SR-A expressing macrophages localize with activated fibroblasts in breast tumors of MMTV-PyMT mice. Together, these results demonstrate that FAP-cleaved collagen is a substrate for SR-A-dependent macrophage adhesion, and suggest that by modifying the ECM, FAP plays a novel role in mediating communication between activated fibroblasts and macrophages. PMID:26934296

1059 and 1328nm LD pumped Nd:S-FAP solid state laser

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun Lianke; Zhang Shaojun; Zhao Shengzhi

In this paper the authors introduce a new laser crystal--Nd{sup 3+}:Sr{sub 5}(PO{sub 4}){sub 3}F, Nd:S-FAP, and present its optical and physical characteristics. Based on the experiment lasing performance of CW LD pumped Nd:S-FAP crystal is reported here: the threshold and slope efficiency of 1059 nm Nd:S-FAP laser pumped by CW LD at 805nm are 7mW and 41%, and that of 1328nm Nd:S-FAP laser are 19mW and 35%. The comparison between experimental result and theoretical calculation is also discussed in this paper.

UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins-TGF-β1-FAP-α.

PubMed

Wäster, Petra; Orfanidis, Kyriakos; Eriksson, Ida; Rosdahl, Inger; Seifert, Oliver; Öllinger, Karin

2017-08-08

Ultraviolet radiation (UVR) is the major risk factor for development of malignant melanoma. Fibroblast activation protein (FAP)-α is a serine protease expressed on the surface of activated fibroblasts, promoting tumour invasion through extracellular matrix (ECM) degradation. The signalling mechanism behind the upregulation of FAP-α is not yet completely revealed. Expression of FAP-α was analysed after UVR exposure in in vitro co-culture systems, gene expression arrays and artificial skin constructs. Cell migration and invasion was studied in relation to cathepsin activity and secretion of transforming growth factor (TGF)-β1. Fibroblast activation protein-α expression was induced by UVR in melanocytes of human skin. The FAP-α expression was regulated by UVR-induced release of TGF-β1 and cathepsin inhibitors prevented such secretion. In melanoma cell culture models and in a xenograft tumour model of zebrafish embryos, FAP-α mediated ECM degradation and facilitated tumour cell dissemination. Our results provide evidence for a sequential reaction axis from UVR via cathepsins, TGF-β1 and FAP-α expression, promoting cancer cell dissemination and melanoma metastatic spread.

Acylated Gly-(2-cyano)pyrrolidines as inhibitors of fibroblast activation protein (FAP) and the issue of FAP/prolyl oligopeptidase (PREP)-selectivity.

PubMed

Ryabtsova, Oxana; Jansen, Koen; Van Goethem, Sebastiaan; Joossens, Jurgen; Cheng, Jonathan D; Lambeir, Anne-Marie; De Meester, Ingrid; Augustyns, Koen; Van der Veken, Pieter

2012-05-15

A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure-activity relationship (SAR) data for this class of compounds as inhibitors of fibroblast activation protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery. Copyright © 2012 Elsevier Ltd. All rights reserved.

Detection of familial adenomatous polyposis with polarized spectroscopic imaging and oral vascular density

NASA Astrophysics Data System (ADS)

Basiri, Ali; Edelstein, Daniel L.; Giardiello, Francis M.; Ramella-Roman, J. C.

2011-03-01

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disease characterized by the development of multiple colonic polyps at younger age with a near 100% lifetime risk of colorectal cancer in later years. The determination of FAP is made after extensive clinical evaluation and genetic testing of at risk individuals. Genetic testing is expensive and in some cases deleterious mutations are not found in all patients with a clinical diagnosis of FAP. As such, the early identification of affected individuals could substantially eliminate associated morbidity and mortality. We investigated a novel spectro-polarimetric imaging system to capture images of the oral mucosa at different wavelengths in an attempt to distinguish patients with FAP from controls. Total diffused oral mucosal reflectance (OMR) and oral mucosal vascular density (OMVD) were calculated from spectral data collected from 33 patients with gene positive FAP, 5 patients who tested negative for FAP, and 45 controls. A statistically significant difference in OMVD (p < 0.001) was observed between individuals with FAP and controls. Analysis of OMR showed no significant difference between the two subject groups.

Plans for Assessing Contractor Performance for the Camp Lemonnier Base Operations Support Contract Needed Improvement

DTIC Science & Technology

2015-08-27

ensure the functional assessment plans ( FAP ) for the three services contained all contractor work requiring assessment, measurable performance...review the FAPs after development and revisions to the FAPs , and did not require additional controls over the contractor assessment process in an...revised as follows: • Business Management System B-14.3 was updated to require the contract officer representative conduct a FAP review to ensure

Impaired conditioned pain modulation in youth with functional abdominal pain

PubMed Central

Morris, Matthew C.; Walker, Lynn S.; Bruehl, Stephen; Stone, Amanda L.; Mielock, Alyssa S.; Rao, Uma

2016-01-01

Functional abdominal pain (FAP) is associated with enhanced pain responsiveness. Although impaired conditioned pain modulation (CPM) characterizes adults with a variety of chronic pain conditions, relatively little is known about CPM in youth with FAP. The present study assessed CPM to evoked thermal pain in 140 youth (ages 10 to 17), 63 of whom had FAP and 77 of whom were healthy controls. Multilevel models demonstrated weaker CPM effects in FAP than healthy youth, as evident in slower within-person decreases in pain ratings during the conditioning phase. Weaker CPM effects were associated with greater somatic symptom severity and functional disability. Pain responses in FAP youth were heterogeneous, with 43% of youth showing an unexpected increase in pain ratings during the conditioning phase, suggesting sensitization rather than CPM-related pain inhibition. These findings highlight directions for future research on the emergence and maintenance of FAP in youth. PMID:27389918

Impaired conditioned pain modulation in youth with functional abdominal pain.

PubMed

Morris, Matthew C; Walker, Lynn S; Bruehl, Stephen; Stone, Amanda L; Mielock, Alyssa S; Rao, Uma

2016-10-01

Functional abdominal pain (FAP) is associated with enhanced pain responsiveness. Although impaired conditioned pain modulation (CPM) characterizes adults with a variety of chronic pain conditions, relatively little is known about CPM in youth with FAP. This study assessed CPM to evoked thermal pain in 140 youth (ages 10-17), 63 of whom had FAP and 77 of whom were healthy controls. Multilevel models demonstrated weaker CPM effects in youth with FAP than in healthy youth, as evident in slower within-person decreases in pain ratings during the conditioning phase. Weaker CPM effects were associated with greater somatic symptom severity and functional disability. Pain responses in youth with FAP were heterogeneous, with 43% of youth showing an unexpected increase in pain ratings during the conditioning phase, suggesting sensitization rather than CPM-related pain inhibition. These findings highlight directions for future research on the emergence and maintenance of FAP in youth.

Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy.

PubMed

Hamson, Elizabeth J; Keane, Fiona M; Tholen, Stefan; Schilling, Oliver; Gorrell, Mark D

2014-06-01

Fibroblast activation protein (FAP) is best known for its heightened expression in tumour stroma. This atypical serine protease has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. FAP expression is difficult to detect in non-diseased adult organs, but is greatly upregulated in sites of tissue remodelling, which include liver fibrosis, lung fibrosis, atherosclerosis, arthritis, tumours and embryonic tissues. Due to its restricted expression pattern and dual enzymatic activities, FAP is emerging as a unique therapeutic target. However, methods to exploit and target this protease are advancing more rapidly than knowledge of the fundamental biology of FAP. This review highlights this imbalance, emphasising the need to better define the substrate repertoire and expression patterns of FAP to elucidate its role in biological and pathological processes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of a Community College's Nursing Faculty Advising Program Relative to Students' Satisfaction and Retention

ERIC Educational Resources Information Center

Harrell, Johnna C.; Reglin, Gary

2018-01-01

Problem was the community college recognized a decline in student retention rates from 2009 to 2012 in the School of Nursing. Purpose of this program evaluation was to evaluate a faculty advising program (FAP) in the School of Nursing at a community college in regard to students' satisfaction and retention. Evaluation period was from Fall 2012 to…

Attitudes toward genetic testing in childhood and reproductive decision-making for familial adenomatous polyposis.

PubMed

Douma, Kirsten F L; Aaronson, Neil K; Vasen, Hans F A; Verhoef, Senno; Gundy, Chad M; Bleiker, Eveline M A

2010-02-01

Childhood DNA testing, prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD) are available for familial adenomatous polyposis (FAP). However, the use of PND and PGD is controversial. The purpose of this study was to investigate attitudes toward, and experiences with, childhood DNA testing, PND and PGD among members of families at high risk for FAP. In this nationwide, cross-sectional study, questionnaires were sent to individuals from families at high risk for FAP assessing attitudes toward and experiences with childhood testing, PND and PGD, as well as several sociodemographic, clinical and psychosocial variables. Of the individuals from FAP families invited to participate in the study, 525 members participated (response rate=64%). Most parents who had children who were minors (n=93) (82%) were satisfied with the DNA testing procedure. One-third of all individuals wanted DNA testing for their children before age 12. Forty percent of FAP patients indicated that the disease influenced their desire to have children. Only 15% considered termination of pregnancy for FAP acceptable. Approximately 30% of individuals with a FAP diagnosis and their partners considered PND and PGD as acceptable for themselves. A positive attitude was associated with higher levels of guilt and a positive attitude toward termination of pregnancy. Importantly, of those with FAP at childbearing age, 84% had had no previous information at all about either PND or PGD. Future efforts should be aimed at educating FAP family members about reproductive options, allowing them to make an informed choice about family planning. Routine discussion of all reproductive options with a medical specialist should be encouraged.

Functional abdominal pain in childhood and long-term vulnerability to anxiety disorders.

PubMed

Shelby, Grace D; Shirkey, Kezia C; Sherman, Amanda L; Beck, Joy E; Haman, Kirsten; Shears, Angela R; Horst, Sara N; Smith, Craig A; Garber, Judy; Walker, Lynn S

2013-09-01

Cross-sectional studies link functional abdominal pain (FAP) to anxiety and depression in childhood, but no prospective study has evaluated psychiatric status in adulthood or its relation to pain persistence. Pediatric patients with FAP (n = 332) and control subjects (n = 147) were tracked prospectively and evaluated for psychiatric disorders and functional gastrointestinal disorders (FGIDs) at follow-up in adolescence and young adulthood (mean age = 20.01 years). Participants were classified according to presence (FGID-POS) or absence (FGID-NEG) of FGIDs at follow-up. Lifetime and current risk of anxiety disorders was higher in FAP than controls (lifetime: 51% vs 20%; current: 30% vs 12%). Controlling for gender and age, the odds ratio was 4.9 (confidence interval = 2.83-7.43) for lifetime anxiety disorder and 3.57 (confidence interval = 2.00-6.36) for current anxiety disorder at follow-up for FAP versus controls. Lifetime risk of depressive disorder was significantly higher in FAP versus controls (40% vs. 16%); current risk did not differ. In most cases, initial onset of anxiety disorders was before pediatric FAP evaluation; onset of depressive disorders was subsequent to FAP evaluation. Within the FAP group, risk of current anxiety disorders at follow-up was significantly higher for FGID-POS versus FGID-NEG (40% vs 24%), and both were higher than controls (12%); current depressive disorders did not differ across FGID-POS, FGID-NEG, and controls. Patients with FAP carry long-term vulnerability to anxiety that begins in childhood and persists into late adolescence and early adulthood, even if abdominal pain resolves.

Transthyretin amyloid polyneuropathies mimicking a demyelinating polyneuropathy.

PubMed

Lozeron, Pierre; Mariani, Louise-Laure; Dodet, Pauline; Beaudonnet, Guillemette; Théaudin, Marie; Adam, Clovis; Arnulf, Bertrand; Adams, David

2018-06-15

To clearly define transthyretin familial amyloid polyneuropathies (TTR-FAPs) fulfilling definite clinical and electrophysiologic European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). From a cohort of 194 patients with FAP, 13 of 84 patients (15%) of French ancestry had late-onset demyelinating TTR-FAP. We compared clinical presentation and electrophysiology to a cohort with CIDP and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome. We assessed nerve histology and the correlation between motor/sensory amplitudes/velocities. Predictors of demyelinating TTR-FAP were identified from clinical and electrophysiologic data. Pain, dysautonomia, small fiber sensory loss above the wrists, upper limb weakness, and absence of ataxia were predictors of demyelinating TTR-FAP ( p < 0.01). The most frequent demyelinating features were prolonged distal motor latency of the median nerve and reduced sensory conduction velocity of the median and ulnar nerves. Motor axonal loss was severe and frequent in the median, ulnar, and tibial nerves ( p < 0.05) in demyelinating FAP. Ulnar nerve motor amplitude <5.4 mV and sural nerve amplitude <3.95 μV were distinguishing characteristics of demyelinating TTR-FAP. Nerve biopsy showed severe axonal loss and occasional segmental demyelination-remyelination. Misleading features of TTR-FAP fulfilling criteria for CIDP are not uncommon in sporadic late-onset TTR-FAP, which highlights the limits of European Federation of Neurological Societies/Peripheral Nerve Society criteria. Specific clinical aspects and marked electrophysiologic axonal loss are red flag symptoms that should alert to this diagnosis and prompt TTR gene sequencing. © 2018 American Academy of Neurology.

Congenital hypertrophy of retinal pigment epithelium (CHRPE) in patients with familial adenomatous polyposis (FAP); a polyposis registry experience.

PubMed

Nusliha, Anwer; Dalpatadu, Ushantha; Amarasinghe, Binara; Chandrasinghe, Pramodh Chitral; Deen, Kemal Ismail

2014-10-18

Familial Adenomatous Polyposis (FAP) is an autosomal dominant condition giving rise to multiple adenomatous polyps in the colon which invariably become malignant by the fourth decade. Congenital hypertrophy of retinal pigment epithelium (CHRPE) is one of its extra intestinal manifestations early in childhood seen, present in 90% of FAP population and is easy to detect. Patients diagnosed with FAP and at risk first degree family members were screened for CHRPE using a slit lamp and indirect ophthalmoscopy. The retina of 17 diagnosed FAP patients and 13 individuals at risk were examined. The site and size of CHRPE lesions were documented. Thirteen (76%) of 17 FAP patients (male-10, female - 7, median age - 30 years; range 15-55 years) had CHRPE lesions; seven (54%) had bilateral CHRPE lesions and six (46%) had unilateral lesions. A single lesion was detected in 6 (46%) while 7 (54%) patients had multiple lesions. Of 13 at risk individuals (7- male, female-6 ; median age 34; range 16-52 years), one was positive for CHRPE and 12 were free of retinal lesions. The sensitivity of the presence of a CHRPE lesion in association with colonic polyps in FAP was 76%, specificity 92%, positive predictive value 93%, and negative predictive value 75%. This study found a high sensitivity and specificity for a CHRPE lesion to be associated with colonic polyps of FAP and hence a useful screening method in a burdened health-care system. The method is minimally invasive and simple and would be of particular value in screening children at risk for FAP.

Comprehensive Freshman Advising. The Ursinus College Freshman Advising Program: Three-Year Follow-Up.

ERIC Educational Resources Information Center

Chambliss, Catherine

In 1982, Ursinus College instituted a new Freshman Advising Program (FAP), involving: a greatly expanded role for the advisor; postponement of the declaration of major; greater emphasis on student-centered developmental advising; a focus on the transition needs of freshmen; a focus on the problem of false starts and student encounters with…

Adaptation of facial synthesis to parameter analysis in MPEG-4 visual communication

NASA Astrophysics Data System (ADS)

Yu, Lu; Zhang, Jingyu; Liu, Yunhai

2000-12-01

In MPEG-4, Facial Definition Parameters (FDPs) and Facial Animation Parameters (FAPs) are defined to animate 1 a facial object. Most of the previous facial animation reconstruction systems were focused on synthesizing animation from manually or automatically generated FAPs but not the FAPs extracted from natural video scene. In this paper, an analysis-synthesis MPEG-4 visual communication system is established, in which facial animation is reconstructed from FAPs extracted from natural video scene.

Ferrous ammonium phosphate (FeNH₄PO₄) as a new food fortificant: iron bioavailability compared to ferrous sulfate and ferric pyrophosphate from an instant milk drink.

PubMed

Walczyk, Thomas; Kastenmayer, Peter; Storcksdieck Genannt Bonsmann, Stefan; Zeder, Christophe; Grathwohl, Dominik; Hurrell, Richard F

2013-06-01

The main purpose of this study was to establish bioavailability data in humans for the new (Fe) fortification compound ferrous ammonium phosphate (FAP), which was specially developed for fortification of difficult-to-fortify foods where soluble Fe compounds cannot be used due to their negative impact on product stability. A double-blind, randomized clinical trial with cross-over design was conducted to obtain bioavailability data for FAP in humans. In this trial, Fe absorption from FAP-fortified full-cream milk powder was compared to that from ferric pyrophosphate (FPP) and ferrous sulfate. Fe absorption was determined in 38 young women using the erythrocyte incorporation dual stable isotope technique (⁵⁷Fe, ⁵⁸Fe). Geometric mean Fe absorption from ferrous sulfate, FAP and FPP was 10.4, 7.4 and 3.3 %, respectively. Fe from FAP was significantly better absorbed from milk than Fe from FPP (p < 0.0001). Fe absorption from FAP was significantly lower than Fe absorption from ferrous sulfate, which was used as water-soluble reference compound (p = 0.0002). Absorption ratios of FAP and FPP relative to ferrous sulfate as a measure of relative bioavailability were 0.71 and 0.32, respectively. The results of the present studies show that replacing FPP with FAP in full-cream milk could significantly improve iron bioavailability.

Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP.

PubMed

Parman, Yesim; Adams, David; Obici, Laura; Galán, Lucía; Guergueltcheva, Velina; Suhr, Ole B; Coelho, Teresa

2016-02-01

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a highly disabling, life-threatening disease characterized by progressive sensorimotor and autonomic neuropathy. The profile of the disease across Europe is inadequately understood at present. The incidence and clinical presentation of TTR-FAP varies widely within Europe, with early and late-onset disease subtypes. In those regions in which the disease is endemic (Portugal, Sweden, Cyprus, and Majorca), a Val30Met substitution in the TTR gene is the predominant genetic cause, whereas in the rest of Europe, cases of TTR-FAP are mainly sporadic with genetic heterogeneity. Current management strategies lack cohesion and patients can experience years of misdiagnosis and suboptimal treatment. The article aims to disseminate the findings and recommendations from two recent meetings of the European Network for TTR-FAP (ATTReuNET), a panel comprising representatives from 10 European countries (Bulgaria, Cyprus, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and Turkey) with expertise in the diagnosis and management of TTR-FAP. We explore the epidemiology and genetic mark of TTR-FAP across Europe and assess current management strategies, with a view to developing an alternative framework - a networked approach to disease management with an emphasis on collaboration and sharing of best practice.

The effect of a germline mutation in the APC gene on β-catenin in human embryonic stem cells.

PubMed

Yedid, Nofar; Kalma, Yael; Malcov, Mira; Amit, Ami; Kariv, Revital; Caspi, Michal; Rosin-Arbesfeld, Rina; Ben-Yosef, Dalit

2016-12-23

Most cases of colorectal cancer (CRC) are initiated by inactivation mutations in the APC gene, which is a negative regulator of the Wnt-β-catenin pathway. Patients with familial adenomatous polyposis (FAP) inherit a germline mutation in one APC allele, and loss of the second allele leads to the development of polyps that will turn malignant if not removed. It is not fully understood which molecular mechanisms are activated by APC loss and when the loss of the second APC allele occurs. Two FAP human embryonic stem cell (hESCs) lines were derived from APC mutated embryos following pre-implantation genetic diagnosis (PGD) for FAP. These FAP-hESCs were cultured in vitro and following extended culture: 1) β-catenin expression was analyzed by Western blot analysis; 2) Wnt-β-catenin/TCF-mediated transcription luciferase assay was performed; 3) cellular localization of β-catenin was evaluated by immunoflorecence confocal microscopy; and 4) DNA sequencing of the APC gene was performed. We have established a novel human in-vitro model for studying malignant transformation, using hESCs that carry a germline mutation in the APC gene following PGD for FAP. Extended culturing of FAP1 hESCs led to activation of the Wnt signaling pathway, as demonstrated by enhanced β-catenin/TCF-mediated activity. Additionally, β-catenin showed a distinct perinuclear distribution in most (91 %) of the FAP1 hESCs high passage colonies. DNA sequencing of the whole gene detected several polymorphisms in FAP1 hESCs, however, no somatic mutations were discovered in the APC gene. On the other hand, no changes in β-catenin were detected in the FAP2 hESCs, demonstrating the natural diversity of the human FAP population. Our results describe the establishment of novel hESC lines from FAP patients with a predisposition for cancer mutation. These cells can be maintained in culture for long periods of time and may serve as a platform for studying the initial molecular and cellular changes that occur during early stages of malignant transformation.

Daily behavior of urban Fluorescing Aerosol Particles in northwest Spain

NASA Astrophysics Data System (ADS)

Calvo, A. I.; Baumgardner, D.; Castro, A.; Fernández-González, D.; Vega-Maray, A. M.; Valencia-Barrera, R. M.; Oduber, F.; Blanco-Alegre, C.; Fraile, R.

2018-07-01

Measurements of ambient aerosol particles at the University of León, León, Spain, were made in May and June 2015 with a Wideband Integrated Bioaerosol Spectrometer (WIBS). The WIBS detects Fluorescing Aerosol Particles (FAP) in the size range from 0.5 to 20 μm. These measurements were complemented with an analysis of pollen concentrations assessed with optical microscopy of samples captured with a volumetric Hirst spore trap. The total particle, FAP and pollen concentrations show clear, daily cycles. Whereas the total particle concentrations maximize at 0800 and 2200 UTC, the FAP concentrations have peaks at midnight and 0800 UTC while the pollen has a broad peak between 1200 and 2000 UTC. The FAP larger than 2 μm represent 15-35% of the total particle population in this size range, maximizing at midnight UTC. Similar to what has been found by investigators at other locations, there is a strong positive correlation of the WIBS measured FAP with relative humidity; however, the pollen concentration is positively correlated with the temperature and anti-correlated with the relative humidity. Back trajectory analysis indicates that the largest FAP to total particle fractions are found in air masses arriving from the northeast with the second largest coming from the southwest. Given the location of the university in relation to the city and forested areas, this implies that the higher concentration FAP are coming from rural, probably natural, sources; however, more local, anthropogenic sources cannot be ruled out as a secondary source. The majority of the FAP that are identified from microscopy are fungal spores (Cladosporium, Aspergillus, Alternaria, Oidium) and pollen grains (mainly Poaceae, Quercus, Plantago, Rumex and Urticaceae). A comparison of the fluorescence fingerprints between laboratory generated FAP and the ambient particles showed some similarities; however, a significant fraction of the FAP are those whose fluorescence patterns do not match any of those that have been previously classified in the laboratory.

IBS and FAPS in children: a comparison of psychological and clinical characteristics.

PubMed

Rutten, Juliette M T M; Benninga, Marc A; Vlieger, Arine M

2014-10-01

It has been suggested that different subcategories of childhood abdominal pain-related functional gastrointestinal disorders (AP-FGIDs) are not separate clinical entities, but represent variable expressions of the same FGID. The aim of the present study was to compare clinical and psychological characteristics of children with irritable bowel syndrome (IBS), functional abdominal pain (FAP), and functional abdominal pain syndrome (FAPS). A total of 259 children, ages 8 to 18 years, fulfilling Rome III criteria for IBS or FAPS were included in a randomized controlled trial evaluating the effect of hypnotherapy. At inclusion, questionnaires assessed demographics, clinical features, abdominal pain frequency and intensity, depression and anxiety, somatization, health-related quality of life, pain beliefs, and coping strategies. No differences were found between children with IBS and those with FAPS with respect to the main outcomes: frequency and intensity of abdominal pain, symptoms of depression and anxiety, somatization, health-related quality of life, pain beliefs, and coping strategies. A significantly higher percentage of patients with IBS had a positive family history for AP-FGIDs (56.8% vs 37.8%; P = 0.00). Characteristics of patients with IBS subtypes did not differ. Patients with FAP or FAPS differed only with respect to problem-focused coping strategy (2.21 ± 0.61 vs 2.52 ± 0.49; P = 0.00). Pediatric patients with IBS and those with FAPS have similar psychosocial profiles. These results may explain why treatment response of psychological therapies in these AP-FGIDs is similar. These results may indicate that pediatric IBS and FAPS are different expressions of 1 underlying functional disorder, but similarities in psychosocial characteristics do not exclude the possibility that these disorders are different entities, because these similarities can exist between disorders of various causes. Therefore, future research is required on the role of other (physiological) factors in pediatric IBS and FAPS.

A case report of desmoid tumour-a forgotten aspect of FAP?

PubMed

Xuereb, Sarah; Xuereb, Rachel; Buhagiar, Chiara; Gauci, Jonathan; Magri, Claude

2017-01-01

Desmoid tumours are locally aggressive tumours which are common in Familial Adenomatous Polyposis (FAP). A 20-year old Familial Adenomatous Polyposis (FAP) patient presented with abdominal pain and distention. Abdominal imaging showed small bowel obstruction and hydronephrosis due to a pelvic mass. This mass showed significant enlargement on repeat imaging, and a diagnostic biopsy confirmed desmoid tumour. The mass was deemed unresectable and he was initially started on sulindac and raloxifene. Repeat imaging however showed further enlargement of the tumour, and therefore vinblastine+methotrexate chemotherapy was commenced, with a good response. FAP is an autosomal dominant condition caused by a germline mutation in the adenomatous polyposis coli (APC) gene. Gardner's syndrome is also caused by a mutation in the APC gene, and is now considered a different phenotypic presentation of FAP. Desmoid tumours are initially kept under observation while their size remains stable. Treatment options for enlarging desmoids tumours include surgery (first-line), radiotherapy, and systemic therapy with non-cytotoxic and cytotoxic therapy. FAP patients should be examined regularly post-panprocotocolectomy, since desmoid tumours may arise. The presence of epidermal cysts in this FAP patient suggests a diagnosis of Gardner's syndrome. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Integrated Range-Doppler Map and Extended Target Classification with Adaptive Waveform for Cognitive Radar

DTIC Science & Technology

2014-12-01

location for multiple targets of unknown types assuming unity noise energy ( 10ψ = percent and FAP = 0.1...2E )),D FAP Q Q P NR −= − (51) where 2sE NR /x hE E σ= where sE specifically means return (echo) energy using the wideband waveform. It can...probabilities ( FAP ). Considering Fig. 22, the performance of the eigenwaveform is superior to rectangular and wideband waveforms (given a fixed FAP

[Femoral artery pseudoaneurysms encountered in orthopedics and traumatology].

PubMed

Raherinantenaina, F; Rajaonanahary, T M A; Rakoto Ratsimba, H N

2015-12-01

Most published articles regarding orthopedic- and trauma-related femoral artery pseudoaneurysms (FAPs) are case reports in English. Reported cases are often associated with a literature review but actually provide little robust data. We wanted to summarize the current knowledge on diagnostic and therapeutic features of these FAPs. A new case of superficial FAP is described followed by a review of the literature. A bibliographic search was performed online (PubMed, ScinceDirect) from 1964 to 2015 using the descriptors "traumatic femoral pseudoaneurysm, orthopedic surgery, osteochondroma". A total of 64 cases of FAPs was analyzed. There were 50 men with an average age of 40.72±26.45 years old. The most common clinical presentation was painful swelling (34%). Arteriography was the commonest radiological investigation used (63%). The main etiologies were orthopedic injuries (47%), surgery of the upper thigh (30%) and femoral osteochondromas (23%). Arterial injuries included superficial femoral (47%) and profunda femoris artery (50%). The treatment was open surgery (56%) or endovascular repair (36%). Deep femoral artery and its branches were embolized (47%) or ligated (38%). Endovascular stenting was performed in 30% of posttraumatic FAPs. All FAPs relating to osteochondromas were repaired surgically. Postoperative courses were uneventful in 95% of patients. Endovascular embolization is preferred in management of postsurgical FAPs which have usually involved the deep femoral artery. Endovascular stenting graft may be proposed for posttraumatic FAPs, for which the superficial femoral trunk is the most often involved vessel. Surgical repair should be performed when endovascular stenting graft is not feasible. Surgical repair is mandatory for all FAPs secondary to traumatic exostoses. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Pharmacokinetics and Toxicology of a Fibroblast Activation Protein (FAP)-activated Prodrug in Murine Xenograft Models of Human Cancer

PubMed Central

Brennen, W. Nathaniel; Rosen, D. Marc; Chaux, Alcides; Netto, George J.; Isaacs, John T.; Denmeade, Samuel R.

2014-01-01

Background As carcinoma progresses, the stroma undergoes a variety of phenotypic changes, including the presence of carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). FAP is a post-prolyl endopeptidase whose expression in a healthy adult is largely restricted to the cancer-associated stroma. FAP-targeted prodrugs with a 100-fold greater therapeutic window over the parent compound were previously generated. Methods Prodrugs and non-cleavable controls were incubated in the presence of FAP. Plasma and tumor half-lives (t1/2) of the full-length and active forms of the prodrugs were determined using LCMS. Biodistribution studies of prodrug activation were performed. Histopathological analysis of tissues from treated animals were compared to vehicle-treated controls. Toxicity and efficacy studies were performed in human breast (MDA-MB-231 and MCF-7) and prostate (LNCaP) cancer xenografts models. Results These FAP-activated prodrugs have a significantly slower clearance from tumor tissue than the circulation (~12 vs. ~4.5 hrs). Micromolar concentrations of active drug persist in the tumor. Active drug is detected in non-target tissues; however, histopathologic evaluation reveals no evidence of drug-induced toxicity. A FAP-activated prodrug (ERGETGP-S12ADT) inhibits tumor growth in multiple human breast and prostate cancer xenograft models. The anti-tumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity. Conclusion FAP-activated prodrugs are a viable strategy for the management of prostate and other cancers. These prodrugs exhibit less toxicity than a commonly used chemotherapeutic agent. Further refinement of the FAP cleavage site for greater specificity may reduce prodrug activation in non-target tissues and enhance clinical benefit. PMID:25053236

FAP-related desmoid tumors: a series of 44 patients evaluated in a cancer referral center.

PubMed

Colombo, Chiara; Foo, Wai Chin; Whiting, David; Young, Eric D; Lusby, Kristelle; Pollock, Raphael E; Lazar, Alexander J; Lev, Dina

2012-05-01

Desmoid tumors (DTs), the commonest extra-intestinal manifestation of familial adenomatosis polyposis (FAP), are monoclonal neoplasms demonstrating fibroblastic - myofibroblastic differentiation; they are locally invasive without metastatic capacity. FAP-associated DT natural history knowledge is limited; we examined patient and tumor characteristics for a FAP-DT cohort and evaluated anti-DT therapy molecular target expression levels (immunohistochemical analyses, FAP-DT tissue microarray; TMA). Forty-four patients were classified as intra-abdominal (IA; n=26), abdominal wall (AW)/extra-abdominal (EA; n=12) or concomitant IA/AW (n=6) based on DT primary diagnosis location. Positive family histories were found in 62% of FAP versus 10% of DT patients. Surgery was the mainstay therapy for AW/EW patients, whereas IA DTs received surgery, chemotherapy, radiotherapy, tamoxifen, NSAIDs, and/or imatinib. Eight of 20 completely resected DTs in the IA and AW/EA groups recurred; 12 of 38 patients in these groups (33%) developed secondary lesions elsewhere. Two intestinal mesenteric DT patients died of disease, three from other cancers, 27 are alive with disease and 12 are alive without disease. All evaluable FAP-DT exhibited nuclear β-catenin, 65% were positive for cyclin D1, and 66% expressed nuclear p53. No ERα expression was observed, but ERβ was expressed in 72%. COX2 was expressed in all evaluable FAP-DTs. KIT was rarely found in DTs but both PDGFRs and their ligands were expressed. Comparing biomarker expression (IA vs. EA DTs), only nuclear ER-ß staining was significantly higher in EA lesions (p=0.0070); no other markers were site informative. Enhanced knowledge of FAP-DT molecular underpinnings will facilitate development of novel therapeutic strategies.

Bispecific single-chain diabody-immunoliposomes targeting endoglin (CD105) and fibroblast activation protein (FAP) simultaneously.

PubMed

Rabenhold, Markus; Steiniger, Frank; Fahr, Alfred; Kontermann, Roland E; Rüger, Ronny

2015-03-10

Liposomes are well-established drug delivery systems with cancer chemotherapy as main focus. To increase the cellular drug delivery, liposomes can be endowed with ligands, e.g. recombinant antibody fragments, which ensure specific cell interaction. Multispecific immunoliposomes can be prepared to improve the liposome to cell interaction by targeting multiple different targets at the same time, for instance by coupling two or more different ligands to the liposomal surface, resulting in a synergistic or additive increase in binding. An alternative approach is the use of bispecific ligands to address at least two different targets. For this purpose we cloned a single-chain diabody fragment (scDb`), a bispecific molecule targeting two antigens, endoglin (CD105) and fibroblast activation protein (FAP), expressed on cells of the tumor microenvironment. As model cell system, a human fibrosarcoma cell line was used expressing endoglin and FAP simultaneously. Monospecific immunoliposomes directed either against endoglin or FAP were compared in vitro for cell binding and cytotoxic activity with bispecific dual-targeted scFv`-IL (bispecific scFv`FAP/CD105-IL) and bispecific single-chain diabody`-IL (scDb`CD105/FAP-IL) targeting endoglin and FAP simultaneously. In the underlying study, bispecific scFv`FAP/CD105-IL interacted stronger with cells expressing FAP and endoglin (both targets simultaneously) compared to the monospecific immunoliposomes. Furthermore, bispecific scDb`-immunoliposomes increased the cell interaction massively and showed enhanced cytotoxicity against target cells using doxorubicin-loaded immunoliposomes. The use of recombinant bispecific ligands as scDb`-molecules facilitates the generation of bispecific immunoliposomes by using the established post-insertion technique, enabling an extension of the ligand specificity spectrum via genetic modification. Copyright © 2015 Elsevier B.V. All rights reserved.

Pharmacokinetics and toxicology of a fibroblast activation protein (FAP)-activated prodrug in murine xenograft models of human cancer.

PubMed

Brennen, W Nathaniel; Rosen, D Marc; Chaux, Alcides; Netto, George J; Isaacs, John T; Denmeade, Samuel R

2014-09-01

As carcinoma progresses, the stroma undergoes a variety of phenotypic changes, including the presence of carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). FAP is a post-prolyl endopeptidase whose expression in a healthy adult is largely restricted to the cancer-associated stroma. FAP-targeted prodrugs with a 100-fold greater therapeutic window over the parent compound were previously generated. Prodrugs and non-cleavable controls were incubated in the presence of FAP. Plasma and tumor half-lives (t1/2) of the full-length and active forms of the prodrugs were determined using LCMS. Biodistribution studies of prodrug activation were performed. Histopathological analysis of tissues from treated animals were compared to vehicle-treated controls. Toxicity and efficacy studies were performed in human breast (MDA-MB-231 and MCF-7) and prostate (LNCaP) cancer xenografts models. These FAP-activated prodrugs have a significantly slower clearance from tumor tissue than the circulation (∼12 vs. ∼4.5 hr). Micromolar concentrations of active drug persist in the tumor. Active drug is detected in non-target tissues; however, histopathologic evaluation reveals no evidence of drug-induced toxicity. A FAP-activated prodrug (ERGETGP-S12ADT) inhibits tumor growth in multiple human breast and prostate cancer xenograft models. The anti-tumor effect is comparable to that observed with docetaxel, but results in significantly less toxicity. FAP-activated prodrugs are a viable strategy for the management of prostate and other cancers. These prodrugs exhibit less toxicity than a commonly used chemotherapeutic agent. Further refinement of the FAP cleavage site for greater specificity may reduce prodrug activation in non-target tissues and enhance clinical benefit. © 2014 Wiley Periodicals, Inc.

An Ap-Structure with Finslerian Flavor II:. Torsion, Curvature and Other Objects

NASA Astrophysics Data System (ADS)

Wanas, M. I.; Kamal, Mona M.

An absolute parallelism (AP-) space having Finslerian properties is called FAP-space. This FAP-structure is wider than both conventional AP and Finsler structures. In the present work, more geometric objects as curvature and torsion tensors are derived in the context of this structure. Also second order tensors, usually needed for physical applications, are derived and studied. Furthermore, the anti-curvature and the W-tensor are defined for the FAP-structure. Relations between Riemannian, AP, Finsler and FAP structures are given. These relations facilitate comparison between results of applications carried out in the framework of these structures. We hope that the use of the FAP-structure, in applications may throw some light on some of the problems facing geometric field theories.

Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics.

PubMed

Puré, Ellen; Blomberg, Rachel

2018-05-03

Fibroblast activation protein (FAP) is a cell-surface serine protease that acts on various hormones and extracellular matrix components. FAP is highly upregulated in a wide variety of cancers, and is often used as a marker for pro-tumorigenic stroma. It has also been proposed as a molecular target of cancer therapies, and, especially in recent years, a great deal of research has gone into design and testing of diverse FAP-targeted treatments. Yet despite this growing field of research, our knowledge of FAP's basic biology and functional roles in various cancers has lagged behind its use as a tumor-stromal marker. In this review, we summarize and analyze recent advances in understanding the functions of FAP in cancer, most notably its prognostic value in various tumor types, cellular effects on various cell types, and potential as a therapeutic target. We highlight outstanding questions in the field, the answers to which could shape preclinical and clinical studies of FAP.

Interactions in the ionic liquid [EMIM][FAP]: a coupled experimental and computational analysis.

PubMed

Voroshylova, Iuliia V; Teixeira, Filipe; Costa, Renata; Pereira, Carlos M; Cordeiro, M Natália D S

2016-01-28

Gas-phase electronic and structural properties of the room temperature ionic liquid 1-ethyl-3-methylimidazolium tris(perfluoroethyl)trifluorophosphate ([EMIM][FAP]) were studied using density functional theory, and confirmed with results from infrared spectroscopy. A conformational analysis allowed the identification of several plausible conformers of the ion pairs. For the detected conformers, the infrared spectra were predicted and their thermodynamic properties were evaluated. The topology of the electronic density of the most stable conformers of [EMIM][FAP] ion pairs were characterised using the quantum theory of atoms in molecules. A number of possible hydrogen bonds between the cations and anions of the ionic liquid were identified. Excellent correspondence was found between the predicted spectra of gas-phase [EMIM][FAP] conformers and the experimental infrared spectrum, which in turn allowed a clear attribution of the vibration modes of [EMIM][FAP]. Finally, the contribution of the various conformers of both isomers of the [FAP](-) anion to the ionic liquid macro-properties is shown.

Rapid fibroblast activation in mammalian cells induced by silicon nanowire arrays

NASA Astrophysics Data System (ADS)

Ha, Qing; Yang, Gao; Ao, Zhuo; Han, Dong; Niu, Fenglan; Wang, Shutao

2014-06-01

Activated tumor-associated fibroblasts (TAFs) with abundant fibroblast activation protein (FAP) expression attract tremendous attention in tumor progression studies. In this work, we report a rapid 24 h FAP activation method for fibroblasts using silicon nanowires (SiNWs) as culture substrates instead of growth factors or chemokines. In contrast with cells cultured on flat silicon which rarely express FAP, SiNW cultivated cells exhibit FAP levels similar to those found in cancerous tissue. We demonstrated that activated cells grown on SiNWs maintain their viability and proliferation in a time-dependent manner. Moreover, environmental scanning electron microscopy (ESEM) and focused ion beam and scanning electron microscopy (FIB-SEM) analysis clearly revealed that activated cells on SiNWs adapt to the structure of their substrates by filling inter-wire cavities via filopodia in contrast to cells cultured on flat silicon which spread freely. We further illustrated that the expression of FAP was rarely detected in activated cells after being re-cultured in Petri dishes, suggesting that the unique structure of SiNWs may have a certain influence on FAP activation.Activated tumor-associated fibroblasts (TAFs) with abundant fibroblast activation protein (FAP) expression attract tremendous attention in tumor progression studies. In this work, we report a rapid 24 h FAP activation method for fibroblasts using silicon nanowires (SiNWs) as culture substrates instead of growth factors or chemokines. In contrast with cells cultured on flat silicon which rarely express FAP, SiNW cultivated cells exhibit FAP levels similar to those found in cancerous tissue. We demonstrated that activated cells grown on SiNWs maintain their viability and proliferation in a time-dependent manner. Moreover, environmental scanning electron microscopy (ESEM) and focused ion beam and scanning electron microscopy (FIB-SEM) analysis clearly revealed that activated cells on SiNWs adapt to the structure of their substrates by filling inter-wire cavities via filopodia in contrast to cells cultured on flat silicon which spread freely. We further illustrated that the expression of FAP was rarely detected in activated cells after being re-cultured in Petri dishes, suggesting that the unique structure of SiNWs may have a certain influence on FAP activation. Electronic supplementary information (ESI) available: (1) ESEM cross-sectional view images of the flat silicon and SiNW substrates. (2) Bright field morphology images of fibroblasts cultured in Petri dishes. (3) FIB/SEM 52° tilt images of fibroblasts cultured on SiNW 2 and SiNW 3. (4) Immunofluorescence images of FAP expression in fibroblasts re-cultured in Petri dishes after detachment from flat silicon and a series of SiNW substrates. (5) ESEM images of cells re-cultured in Petri dishes after detachment from each group. See DOI: 10.1039/c4nr01415d

Iterative design of emetine-based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy.

PubMed

Akinboye, Emmanuel S; Brennen, W Nathaniel; Rosen, D Marc; Bakare, Oladapo; Denmeade, Samuel R

2016-06-01

There is an urgent need to develop new agents for treating metastatic prostate cancer to overcome multiple drug resistance to the current standard targeted cancer therapy. Emetine is a highly cytotoxic natural product protein synthesis inhibitor, which is toxic to all cell types. Its cytotoxicity can be blocked by derivatizing its N-2' position. Thus emetine can be selectively delivered to cancer cells in the region of metastatic cancer as a prodrug that will be activated by an enzyme selectively overexpressed within the metastatic tumor microenvironment. In this work, we convert emetine to a prodrug activatable by the fibroblast activation protein (FAP), a serine protease overexpressed by the carcinoma associated fibroblasts. By using an iterative structure-activity relationship strategy, several peptidyl emetine prodrug analogs (1-11) were synthesized by chemical derivatization of emetine at its N-2' position and tested for in-vitro activation by FAP. The lead prodrug 11 is made up of a DPPIV activatable prodrug precursor 10 (Ala-Pro-PABC-Emetine) coupled to FAP substrate (Ala-Ser-Gly-Pro-Ala-Gly-Pro). Activation assays of the prodrugs were performed in purified FAP, DPPIV, FBS, and human serum and were analyzed by LCMS. In vitro cytotoxicity assays of these prodrugs are carried out in prostate (LNCaP, PC3) and breast (MCF7 and MDA-MB-231) cancer cell lines. The prodrugs are also tested in normal immortalized human prostatic epithelial cell line (PrEC). The lead FAP activated emetine prodrug 11 is activated to emetine in tandem by FAP and DPPIV in about 70% conversion within 24 hr. In prostate and breast cancer cell lines treated with prodrug 11, it is found to be equipotent with emetine in the presence of FAP and DPPIV. However, in the PrEC cell line grown in serum free media, prodrug 11 is more than 200-fold less cytotoxic than emetine in the absence of FAP and DPPIV. This FAP activated prodrug of cytotoxic agent emetine further shows the crucial role of the N-2' position of emetine in controlling its cytotoxicity. Significantly reduced toxicity observed in the PrEC cell line in the absence of FAP and DPPIV shows that prodrug 11 could be systemically delivered to regions of metastatic prostate cancer or other solid tumor for activation by cancer selective enzymes within the cancer microenvironment, such as FAP that is overexpressed by the carcinoma-associated fibroblasts. The two-step tandem enzymatic activation of prodrug 11 by FAP and DPPIV is a strategy for overcoming steric hindrance. © 2016 Wiley Periodicals, Inc.

Annual Costs of Care for Pediatric Irritable Bowel Syndrome, Functional Abdominal Pain, and Functional Abdominal Pain Syndrome.

PubMed

Hoekman, Daniël R; Rutten, Juliette M T M; Vlieger, Arine M; Benninga, Marc A; Dijkgraaf, Marcel G W

2015-11-01

To estimate annual medical and nonmedical costs of care for children diagnosed with irritable bowel syndrome (IBS) or functional abdominal pain (syndrome; FAP/FAPS). Baseline data from children with IBS or FAP/FAPS who were included in a multicenter trial (NTR2725) in The Netherlands were analyzed. Patients' parents completed a questionnaire concerning usage of healthcare resources, travel costs, out-of-pocket expenses, productivity loss of parents, and supportive measures at school. Use of abdominal pain related prescription medication was derived from case reports forms. Total annual costs per patient were calculated as the sum of direct and indirect medical and nonmedical costs. Costs of initial diagnostic investigations were not included. A total of 258 children, mean age 13.4 years (±5.5), were included, and 183 (70.9%) were female. Total annual costs per patient were estimated to be €2512.31. Inpatient and outpatient healthcare use were major cost drivers, accounting for 22.5% and 35.2% of total annual costs, respectively. Parental productivity loss accounted for 22.2% of total annual costs. No difference was found in total costs between children with IBS or FAP/FAPS. Pediatric abdominal pain related functional gastrointestinal disorders impose a large economic burden on patients' families and healthcare systems. More than one-half of total annual costs of IBS and FAP/FAPS consist of inpatient and outpatient healthcare use. Netherlands Trial Registry: NTR2725. Copyright © 2015 Elsevier Inc. All rights reserved.

Functional Analytic Psychotherapy and Supervision

ERIC Educational Resources Information Center

Callaghan, Glenn M.

2006-01-01

The interpersonal behavior therapy, Functional Analytic Psychotherapy (FAP) has been empirically investigated and described in the literature for a little over a decade. Still, little has been written about the process of supervision in FAP. While there are many aspects of FAP supervision shared by other contemporary behavior therapies and…

CASPER: A GENERALIZED PROGRAM FOR PLOTTING AND SCALING DATA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lietzke, M.P.; Smith, R.E.

A Fortran subroutine was written to scale floating-point data and generate a magnetic tape to plot it on the Calcomp 570 digital plotter. The routine permits a great deal of flexibility, and may be used with any type of FORTRAN or FAP calling program. A simple calling program was also written to permit the user to read in data from cards and plot it without any additional programming. Both the Fortran and binary decks are available. (auth)

Family Violence Measurement: A Sourcebook for FAP.

DTIC Science & Technology

1998-02-26

child abuse ? (6) What information can FAP gain from the source of referral? This document will serve several purposes: (1) to teach some basic research methods; (2) to help FAP managers gather and analyze information from subordinates, and (3) to help people in the field analyze their own unique

Organizing the Cellular and Molecular Heterogeneity in High Grade Serous Ovarian Cancer by Mass Cytometry

DTIC Science & Technology

2015-10-01

expressed and the intensity by IHC and CyTOF (E-cadherin, vimentin, CD45, pAKT, FAP and p53). The examples show Figure 1: IHC of E-cadherin and...into CyTOF panels. Markers CD45, FAP and CD31 from the tumor antibody panel allow us to enumerate tumor, immune and stroma/angiogenic compartments...compartment as CD45-/CD31-/ FAP -, the immune compartment as CD45+/CD31-/ FAP . Data analysis of tumor compartment As with our pilot experiments from years 1 and

Gastric cancer in FAP: a concerning rise in incidence.

PubMed

Mankaney, Gautam; Leone, Pamela; Cruise, Michael; LaGuardia, Lisa; O'Malley, Margaret; Bhatt, Amit; Church, James; Burke, Carol A

2017-07-01

The highest cancer risks in familial adenomatous polyposis (FAP) include colorectal, duodenal, and thyroid for which surveillance is recommended. Nearly all patients with FAP have gastric fundic gland polyposis (FGP), but gastric cancers are rarely reported with a similar incidence as the general population. We describe a recent, sudden increase in the incidence of gastric cancer in FAP. Seven of the ten cases were diagnosed in the last 20 months. Comparing our population to the SEER database for gastric cancer, the standardized incidence ratio is 140. All cases arose in patients with a carpeting of FGP and associated with large mounds of proximal gastric polyps. Nearly all patients were under upper endoscopic surveillance. This is a concerning observation and reflects a change in the phenotypic presentation of FAP in Western patients.

Evaluation of the radiolabeled boronic acid-based FAP inhibitor MIP-1232 for atherosclerotic plaque imaging.

PubMed

Meletta, Romana; Müller Herde, Adrienne; Chiotellis, Aristeidis; Isa, Malsor; Rancic, Zoran; Borel, Nicole; Ametamey, Simon M; Krämer, Stefanie D; Schibli, Roger

2015-01-27

Research towards the non-invasive imaging of atherosclerotic plaques is of high clinical priority as early recognition of vulnerable plaques may reduce the incidence of cardiovascular events. The fibroblast activation protein alpha (FAP) was recently proposed as inflammation-induced protease involved in the process of plaque vulnerability. In this study, FAP mRNA and protein levels were investigated by quantitative polymerase chain reaction and immunohistochemistry, respectively, in human endarterectomized carotid plaques. A published boronic-acid based FAP inhibitor, MIP-1232, was synthetized and radiolabeled with iodine-125. The potential of this radiotracer to image plaques was evaluated by in vitro autoradiography with human carotid plaques. Specificity was assessed with a xenograft with high and one with low FAP level, grown in mice. Target expression analyses revealed a moderately higher protein level in atherosclerotic plaques than normal arteries correlating with plaque vulnerability. No difference in expression was determined on mRNA level. The radiotracer was successfully produced and accumulated strongly in the FAP-positive SK-Mel-187 melanoma xenograft in vitro while accumulation was negligible in an NCI-H69 xenograft with low FAP levels. Binding of the tracer to endarterectomized tissue was similar in plaques and normal arteries, hampering its use for atherosclerosis imaging.

Familial adenomatous polyposis

PubMed Central

Half, Elizabeth; Bercovich, Dani; Rozen, Paul

2009-01-01

Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after the appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present with some extraintestinal manifestations such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner variant of FAP. Classic FAP is inherited in an autosomal dominant manner and results from a germline mutation in the adenomatous polyposis (APC) gene. Most patients (~70%) have a family history of colorectal polyps and cancer. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract. Diagnosis is based on a suggestive family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed. Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing is possible. Referral to a geneticist or genetic counselor is mandatory. Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome). Cancer prevention and maintaining a good quality of life are the main goals of management and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy, they need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery (when possible to perform). Adjunctive therapy with celecoxib has been approved by the US Food and Drug Administration and the European Medicines Agency in patients with FAP. Individuals with FAP carry a 100% risk of CRC; however, this risk is reduced significantly when patients enter a screening-treatment program. PMID:19822006

Reconstruction of bacteriochlorophyll biosynthesis pathways in the filamentous anoxygenic phototrophic bacterium Oscillochloris trichoides DG-6 and evolution of anoxygenic phototrophs of the order Chloroflexales.

PubMed

Grouzdev, Denis S; Kuznetsov, Boris B; Keppen, Olga I; Krasil'nikova, Elena N; Lebedeva, Natalia V; Ivanovsky, Ruslan N

2015-01-01

It is commonly accepted that green filamentous anoxygenic phototrophic (FAP) bacteria are the most ancient representatives of phototrophic micro-organisms. Modern FAPs belonging to the order Chloroflexales are divided into two suborders: Chloroflexineae and Roseiflexineae. Representatives of Roseiflexineae lack chlorosomes and synthesize bacteriochlorophyll a, whereas those of Chloroflexineae synthesize bacteriochlorophylls a and c and utilize chlorosomes for light harvesting. Though they constitute a small number of species, FAPs are quite diverse in their physiology. This bacterial group includes autotrophs and heterotrophs, thermophiles and mesophiles, aerobes and anaerobes, occupying both freshwater and halophilic environments. The anaerobic mesophilic autotroph Oscillochloris trichoides DG-6 is still not well studied in its physiology, and its evolutionary origin remains unclear. The goals of this study included identification of the reaction centre type of O. trichoides DG-6, reconstruction of its bacteriochlorophyll biosynthesis pathways, and determination of its evolutionary relationships with other FAPs. By enzymic and genomic analysis, the presence of RCII in O. trichoides DG-6 was demonstrated and the complete gene set involved in biosynthesis of bacteriochlorophylls a and c was established. We found that the bacteriochlorophyll gene sets differed between aerobic and anaerobic FAPs. The aerobic FAP genomes code oxygen-dependent AcsF cyclases, but lack the bchQ/bchR genes, which have been associated with adaptation to low light conditions in the anaerobic FAPs. A scenario of evolution of FAPs belonging to the order Chloroflexales is proposed. © 2015 The Authors.

Fibroblast activation protein (FAP) as a novel metabolic target.

PubMed

Sánchez-Garrido, Miguel Angel; Habegger, Kirk M; Clemmensen, Christoffer; Holleman, Cassie; Müller, Timo D; Perez-Tilve, Diego; Li, Pengyun; Agrawal, Archita S; Finan, Brian; Drucker, Daniel J; Tschöp, Matthias H; DiMarchi, Richard D; Kharitonenkov, Alexei

2016-10-01

Fibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily. This enzyme has been implicated in cancer development and recently reported to regulate degradation of FGF21, a potent metabolic hormone. Using a known FAP inhibitor, talabostat (TB), we explored the impact of FAP inhibition on metabolic regulation in mice. To address this question we evaluated the pharmacology of TB in various mouse models including those deficient in FGF21, GLP1 and GIP signaling. We also studied the ability of FAP to process FGF21 in vitro and TB to block FAP enzymatic activity. TB administration to diet-induced obese (DIO) animals led to profound decreases in body weight, reduced food consumption and adiposity, increased energy expenditure, improved glucose tolerance and insulin sensitivity, and lowered cholesterol levels. Total and intact plasma FGF21 were observed to be elevated in TB-treated DIO mice but not lean animals where the metabolic impact of TB was significantly attenuated. Furthermore, and in stark contrast to naïve DIO mice, the administration of TB to obese FGF21 knockout animals demonstrated no appreciable effect on body weight or any other measures of metabolism. In support of these results we observed no enzymatic degradation of human FGF21 at either end of the protein when FAP was inhibited in vitro by TB. We conclude that pharmacological inhibition of FAP enhances levels of FGF21 in obese mice to provide robust metabolic benefits not observed in lean animals, thus validating this enzyme as a novel drug target for the treatment of obesity and diabetes.

77 FR 34052 - Pfizer, Inc.; Withdrawal of Approval of Familial Adenomatous Polyposis Indication for CELEBREX

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-08

... withdrawing approval of the familial adenomatous polyposis (FAP) indication for CELEBREX (celecoxib) Capsules... Spring, MD 20993-0002, 301- 796-3601. SUPPLEMENTARY INFORMATION: FDA approved the FAP indication for..., subpart H. In addition to FAP, CELEBREX is indicated for the relief of the signs and symptoms of...

The Challenge of Developing a Universal Case Conceptualization for Functional Analytic Psychotherapy

ERIC Educational Resources Information Center

Bonow, Jordan T.; Maragakis, Alexandros; Follette, William C.

2012-01-01

Functional Analytic Psychotherapy (FAP) targets a client's interpersonal behavior for change with the goal of improving his or her quality of life. One question guiding FAP case conceptualization is, "What interpersonal behavioral repertoires will allow a specific client to function optimally?" Previous FAP writings have suggested that a therapist…

Evaluating the Acceptability and Effectiveness of Family Assessment Portfolios

ERIC Educational Resources Information Center

Meadan, Hedda; Thompson, James R.; Hagiwara, Mayumi; Herold, Julie; Hoekstra, Sarah; Manser, Samantha

2009-01-01

The Family Assessment Portfolio (FAP) is a new tool that includes scrapbooks, web-based profiles, and movies that families create to introduce their children to educators. FAP was developed to promote good home/school communication and collaboration. Although FAPs appear to be a promising practice for the field of special education, there is…

First Steps in FAP: Experiences of Beginning Functional Analytic Psychotherapy Therapist with an Obsessive-Compulsive Personality Disorder Client

ERIC Educational Resources Information Center

Manduchi, Katia; Schoendorff, Benjamin

2012-01-01

Practicing Functional Analytic Psychotherapy (FAP) for the first time can seem daunting to therapists. Establishing a deep and intense therapeutic relationship, identifying FAP's therapeutic targets of clinically relevant behaviors, and using contingent reinforcement to help clients emit more functional behavior in the therapeutic relationship all…

Rapid fibroblast activation in mammalian cells induced by silicon nanowire arrays.

PubMed

Ha, Qing; Yang, Gao; Ao, Zhuo; Han, Dong; Niu, Fenglan; Wang, Shutao

2014-07-21

Activated tumor-associated fibroblasts (TAFs) with abundant fibroblast activation protein (FAP) expression attract tremendous attention in tumor progression studies. In this work, we report a rapid 24 h FAP activation method for fibroblasts using silicon nanowires (SiNWs) as culture substrates instead of growth factors or chemokines. In contrast with cells cultured on flat silicon which rarely express FAP, SiNW cultivated cells exhibit FAP levels similar to those found in cancerous tissue. We demonstrated that activated cells grown on SiNWs maintain their viability and proliferation in a time-dependent manner. Moreover, environmental scanning electron microscopy (ESEM) and focused ion beam and scanning electron microscopy (FIB-SEM) analysis clearly revealed that activated cells on SiNWs adapt to the structure of their substrates by filling inter-wire cavities via filopodia in contrast to cells cultured on flat silicon which spread freely. We further illustrated that the expression of FAP was rarely detected in activated cells after being re-cultured in Petri dishes, suggesting that the unique structure of SiNWs may have a certain influence on FAP activation.

[A Case of Metachronous Multiple Thyroid Papillary Carcinoma with FAP].

PubMed

Tajima, Yusuke; Kumamoto, Kensuke; Yamamoto, Azusa; Chika, Noriyasu; Watanabe, Yuichiro; Matsuzawa, Takeaki; Ishibashi, Keiichiro; Mochiki, Erito; Iwama, Takeo; Akagi, Kiwamu; Ishida, Hideyuki

2015-11-01

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, the result of a germ line mutation in the adenomatous polyposis coli (APC) gene. FAP can be associated with various extracolonic lesions, including thyroid cancer, which frequently occurs in women. We report the case of a 36-year-old woman diagnosed as having FAP with multiple metachronous thyroid papillary carcinomas. She underwent left thyroidectomy at the age of 19 years without a diagnosis of FAP. Multiple polyps in her stomach were detected by medical examination and more than 100 polyps in the colon were found by colonoscopy. She was referred to our hospital after a diagnosis of non-profuse FAP. Multiple tumors with a maximum diameter of 10mm were detected in the right lobe of the thyroid gland during the preoperative examination. Papillary carcinoma was suspected based on fine-needle aspiration cytology. We performed a right thyroidectomy after prophylactic colectomy. Pathological findings revealed a cribriform-morula variant of papillary thyroid carcinoma. The patient remains well after 2 year 6 months with no recurrence.

The gene for fibroblast activation protein {alpha} (FAP), a putative cell surface-bound serine protease expressed in cancer stroma and wound healing, maps to chromosome band 2q23

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mathew, S.; Murty, V.V.V.S.; Chaganti, R.S.K.

The human fibroblast activation protein {alpha} (FAP{alpha}) is an inducible cell surface glycoprotein of M{sub r} 95,000 recognized by a number of monoclonal antibodies (mAbs), including the prototype mAb F19. Immunohistochemical studies have shown that FAP{alpha} expression in vivo is tightly regulated, with transient expression in some fetal mesenchymal tissues but absence of expression in most normal adult tissues. Reexpression of FAP{alpha} is observed in the reactive stromal fibroblasts of several common types of epithelial cancers, including >90% of breast, colorectal, and lung carcinomas and healing wounds. Cloning and sequence analysis of an FAP{alpha}-specific cDNA has revealed that the moleculemore » is encoded by a novel gene, FAP, which shows sequence similarity to members of the serine protease family of integral membrane proteins, namely dipeptidyl peptidase IV (DPPIV, also known as lymphocyte activation antigen, CD26, or adenosine dearoinase binding protein) and DPPX, a DPPIV-related molecule of unknown function. 15 refs., 1 fig.« less

Ecology and Biogenesis of Functional Amyloids in Pseudomonas.

PubMed

Rouse, Sarah L; Matthews, Stephen J; Dueholm, Morten S

2018-05-16

Functional amyloids can be found in the extracellular matrix produced by many bacteria during biofilm growth. They mediate the initial attachment of bacteria to surfaces and provide stability and functionality to mature biofilms. Efficient amyloid biogenesis requires a highly coordinated system of amyloid subunits, molecular chaperones and transport systems. The functional amyloid of Pseudomonas (Fap) represents such a system. Here, we review the phylogenetic diversification of the Fap system, its potential ecological role and the dedicated machinery required for Fap biogenesis, with a particular focus on the amyloid exporter FapF, the structure of which has been recently resolved. We also present a sequence covariance-based in silico model of the FapC fiber-forming subunit. Finally, we highlight key questions that remain unanswered and we believe deserve further attention by the scientific community. Copyright © 2018. Published by Elsevier Ltd.

Emotion awareness and coping in children with functional abdominal pain: a controlled study.

PubMed

van der Veek, Shelley M C; Derkx, H H F; de Haan, Else; Benninga, Marc A; Boer, Frits

2012-01-01

Literature on somatization suggests that patients suffering from medically unexplained symptoms are less aware of their emotions and use maladaptive coping strategies when coping with everyday problems. In addition, coping is hypothesized to mediate between emotion awareness and medically unexplained symptoms. Scientific evidence for the relevance of this hypothesis for children with functional abdominal pain (FAP) is, however, lacking. Therefore, the purpose of the present study was to investigate this hypothesis in Dutch children with functional abdominal pain (FAP), aged 7-18 years. Between April 2007 and April 2010, a total of 114 referred children with FAP, 235 schoolchildren without abdominal pain and 407 schoolchildren with some abdominal pain (AP) of diverse etiology filled out questionnaires concerning their pain, emotion awareness and coping. MANOVA was used to investigate group differences in emotional awareness and coping. Structural equation modeling was used to investigate the mediational role of coping. The results showed that children with FAP scored significantly lower on most aspects of emotion awareness than children without AP, although these differences were small. Contrary to expectations, children with FAP were more aware of a link between emotions and bodily sensations than children without AP. As for coping, we found that children with FAP used avoidant coping more often than children without AP. Overall, children with FAP mostly did not differ in their emotional awareness and coping compared to children with some AP. Problem focused coping had a small mediating effect for two aspects of emotion awareness. We conclude that children with FAP show only small differences in emotion awareness and coping compared to children without AP, and are practically no different from children with some AP. Contrary to common belief, it can be questioned whether emotion awareness and general coping are useful targets for psychological treatments of FAP to focus on. Copyright © 2011 Elsevier Ltd. All rights reserved.

Novel mutations and phenotypic associations identified through APC, MUTYH, NTHL1, POLD1, POLE gene analysis in Indian Familial Adenomatous Polyposis cohort.

PubMed

Khan, Nikhat; Lipsa, Anuja; Arunachal, Gautham; Ramadwar, Mukta; Sarin, Rajiv

2017-05-22

Colo-Rectal Cancer is a common cancer worldwide with 5-10% cases being hereditary. Familial Adenomatous Polyposis (FAP) syndrome is due to germline mutations in the APC or rarely MUTYH gene. NTHL1, POLD1, POLE have been recently reported in previously unexplained FAP cases. Unlike the Caucasian population, FAP phenotype and its genotypic associations have not been widely studied in several geoethnic groups. We report the first FAP cohort from South Asia and the only non-Caucasian cohort with comprehensive analysis of APC, MUTYH, NTHL1, POLD1, POLE genes. In this cohort of 112 individuals from 53 FAP families, we detected germline APC mutations in 60 individuals (45 families) and biallelic MUTYH mutations in 4 individuals (2 families). No NTHL1, POLD1, POLE mutations were identified. Fifteen novel APC mutations and a new Indian APC mutational hotspot at codon 935 were identified. Eight very rare FAP phenotype or phenotypes rarely associated with mutations outside specific APC regions were observed. APC genotype-phenotype association studies in different geo-ethnic groups can enrich the existing knowledge about phenotypic consequences of distinct APC mutations and guide counseling and risk management in different populations. A stepwise cost-effective mutation screening approach is proposed for genetic testing of south Asian FAP patients.

Characterisation of serum transthyretin by electrospray ionisation-ion mobility mass spectrometry: Application to familial amyloidotic polyneuropathy type I (FAP-I).

PubMed

Pont, Laura; Benavente, Fernando; Vilaseca, Marta; Giménez, Estela; Sanz-Nebot, Victoria

2015-11-01

Transthyretin (TTR) is a homotetrameric protein which is known to misfold and aggregate causing different types of amyloidosis, such as familial amyloidotic polyneuropathy type I (FAP-I). FAP-I is associated with a specific TTR mutant variant (TTR (Met30)) that can be easily detected analysing the monomeric forms of the mutant protein. Meanwhile, the mechanism of protein aggregation onset, which could be triggered by structural changes on the native tetrameric protein complex, remains uncertain. We developed and described herein a new sample pretreatment based on immunoprecipitation (IP) to purify TTR from serum under non-denaturing conditions. Later, a nano-electrospray ionization-ion mobility mass spectrometry (nano-ESI-IM-MS or IM-MS) method was optimised to analyse the protein complexes in serum samples from healthy controls and FAP-I patients. IM-MS allowed separation and characterisation of tetrameric, trimeric and dimeric TTR gas ions due to their differential drift time, which is related to ion size and charge. The tetramer-to-dimer abundance ratio was differential between healthy controls and FAP-I patients (asymptomatic, symptomatic and an iatrogenic patient originally without the mutation who received a liver transplant from an FAP-I patient), and was also indicative of the effectiveness of liver transplantation as a treatment for FAP-I. Copyright © 2015 Elsevier B.V. All rights reserved.

An Example of a Hakomi Technique Adapted for Functional Analytic Psychotherapy

ERIC Educational Resources Information Center

Collis, Peter

2012-01-01

Functional Analytic Psychotherapy (FAP) is a model of therapy that lends itself to integration with other therapy models. This paper aims to provide an example to assist others in assimilating techniques from other forms of therapy into FAP. A technique from the Hakomi Method is outlined and modified for FAP. As, on the whole, psychotherapy…

Functional Analytic Psychotherapy (FAP): A Review of Publications from 1990 to 2010

ERIC Educational Resources Information Center

Mangabeira, Victor; Kanter, Jonathan; Del Prette, Giovana

2012-01-01

Functional Analytic Psychotherapy (FAP), a therapy based on radical behaviorism, establishes the priority of the therapeutic interaction as a mechanism of change in psychotherapy. Since the first book on FAP appeared in 1991, it has been the focus of many papers and has been incorporated by the community of behavior therapists. This paper is a…

A Single-Case Experimental Demonstration of Functional Analytic Psychotherapy with Two Clients with Severe Interpersonal Problems

ERIC Educational Resources Information Center

Oshiro, Claudia Kami Bastos; Kanter, Jonathan; Meyer, Sonia Beatriz

2012-01-01

Functional Analytic Psychotherapy (FAP) is emerging as an effective psychotherapy for psychiatric clinical cases. However, there is little research demonstrating the process of change of FAP. The present study evaluated the introduction and withdrawal of FAP interventions on therapy-interfering verbal behaviors of two participants who were in…

Understanding women who are violent in intimate relationships: implications for Army family advocacy.

PubMed

Adams, S R

2000-03-01

Women who are violent in intimate relationships is a controversial and neglected subject in the area of spouse abuse in the civilian and military communities. Researchers report that women initiate more acts of violence than their male partners. This article provides a review of the literature, which identifies the high rates of violence by women against their male partners. In addition, this article discusses the context in which women offend and the motivations of women offenders. The implication for the Army Family Advocacy Program (FAP) is to enhance providers' clinical knowledge and increase community members' awareness so that FAP personnel can appropriately intervene with abusive couples. The goal of this author is to argue for broadening the scope of spouse abuse to include violence perpetrated by women.

Targeting Carcinoma-Associated Fibroblasts Within the Tumor Stroma With a Fibroblast Activation Protein-Activated Prodrug

PubMed Central

2012-01-01

Background Fibroblasts undergo a morphological transformation to a reactive phenotype in the tumor microenvironment characterized by the expression of proteins such as fibroblast activation protein (FAP), a post-prolyl endopeptidase with expression largely restricted to carcinoma-associated fibroblasts. Thapsigargin (TG) is a highly toxic natural plant product that triggers a rise in intracellular calcium levels and apoptosis. FAP is therefore a provocative target for the activation of prodrugs consisting of a FAP-specific peptide coupled to a potent cytotoxic analog of TG. Methods The efficacy of FAP-activated peptidyl-TG prodrugs was tested in vitro in cell proliferation assays and effects on intracellular calcium in human cancer cell lines. The effects of FAP-activated prodrugs on tumor growth and host toxicity were tested in Balb-C nude MCF-7 and LNCaP xenograft mice (n = 9–11 per group). P values were calculated using permutation tests based on 50 000 permutations. Mixed effects models were used to account for correlations among replicate measures. All statistical tests were two-sided. Results FAP-activated prodrugs killed human cancer cells at low nanomolar concentrations (MCF-7 cells: IC50 = 3.5nM). Amino acid-12ADT analogs from FAP-cleaved prodrugs, but not uncleaved prodrugs, produced a rapid rise in intracellular calcium within minutes of exposure. Immunohistochemical analysis of xenografts exposed to FAP-prodrugs documented stromal-selective cell death of fibroblasts, pericytes, and endothelial cells of sufficient magnitude to inhibit growth of MCF-7 and LNCaP xenografts with minimal systemic toxicity, whereas non-FAP cleavable prodrugs were inactive. MCF-7 and LNCaP xenografts treated with a FAP-activated prodrug had maximal treated-to-control tumor volume ratios of 0.36 (treated: mean = 0.206mm3, 95% CI = 0.068 to 0.344mm3; control: mean = 0.580mm3, 95% CI = 0.267 to 0.893mm3) and 0.24 (treated: mean = 0.131mm3, 95% CI = 0.09 to 0.180mm3; control: mean = 0.543mm3, 95% CI = 0.173 to 0.913mm3), respectively, on day 21 after therapy. Conclusions This study validates the proteolytic activity of FAP as a target for the activation of a systemically delivered cytotoxic prodrug and demonstrates that targeted killing of cells within the stromal compartment of the tumor microenvironment can produce a therapeutic response. PMID:22911669

Attentional bias to pain and social threat in pediatric patients with functional abdominal pain and pain-free youth before and after performance evaluation.

PubMed

Beck, Joy E; Lipani, Tricia A; Baber, Kari F; Dufton, Lynette; Garber, Judy; Smith, Craig A; Walker, Lynn S

2011-05-01

This study investigated attentional biases for pain and social threat versus neutral stimuli in 54 youth with functional abdominal pain (FAP) and 53 healthy control subjects (ages 10 to 16 years). We assessed attentional bias using a visual probe detection task (PDT) that presented pain and social threat words in comparison to neutral words at conscious (1250 ms) and preconscious (20 ms) presentation rates. We administered the PDT before and after random assignment of participants to a laboratory stressor--failure versus success feedback regarding their performance on a challenging computer game. All analyses controlled for trait anxiety. At the conscious rate of stimulus presentation, FAP patients exhibited preferential attention toward pain compared with neutral stimuli and compared with the control group. FAP patients maintained preferential attention toward conscious pain stimuli after performance feedback in both failure and success conditions. At the preconscious rate of stimulus presentation, FAP patients' attention was neutral at baseline but increased significantly toward pain stimuli after performance feedback in both failure and success conditions. FAP patients' somatic symptoms increased in both failure and success conditions; control youth's somatic symptoms only increased after failure. Regarding social threat, neither FAP nor control youth exhibited attentional bias toward social threat compared with neutral stimuli at baseline, but both FAP and control youth in the failure condition significantly increased attention away from social threat after failure feedback. Results suggest that FAP patients preferentially attend to pain stimuli in conscious awareness. Moreover, performance evaluation may activate their preconscious attention to pain stimuli. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Total prevention of folic acid-preventable spina bifida and anencephaly would reduce child mortality in India: Implications in achieving Target 3.2 of the Sustainable Development Goals.

PubMed

Kancherla, Vijaya; Oakley, Godfrey P

2018-03-15

The potential to reduce child mortality by preventing folic acid-preventable spina bifida and anencephaly (FAP SBA) is inadequately appreciated. To quantify possible reduction in FAP SBA-associated child mortality in low- and middle-income countries, we conducted an analysis to demonstrate in India, a country with more than 25 million births and 1.2 million under-five deaths each year, the decrease in neonatal, infant, and under-five mortality that would occur through total prevention of FAP SBA. We estimated the percent reductions in neonatal, infant, and under-five mortality that would have occurred in India in 2015 had all of FAP SBA been prevented. We also estimated the contributions of these reductions toward India's Sustainable Development Goals on child mortality indicators. We considered the overall prevalence of spina bifida and anencephaly in India as 5 per 1,000 live births, of which 90% were preventable with effective folic acid intervention. In the year 2015, folic acid interventions would have prevented about 116,070 cases of FAP SBA and 101,565 under-five deaths associated with FAP SBA. Prevention of FAP SBA would have reduced annually, neonatal, infant, and under-five mortality by 10.2%, 8.9%, and 8.3%, respectively. These reductions would have contributed 18.5% and 17.2% to the reductions in neonatal and under-five mortality, respectively, needed by India to achieve its 2030 Sustainable Developmental Goal Target 3.2 addressing preventable child mortality. Total prevention of FAP SBA clearly has a significant potential for immediate reductions in neonatal, infant, and under-five mortality in India, and similarly other countries. © 2017 Wiley Periodicals, Inc.

Transthyretin familial amyloid polyneuropathy (TTR-FAP): Parameters for early diagnosis.

PubMed

Escolano-Lozano, Fabiola; Barreiros, Ana Paula; Birklein, Frank; Geber, Christian

2018-01-01

Familial transthyretin amyloidosis is a life-threatening disease presenting with sensorimotor and autonomic polyneuropathy. Delayed diagnosis has a detrimental effect on treatment and prognosis. To facilitate diagnosis, we analyzed data patterns of patients with transthyretin familial amyloid polyneuropathy (TTR-FAP) and compared them to polyneuropathies of different etiology for clinical and electrophysiological discriminators. Twenty-four patients with TTR-FAP and 48 patients with diabetic polyneuropathy (dPNP) were investigated (neurological impairment score NIS; neurological disability score NDS) in a cross-sectional design. Both groups were matched for gender and presence of pain. Quantitative sensory testing (QST), sympathetic skin response (SSR), heart rate variability (HRV), and nerve conduction studies (NCV) were performed. Both groups were compared using univariate analysis. In a stepwise discriminant analysis, discriminators between both neuropathies were identified. These discriminators were validated comparing TTR-FAP patients with a cohort of patients with chemotherapy-induced polyneuropathy (CIN) and chronic inflammatory demyelinating neuropathy (CIDP). TTR-FAP patients scored higher in NDS and NIS and had impaired cold detection (CDT, p  = .024), cold-warm discrimination (TSL, p  = .019) and mechanical hyperalgesia (MPT, p  = .029) at the hands, SSR (upper limb, p  = .022) HRV and ulnar and sural NCS (all p  < .05) were more affected in TTR-FAP. Ulnar nerve sensory NCV, CDT, and the MPT but not the other parameters discriminated TTR-FAP from dPNP (82% of cases), from CIN (86.7%) and from CIDP (68%; only ulnar sNCV). Low ulnar SNCV, impaired cold perception, and mechanical hyperalgesia at the hands seem to characterize TTR-FAP and might help to differentiate from other polyneuropathies.

The genetics of familial adenomatous polyposis (FAP) and MutYH-associated polyposis (MAP).

PubMed

Claes, Kathleen; Dahan, Karin; Tejpar, S; De Paepe, Anne; Bonduelle, Maryse; Abramowicz, Marc; Verellen, Christine; Franchimont, Denis; Van Cutsem, Eric; Kartheuser, Alex

2011-09-01

FAP is characterized by 100-1000s of adenomatous polyps in colon and rectum, and is in 70% of the patients associated with extracolonic manifestations. Attenuated FAP (AFAP) is a less severe form of FAP, marked by the presence of < 100 polyps and a later onset of colorectal cancer (CRC). (A)FAP is caused by autosomal dominantly inherited mutations in the APC (Adenomatous polyposis coli) gene, a tumour suppressor gene that controls beta-catenin turnover in the Wnt pathway. De novo occurrence is reported in 30-40% of the patients. Mutations are detected in 85% of classical FAP families, while only 20%-30% of AFAP cases will exhibit a germline APC mutation. MUTYH is the second (A)FAP-related gene and is involved with base-excision repair of DNA damaged by oxidative stress. MUTYH mutations are inherited in an autosomal recessive way and account for 10%-20% of classical FAP cases without an APC mutation and for 30% of AFAP cases. Genotype-phenotype correlations exist for mutations in the APC gene, however, contradictions in the literature caution against the sole use of the genotype for decisions regarding clinical management. Once the family's specific APC mutation is identified in the proband, predictive testing for first degree relatives is possible from the age of 10 to 12 years on. For AFAP, relatives are tested at age 18 and older. Opinions about the appropriate ages at which to initiate genetic testing may vary. Physicians must have a discussion about prenatal testing with patients in childbearing age. They may either opt for conventional prenatal diagnosis (amniocentesis or chorionic villous sampling) or for preimplantation genetic diagnosis (PGD).

Childhood EEG frontal alpha power as a predictor of adolescent antisocial behavior: A twin heritability study

PubMed Central

Niv, Sharon; Ashrafulla, Syed; Tuvblad, Catherine; Joshi, Anand; Raine, Adrian; Leahy, Richard; Baker, Laura A.

2015-01-01

High EEG frontal alpha power (FAP) is thought to represent a state of low arousal in the brain, which has been related in past research to antisocial behavior (ASB). We investigated a longitudinal sample of 900 twins in two assessments in late childhood and mid-adolescence to verify whether relationships exist between FAP and both aggressive and nonaggressive ASB. ASB was measured by the Child Behavioral Checklist, and FAP was calculated using connectivity analysis methods that used principal components analysis to derive power of the most dominant frontal activation. Significant positive predictive relationships emerged in males between childhood FAP and adolescent aggressive ASB using multilevel mixed modeling. No concurrent relationships were found. Using bivariate biometric twin modeling analysis, the relationship between childhood FAP and adolescent aggressive ASB in males was found to be entirely due to genetic factors, which were correlated r = 0.22. PMID:25456277

Enhanced NIR downconversion luminescence by precipitating nano Ca5(PO4)3F crystals in Eu2+-Yb3+ co-doped glass

NASA Astrophysics Data System (ADS)

Li, Chen; Song, Zhiguo; Li, Yongjin; Lou, Kai; Qiu, Jianbei; Yang, Zhengwen; Yin, Zhaoyi; Wang, Xue; Wang, Qi; Wan, Ronghua

2013-10-01

Eu2+-Yb3+ co-doped transparent glass-ceramic containing nano-Ca5(PO4)3F (FAP) was prepared in reducing atmosphere. XRD and TEM analysis indicated that nano-FAP about 40 nm precipitated homogeneously in glass matrix after heat treatment. Confirmed by spectroscopy measurements, the crystal-like absorption and emission of Eu2+ indicated the partition of Eu2+ into FAP nanocrystals in glass ceramic. NIR emission due to the transition 2F→2F of Yb3+ ions (about 980-1100 nm) was observed from glasses under ultraviolet excitation, ascribed to downconversion from Eu2+ to Yb3+, which can be enhanced by precipitating nano-FAP crystals. The results indicated that Eu2+-Yb3+ co-doped glass-ceramic embedding with nano-FAP is a promising candidate as downconversion materials for enhancing conversion efficiency of solar cells.

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold.

PubMed

Jansen, Koen; Heirbaut, Leen; Cheng, Jonathan D; Joossens, Jurgen; Ryabtsova, Oxana; Cos, Paul; Maes, Louis; Lambeir, Anne-Marie; De Meester, Ingrid; Augustyns, Koen; Van der Veken, Pieter

2013-05-09

Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp(2) hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10(3)) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.

Structural change in lead fluorapatite at high pressure

NASA Astrophysics Data System (ADS)

Fleet, Michael E.; Liu, Xi; Shieh, Sean R.

2010-01-01

The structure of lead fluorapatite [PbFAP; Pb10(PO4)6F2], crystallized from the melt in a platinum capsule at 1,000°C and 1 atm, has been investigated by single-crystal X-ray diffraction. Crystal data are a = 9.7638 (6), c = 7.2866 (4) Å, space group P63/ m, R = 0.043, R w = 0.034. We have also studied the compressional behaviour of the c-axis channel of PbFAP up to 9 GPa at 25°C, using a diamond-anvil cell, synchrotron X-radiation, and Rietveld powder structure refinement. Pressure-volume data for the channel polyhedron of PbFAP fitted to the third-order Birch-Murnaghan equation resulted in K T = 33.2 ± 1.2 GPa when K T ' is fixed at 4. The c-axis channel of PbFAP is about twice as compressible as the unit-cell volume of PbFAP and the channel of calcium apatites. This is attributed to the anomalous narrowing of the channel of PbFAP with increase in confining pressure. Flexibility of the apatite channel is a key factor in the scavenging of toxic heavy metals by calcium apatites.

Low expression of miR-30a-5p induced the proliferation and invasion of oral cancer via promoting the expression of FAP.

PubMed

Ruan, Peng; Tao, Zezhang; Tan, Aili

2018-02-28

The study aimed at investigating the effects of miR-30a-5p on the biological functions of oral cancer cells and figuring out the potential mechanism. We first verified the low expression of miR-30a-5p and high expression of FAP ( Homo sapiens fibroblast activation protein α) in oral cancerous tissues and their negative correlation. Then, the target relationship between miR-30a-5p and FAP was validated by dual luciferase reporter assay and biotin-coupled miRNA pulldown assay. After transfection in Tca-8113 cells and SCC-15 cells, MTT, colony formation, Transwell, and wound healing assays were performed to investigate how miR-30a-5p and FAP adjusted propagation, invasiveness, and migration, respectively. Mounting evidence supported that miR-30a-5p directly targetted FAP and suppressed its expression in oral cavity cancer cells (OSCCs). By suppressing FAP expression, miR-30a-5p significantly inhibited cell propagation, migration, and invasion. Therefore, miR-30a-5p might be a new therapeutic target for oral cancer treatment. © 2018 The Author(s).

Familial Adenomatous Polyposis (FAP)-A Case Study and Review of Literature.

PubMed

Dalavi, Santosh Bhimrao; Vedpalsingh, Tanwar Harshwardhan; Bankar, Sanket Subhash; Ahmed, Mohd Hamid Shafique; Bhosale, Dattatray Nivrutti

2015-03-01

Familial adenomatous polyposis (FAP) is a syndrome characteristically having numerous (hundreds to thousands) polyps in the epithelium of the large intestines with an autosomal dominant inheritance caused by germ line mutations in adenomatous polyposis coli (APC) gene in chromosome 5q21. Most FAP patients have a family history of colorectal polyps and cancer but 25-30% of them are "de novo", without any clinical or genetic evidence of FAP in family members. Prophylactic proctocolectomy is required in almost all patients since all affected patients inevitably develop cancer. We report a case of a 32-year-old man who presented with vague abdominal complaints without any family history, which on evaluation as found to have multiple colorectal polyps and underwent a prophylactic proctocolectomy with end continent ileostomy. Two of his children were evaluated and found to have multiple colorectal polyps on colonoscopy and have been advised regular follow up annually. In conclusion, patients with FAP may present with vague abdominal complaints and without any family history, hence need to be carefully evaluated. Good patient compliance is of prime importance in deciding the treatment and surveillance modality subsequently determining the prognosis of patients with FAP.

Yb:S-FAP Lasers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schaffers, K I

It has recently been reported that several high power, diode-pumped laser systems have been developed based on crystals of Yb:S-FAP [Yb{sup 3+}:Sr{sub 5}(PO{sub 4}){sub 3}F]. The Mercury Laser, at Lawrence Livermore National Laboratory, is the most prominent system using Yb:S-FAP and is currently producing 23J at 5 Hz in a 15 nsec pulse, based on partial activation of the system. In addition, a regenerative amplifier is being developed at Waseda University in Japan and has produced greater than 12 mJ with high beam quality at 50Hz repetition rate. Q-peak has demonstrated 16 mJ of maximum energy/output pulse in a multi-pass,more » diode side-pumped amplifier and ELSA in France is implementing Yb:S-FAP in a 985 nm pump for an EDFA, producing 250 mW. Growth of high optical quality crystals of Yb:S-FAP is a challenge due to multiple crystalline defects. However, at this time, a growth process has been developed to produce high quality 3.5 cm diameter Yb:S-FAP crystals and a process is under development for producing 6.5 cm diameter crystals.« less

Low expression of miR-30a-5p induced the proliferation and invasion of oral cancer via promoting the expression of FAP

PubMed Central

Ruan, Peng; Tao, Zezhang

2017-01-01

The study aimed at investigating the effects of miR-30a-5p on the biological functions of oral cancer cells and figuring out the potential mechanism. We first verified the low expression of miR-30a-5p and high expression of FAP (Homo sapiens fibroblast activation protein α) in oral cancerous tissues and their negative correlation. Then, the target relationship between miR-30a-5p and FAP was validated by dual luciferase reporter assay and biotin-coupled miRNA pulldown assay. After transfection in Tca-8113 cells and SCC-15 cells, MTT, colony formation, Transwell, and wound healing assays were performed to investigate how miR-30a-5p and FAP adjusted propagation, invasiveness, and migration, respectively. Mounting evidence supported that miR-30a-5p directly targetted FAP and suppressed its expression in oral cavity cancer cells (OSCCs). By suppressing FAP expression, miR-30a-5p significantly inhibited cell propagation, migration, and invasion. Therefore, miR-30a-5p might be a new therapeutic target for oral cancer treatment. PMID:29026005

Upper GI tract lesions in familial adenomatous polyposis (FAP): enrichment of pyloric gland adenomas and other gastric and duodenal neoplasms.

PubMed

Wood, Laura D; Salaria, Safia N; Cruise, Michael W; Giardiello, Francis M; Montgomery, Elizabeth A

2014-03-01

Patients with familial adenomatous polyposis (FAP), an autosomal dominant cancer predisposition syndrome caused by mutations in the APC gene, develop neoplasms in both the upper and lower gastrointestinal (GI) tract. To clarify the upper GI tract lesions in FAP patients in a tertiary care setting, we reviewed specimens from 321 endoscopies in 66 patients with FAP. Tubular adenomas in the small bowel were the most common neoplasms (present in 89% of patients), although only 1 patient developed invasive carcinoma of the small bowel. Several types of gastric neoplasms were identified--65% of patients had at least 1 fundic gland polyp, and 23% of patients had at least 1 gastric foveolar-type gastric adenoma. Pyloric gland adenomas were also enriched, occurring in 6% of patients--this is a novel finding in FAP patients. Despite the high frequency of gastric neoplasms, only 1 patient developed carcinoma in the stomach. The very low frequency of carcinoma in these patients suggests that current screening procedures prevent the vast majority of upper GI tract carcinomas in patients with FAP, at least in the tertiary care setting.

Surgical considerations in FAP-related pouch surgery: Could we do better?

PubMed

Möslein, Gabriela

2016-07-01

The ileoanal pouch has become the standard restorative procedure of choice for patients with the classical phenotype in FAP (familial adenomatous polyposis) and also for ulcerative colitis (UC). Whilst we tend to encounter descriptive analyses comparing functional outcome, fertility and quality of life (QOL) between series in literature, there may be an urgent need to discuss the subtle technical modifications that may be pivotal for improving long-term QOL in FAP patients. Our aim is to review the current literature and discuss the aspects of ileal pouch-anal anastomosis that may require specific reevaluation for FAP. Surgical strategies aimed at minimizing post-interventional desmoid growth is one of the most important aspects. For this study, the following topics of interest were selected: Timing of surgery, IRA or ileoanal pouch for classical FAP, laparoscopic or conventional surgery, TME or mesenteric dissection, preservation of the ileocolic vessels, handsewn or double-staple anastomosis, shape and size of pouch, protective ileostomy, Last and definitely not least: how to manage desmoid plaques or desmoids at the time of prophylactic surgery. For the depicted technicalities of the procedure, a review of recent literature was performed and evaluated. For the topics selected, only sparse reference in literature was identified that was focused on the specific condition situation of FAP. Almost all pouch literature focusses on the procedural aspects, and FAP patients are always a very minor number. Therefore it becomes obvious that the specific entity is not adequately taken into account. This is a serious bias for identification of important steps in the procedure that may be beneficial for patients with either of the diseases. The results of this study demonstrate that several technical differences for construction of ileoanal pouches in FAP patients deserve more attention and prospective evaluation-perhaps even randomized trials. The role, importance and potential benefit or deterioration of outcome in most of the discussed technicalities remains unclear to date. Significant differences between the underlying diseases (UC and FAP) have not been taken into consideration, such as specifically the management of precursor desmoid lesions at the time of prophylactic surgery as well as prevention of desmoid tumors. Several of the aspects discussed in this paper should be prospectively evaluated in larger and exclusive series of FAP patients.

Isolation and characterization of Chinese standard fulvic acid sub-fractions separated from forest soil by stepwise elution with pyrophosphate buffer.

PubMed

Bai, Yingchen; Wu, Fengchang; Xing, Baoshan; Meng, Wei; Shi, Guolan; Ma, Yan; Giesy, John P

2015-03-04

XAD-8 adsorption technique coupled with stepwise elution using pyrophosphate buffers with initial pH values of 3, 5, 7, 9, and 13 was developed to isolate Chinese standard fulvic acid (FA) and then separated the FA into five sub-fractions: FApH3, FApH5, FApH7, FApH9 and FApH13, respectively. Mass percentages of FApH3-FApH13 decreased from 42% to 2.5%, and the recovery ratios ranged from 99.0% to 99.5%. Earlier eluting sub-fractions contained greater proportions of carboxylic groups with greater polarity and molecular mass, and later eluting sub-fractions had greater phenolic and aliphatic content. Protein-like components, as well as amorphous and crystalline poly(methylene)-containing components were enriched using neutral and basic buffers. Three main mechanisms likely affect stepwise elution of humic components from XAD-8 resin with pyrophosphate buffers including: 1) the carboxylic-rich sub-fractions are deprotonated at lower pH values and eluted earlier, while phenolic-rich sub-fractions are deprotonated at greater pH values and eluted later. 2) protein or protein-like components can be desorbed and eluted by use of stepwise elution as progressively greater pH values exceed their isoelectric points. 3) size exclusion affects elution of FA sub-fractions. Successful isolation of FA sub-fractions will benefit exploration of the origin, structure, evolution and the investigation of interactions with environmental contaminants.

Purification, crystallization and characterization of the Pseudomonas outer membrane protein FapF, a functional amyloid transporter.

PubMed

Rouse, Sarah L; Hawthorne, Wlliam J; Lambert, Sebastian; Morgan, Marc L; Hare, Stephen A; Matthews, Stephen

2016-12-01

Bacteria often produce extracellular amyloid fibres via a multi-component secretion system. Aggregation-prone, unstructured subunits cross the periplasm and are secreted through the outer membrane, after which they self-assemble. Here, significant progress is presented towards solving the high-resolution crystal structure of the novel amyloid transporter FapF from Pseudomonas, which facilitates the secretion of the amyloid-forming polypeptide FapC across the bacterial outer membrane. This represents the first step towards obtaining structural insight into the products of the Pseudomonas fap operon. Initial attempts at crystallizing full-length and N-terminally truncated constructs by refolding techniques were not successful; however, after preparing FapF 106-430 from the membrane fraction, reproducible crystals were obtained using the sitting-drop method of vapour diffusion. Diffraction data have been processed to 2.5 Å resolution. These crystals belonged to the monoclinic space group C121, with unit-cell parameters a = 143.4, b = 124.6, c = 80.4 Å, α = γ = 90, β = 96.32° and three monomers in the asymmetric unit. It was found that the switch to complete detergent exchange into C8E4 was crucial for forming well diffracting crystals, and it is suggested that this combined with limited proteolysis is a potentially useful protocol for membrane β-barrel protein crystallography. The three-dimensional structure of FapF will provide invaluable information on the mechanistic differences of biogenesis between the curli and Fap functional amyloid systems.

Autonomic dysfunction affects cerebral neurovascular coupling.

PubMed

Azevedo, Elsa; Castro, Pedro; Santos, Rosa; Freitas, João; Coelho, Teresa; Rosengarten, Bernhard; Panerai, Ronney

2011-12-01

Autonomic failure (AF) affects the peripheral vascular system, but little is known about its influence on cerebrovascular regulation. Patients with familial amyloidotic polyneuropathy (FAP) were studied as a model for AF. Ten mild (FAPm), 10 severe (FAPs) autonomic dysfunction FAP patients, and 15 healthy controls were monitored in supine and sitting positions for arterial blood pressure (ABP) and heart rate (HR) with arterial volume clamping, and for blood flow velocity (BFV) in posterior (PCA) and contralateral middle cerebral arteries (MCA) with transcranial Doppler. Analysis included resting BFV, cerebrovascular resistance parameters (cerebrovascular resistance index, CVRi; resistance area product, RAP; and critical closing pressure, CrCP), and neurovascular coupling through visually evoked BFV responses in PCA (gain, rate time, attenuation, and natural frequency). In non-stimulation conditions, in each position, there were no significant differences between the groups, regarding HR, BP, resting BFV, and vascular resistance parameters. Sitting ABP was higher than in supine in the three groups, although only significantly in controls. Mean BFV was lower in sitting in all the groups, lacking statistical significance only in FAPs PCA. CVRi and CrCP increased with sitting in all the groups, while RAP increased in controls but decreased in FAPm and FAPs. In visual stimulation conditions, FAPs comparing to controls had a significant decrease of natural frequency, in supine and sitting, and of rate time and gain in sitting position. These results demonstrate that cerebrovascular regulation is affected in FAP subjects with AF, and that it worsens with orthostasis.

Isolation and Characterization of Chinese Standard Fulvic Acid Sub-fractions Separated from Forest Soil by Stepwise Elution with Pyrophosphate Buffer

PubMed Central

Bai, Yingchen; Wu, Fengchang; Xing, Baoshan; Meng, Wei; Shi, Guolan; Ma, Yan; Giesy, John P.

2015-01-01

XAD-8 adsorption technique coupled with stepwise elution using pyrophosphate buffers with initial pH values of 3, 5, 7, 9, and 13 was developed to isolate Chinese standard fulvic acid (FA) and then separated the FA into five sub-fractions: FApH3, FApH5, FApH7, FApH9 and FApH13, respectively. Mass percentages of FApH3-FApH13 decreased from 42% to 2.5%, and the recovery ratios ranged from 99.0% to 99.5%. Earlier eluting sub-fractions contained greater proportions of carboxylic groups with greater polarity and molecular mass, and later eluting sub-fractions had greater phenolic and aliphatic content. Protein-like components, as well as amorphous and crystalline poly(methylene)-containing components were enriched using neutral and basic buffers. Three main mechanisms likely affect stepwise elution of humic components from XAD-8 resin with pyrophosphate buffers including: 1) the carboxylic-rich sub-fractions are deprotonated at lower pH values and eluted earlier, while phenolic-rich sub-fractions are deprotonated at greater pH values and eluted later. 2) protein or protein-like components can be desorbed and eluted by use of stepwise elution as progressively greater pH values exceed their isoelectric points. 3) size exclusion affects elution of FA sub-fractions. Successful isolation of FA sub-fractions will benefit exploration of the origin, structure, evolution and the investigation of interactions with environmental contaminants. PMID:25735451

Female sexual and pelvic floor muscles dysfunctions in familial amyloidotic polyneuropathy (FAP-Portuguese type).

PubMed

Gomes, Mario João; Martins da Silva, Antonio; Salinas, Jesus; Silva, Maria Carolina; Figueiredo, Arnaldo; Cavadas, Vitor; Coelho, Teresa

2012-05-01

The aim of this study was to investigate the prevalence of Sexual and Pelvic Floor Dysfunctions associated with familial type 1 Portuguese amyloid polyneuropathy (FAP). We studied women with FAP in three stages of the disease: asymptomatic women (n=12), women in the early stage of the disease (n=8) and 3 women in the most progressive stage of the disease. We hypothesize that women with FAP suffer from pelvic floor hypotonicity, which may hinder orgasmic function and as such, lead to deteriorated sexual function. Twenty-three women with FAP were studied. Clinical examinations were performed using the following scales: Clinical Evaluation Scale (CES), Visual Analog Scale of Quality of Life (VAS), Female Sexual Function Index (FSFI) and Pelvic Floor Manometry (PFM). Of the women, 5 (21.7%) had a score of < 26 on the FSFI, suggesting sexual dysfunction, 3 of which had FAP at the most progressive stage. None of the asymptomatic women had low FSFI scores. The manometrical rates (PFM) of tonus and strength of the pelvic floor showed significant differences between groups. Female sexual dysfunction (FSD) may occur in the initial stages of the disease but is more prevalent in women in the advanced stages of the disease. There is an increasing incidence of FSD as FAP disease progresses, namely in terms of HSDD and orgasmic sensation. In the asymptomatic group, the females revealed PFM alterations without stress urinary incontinence, which is regarded to be a discrete deterioration of pelvic floor muscle function.

The role of mutation analysis of the APC gene in the management of FAP patients. A controversial issue.

PubMed

Dodaro, Concetta; Grifasi, Carlo; Florio, Jole; Santangelo, Michele L; Duraturo, Francesca; De Rosa, Marina; Izzo, Paola; Renda, Andrea

A correlation between the location of mutation in the adenomatous polyposis coli (APC) gene and clinical manifestations of familial adenomatous polyposis (FAP) has repeatedly been reported. Some Authors suggest the use of mutational analysis as a guide to select the best surgical option in FAP patients. However, data coming from studies on large series have raised questions on this issue. The aim of this study is to discuss the role of the genetic tests in the management of FAP. A literature review was performed considering only peer-reviewed articles published between 1991-2015. All the studies examined the role of genetic as a guide for surgical management of FAP. Of 363 articles identified, 21 were selected for full-text review. We found different positions with regard the use of genetic tests to determine surgical management of FAP. In particular, while consistent correlations between the APC mutation site and FAP phenotype were observed in large series, 8 studies reported a wide variation of genotypephenotype correlation in patients with the same mutation and they recommended that decisions regarding surgical strategy should be based not only on genotype but also on the clinical factors and the will of the patient who must be fully informed. The decision on the type and the timing of surgery should be based on the assessment of many factors and genotype assessment should be used in combination with clinical data. Disease severity, Familial adenomatous polyposis, Genetic tests, Genotype-phenotype correlations, Surgical management.

Rapid progression of familial amyloidotic polyneuropathy

PubMed Central

Coelho, Teresa; Obici, Laura; Merlini, Giampaolo; Mincheva, Zoia; Suanprasert, Narupat; Bettencourt, Brian R.; Gollob, Jared A.; Gandhi, Pritesh J.; Litchy, William J.; Dyck, Peter J.

2015-01-01

Objectives: To assess the association between severity of neuropathy and disease stage, and estimate the rate of neuropathy progression in a retrospective cross-sectional analysis of a multinational population of patients with familial amyloidotic polyneuropathy (FAP). Methods: We characterize neuropathy severity and rate of progression in available patients with FAP in France, the United States, Portugal, and Italy. Neuropathy Impairment Scores (NIS), time from symptom onset to NIS measurement, polyneuropathy disability (PND) scores, FAP disease stage, and manual grip strength data were collected. We estimated neuropathy progression using Loess Fit and Gompertz Fit models. Results: For the 283 patients studied (mean age, 56.4 years), intercountry genotypic variation in the transthyretin (TTR) mutation was observed, with the majority of patients in Portugal (92%) having early-onset Val30Met-FAP. There was also marked intercountry variation in PND score, FAP stage, and TTR stabilizer use. NIS was associated with PND score (NIS 10 and 99 for scores I and IV, respectively; p < 0.0001) and FAP stage (NIS 14 and 99 for stages 1 and 3, respectively; p < 0.0001). In addition, there was an association between NIS and TTR genotype. The estimated rate of NIS progression for a population with a median NIS of 32 was 14.3 points/year; the corresponding estimated rate for the modified NIS+7 is 17.8 points/year. Conclusions: In a multinational population of patients with FAP, rapid neuropathic progression is observed and the severity of neuropathy is associated with functional scales of locomotion. PMID:26208957

Method for fabricating apatite crystals and ceramics

DOEpatents

Soules, Thomas F.; Schaffers, Kathleen I.; Tassano, Jr., John B.; Hollingsworth, Joel P.

2013-09-10

The present invention provides a method of crystallizing Yb:C-FAP [Yb.sup.3+:Ca.sub.5(PO.sub.4).sub.3F], by dissolving the Yb:C-FAP in an acidic solution, following by neutralizing the solution. The present invention also provides a method of forming crystalline Yb:C-FAP by dissolving the component ingredients in an acidic solution, followed by forming a supersaturated solution.

Imaging Prostate Cancer with Positron Emission Tomography

DTIC Science & Technology

2014-07-01

critical role in tumor development. The purpose of this proposal is to utilize fibroblast activation protein alpha ( FAP ) expression on TAFs within...based cell lines, which stably express eGFP and FAP . Ongoing experiments are focused on the in vitro and in vivo evaluation of each radiopharmaceutical...and on understanding the growth characteristics of each transfected cell line in vivo. 15. SUBJECT TERMS PET, Prostate Cancer, FAP , molecular

Fibroblast activation protein is induced by inflammation and degrades type I collagen in thin-cap fibroatheromata

PubMed Central

Brokopp, Chad E.; Schoenauer, Roman; Richards, Peter; Bauer, Stefan; Lohmann, Christine; Emmert, Maximilian Y.; Weber, Benedikt; Winnik, Stephan; Aikawa, Elena; Graves, Kirk; Genoni, Michele; Vogt, Peter; Lüscher, Thomas F.; Renner, Christoph; Hoerstrup, Simon P.; Matter, Christian M.

2011-01-01

Aims Collagen degradation in atherosclerotic plaques with thin fibrous caps renders them more prone to rupture. Fibroblast activation protein (FAP) plays a role in arthritis and tumour formation through its collagenase activity. However, the significance of FAP in thin-cap human fibroatheromata remains unknown. Methods and results We detected enhanced FAP expression in type IV–V human aortic atheromata (n = 12), compared with type II–III lesions (n = 9; P < 0.01) and healthy aortae (n = 8; P < 0.01) by immunostaining and western blot analyses. Fibroblast activation protein was also increased in thin-cap (<65 µm) vs. thick-cap (≥65 µm) human coronary fibroatheromata (n = 12; P < 0.01). Fibroblast activation protein was expressed by human aortic smooth muscle cells (HASMC) as shown by colocalization on immunofluorescent aortic plaque stainings (n = 10; P < 0.01) and by flow cytometry in cell culture. Although macrophages did not express FAP, macrophage burden in human aortic plaques correlated with FAP expression (n = 12; R2= 0.763; P < 0.05). Enzyme-linked immunosorbent assays showed a time- and dose-dependent up-regulation of FAP in response to human tumour necrosis factor α (TNFα) in HASMC (n = 6; P < 0.01). Moreover, supernatants from peripheral blood-derived macrophages induced FAP expression in cultured HASMC (n = 6; P < 0.01), an effect abolished by blocking TNFα (n = 6; P < 0.01). Fibroblast activation protein associated with collagen-poor regions in human coronary fibrous caps and digested type I collagen and gelatin in vitro (n = 6; P < 0.01). Zymography revealed that FAP-mediated collagenase activity was neutralized by an antibody directed against the FAP catalytic domain both in HASMC (n = 6; P < 0.01) and in fibrous caps of atherosclerotic plaques (n = 10; P < 0.01). Conclusion Fibroblast activation protein expression in HASMC is induced by macrophage-derived TNFα. Fibroblast activation protein associates with thin-cap human coronary fibroatheromata and contributes to type I collagen breakdown in fibrous caps. PMID:21292680

Characterisation of FAP-1 expression and CD95 mediated apoptosis in the A818-6 pancreatic adenocarcinoma differentiation system.

PubMed

Winterhoff, Boris J N; Arlt, Alexander; Duttmann, Angelika; Ungefroren, Hendrik; Schäfer, Heiner; Kalthoff, Holger; Kruse, Marie-Luise

2012-03-01

The present study investigated the expression and localisation of FAP-1 (Fas associated phosphatase-1) and CD95 in a 3D differentiation model in comparison to 2D monolayers of the pancreatic adenocarcinoma cell line A818-6. Under non-adherent growth conditions, A818-6 cells differentiate into 3D highly organised polarised epithelial hollow spheres, resembling duct-like structures. A818-6 cells showed a differentiation-dependent FAP-1 localisation. Cells grown as 2D monolayers revealed FAP-1 staining in a juxtanuclear cisternal position, as well as localisation in the nucleus. After differentiation into hollow spheres, FAP-1 was relocated towards the actin cytoskeleton beneath the outer plasma membrane of polarised cells and no further nuclear localisation was observed. CD95 surface staining was found only in a subset of A818-6 monolayer cells, while differentiated hollow spheres appeared to express CD95 in all cells of a given sphere. We rarely observed co-localisation of CD95 and FAP-1 in A818-6 monolayer cells, but strong co-localisation beneath the outer plasma membrane in polarised cells. Analysis of surface expression by flow cytometry revealed that only a subset (36%) of monolayer cells showed CD95 surface expression, and after induction of hollow spheres, CD95 presentation at the outer plasma membrane was reduced to 13% of hollow spheres. Induction of apoptosis by stimulation with agonistic anti-CD95 antibodies, resulted in increased caspase activity in both, monolayer cells and hollow spheres. Knock down of FAP-1 mRNA in A818-6 monolayer cells did not alter resposiveness to CD95 agonistic antibodies. These data suggested that CD95 signal transduction was not affected by FAP-1 expression in A818-6 monolayer cells. In differentiated 3D hollow spheres, we found a polarisation-induced co-localisation of CD95 and FAP-1. A tight control of receptor surface representation and signalling induced apoptosis ensures controlled removal of individual cells instead of a "snowball effect" of apoptotic events. Copyright © 2011 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Update on diode-pumped solid-state laser experiments for inertial fusion energy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marshall, C.; Smith, L.; Payne, S.

The authors have completed the initial phase of the diode-pumped solid-state laser (DPSSL) experimental program to validate the expected pumping dynamics and extraction cross-sections of Yb{sup 3+}-doped Sr{sub 5}(PO{sub 4}){sub 3}F (Yb:S-FAP) crystals. Yb:S-FAP crystals up to 25 x 25 x 175 mm in size have been grown for this purpose which have acceptable loss characteristics (<1 %/cm) and laser damage thresholds ({approximately}20 J/cm{sup 2}). The saturation fluence for pumping has been measured to be 2.2 J/cm{sup 2} using three different methods based on either the spatial, temporal, or energy transmission properties of a Yb:S-FAP rod. The small signal gainmore » under saturated pumping conditions was measured. These measurements imply an emission cross section of 6.0 x 10{sup {minus}20} cm{sup 2} that falls within error bars of the previously reported value of 7.3 x 10{sup {minus}20} cm{sup 2}, obtained from purely spectroscopic techniques. The effects of radiation trapping on the emission lifetime have been quantified. The long lifetime of Yb:S-FAP has beneficial effects for diode-pumped amplifier designs, relative to materials with equivalent cross sections but shorter lifetimes, in that less peak pump intensity is required (thus lower diode costs) and that lower spontaneous emission rates lead to a reduction in amplified spontaneous emission. Consequently, up to 1.7 J/cm{sup 3} of stored energy density was achieved in a 6x6x44 mm Yb:S-FAP amplifier rod; this stored energy density is large relative to typical flashlamp-pumped Nd:glass values of 0.3 to 0.5 J/cm{sup 3}. A 2.4 kW peak power InGaAs diode array has been fabricated by Beach, Emanuel, and co-workers which meets the central wavelength, bandwidth, and energy specifications for the author`s immediate experiments. These results further increase their optimism of being able to produce a {approximately} 10% efficient diode-pumped solid state laser for inertial fusion energy.« less

Childhood EEG frontal alpha power as a predictor of adolescent antisocial behavior: a twin heritability study.

PubMed

Niv, Sharon; Ashrafulla, Syed; Tuvblad, Catherine; Joshi, Anand; Raine, Adrian; Leahy, Richard; Baker, Laura A

2015-02-01

High EEG frontal alpha power (FAP) is thought to represent a state of low arousal in the brain, which has been related in past research to antisocial behavior (ASB). We investigated a longitudinal sample of 900 twins in two assessments in late childhood and mid-adolescence to verify whether relationships exist between FAP and both aggressive and nonaggressive ASB. ASB was measured by the Child Behavioral Checklist, and FAP was calculated using connectivity analysis methods that used principal components analysis to derive power of the most dominant frontal activation. Significant positive predictive relationships emerged in males between childhood FAP and adolescent aggressive ASB using multilevel mixed modeling. No concurrent relationships were found. Using bivariate biometric twin modeling analysis, the relationship between childhood FAP and adolescent aggressive ASB in males was found to be entirely due to genetic factors, which were correlated r=0.22. Copyright © 2014 Elsevier B.V. All rights reserved.

Functional abdominal pain.

PubMed

Grover, Madhusudan; Drossman, Douglas A

2010-10-01

Functional abdominal pain syndrome (FAPS) is a relatively less common functional gastrointestinal (GI) disorder defined by the presence of constant or frequently recurring abdominal pain that is not associated with eating, change in bowel habits, or menstrual periods (Drossman Gastroenterology 130:1377-1390, 2006), which points to a more centrally targeted (spinal and supraspinal) basis for the symptoms. However, FAPS is frequently confused with irritable bowel syndrome and other functional GI disorders in which abdominal pain is associated with eating and bowel movements. FAPS also differs from chronic abdominal pain associated with entities such as chronic pancreatitis or chronic inflammatory bowel disease, in which the pain is associated with peripherally acting factors (eg, gut inflammation or injury). Given the central contribution to the pain experience, concomitant psychosocial disturbances are common and strongly influence the clinical expression of FAPS, which also by definition is associated with loss of daily functioning. These factors make it critical to use a biopsychosocial construct to understand and manage FAPS, because gut-directed treatments are usually not successful in managing this condition.

Evaluation of (/sup 18/F)-4-fluoroantipyrine as a new blood flow tracer for multiradionuclide autoradiography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sako, K.; Diksic, M.; Kato, A.

This article reports the evaluation of (/sup 18/F)-4-fluoroantipyrine (FAP) as a quantitative blood flow tracer by comparing blood flow measured with (/sup 18/F)FAP to that determined simultaneously with (/sup 14/C)-4-iodoantipyrine (IAP), a standard blood flow tracer, by means of double-tracer autoradiography. The single-pass extraction value (m), which indicates diffusibility of a tracer, was determined according to the procedure described by Crone. The diffusibility of FAP was essentially the same as that of IAP. The brain-blood partition coefficient for FAP was found to be similar to that for IAP, 0.89 +/- 0.01. Values of local cerebral blood flow obtained with FAPmore » agree with those determined with IAP. From these results, we concluded that FAP is indeed as good a blood flow tracer as IAP. Since /sup 18/F is a positron-emitting radionuclide, it might be a useful tracer for blood flow measurement by positron emission tomography.« less

Functional amyloid in Pseudomonas.

PubMed

Dueholm, Morten S; Petersen, Steen V; Sønderkær, Mads; Larsen, Poul; Christiansen, Gunna; Hein, Kim L; Enghild, Jan J; Nielsen, Jeppe L; Nielsen, Kåre L; Nielsen, Per H; Otzen, Daniel E

2010-08-01

Amyloids are highly abundant in many microbial biofilms and may play an important role in their architecture. Nevertheless, little is known of the amyloid proteins. We report the discovery of a novel functional amyloid expressed by a Pseudomonas strain of the P. fluorescens group. The amyloid protein was purified and the amyloid-like structure verified. Partial sequencing by MS/MS combined with full genomic sequencing of the Pseudomonas strain identified the gene coding for the major subunit of the amyloid fibril, termed fapC. FapC contains a thrice repeated motif that differs from those previously found in curli fimbrins and prion proteins. The lack of aromatic residues in the repeat shows that aromatic side chains are not needed for efficient amyloid formation. In contrast, glutamine and asparagine residues seem to play a major role in amyloid formation as these are highly conserved in curli, prion proteins and FapC. fapC is conserved in many Pseudomonas strains including the opportunistic pathogen P. aeruginosa and is situated in a conserved operon containing six genes, of which one encodes a fapC homologue. Heterologous expression of the fapA-F operon in Escherichia coli BL21(DE3) resulted in a highly aggregative phenotype, showing that the operon is involved in biofilm formation. © 2010 Blackwell Publishing Ltd.

Therapeutic Response for Functional Abdominal Pain in Children with Occult Constipation: Laxatives versus Prokinetic Drugs.

PubMed

Ha, Eun Kyo; Jang, Homin; Jeong, Su Jin

2017-01-01

The relationship between functional abdominal pain (FAP) and occult constipation (OC) in children who did not meet the Rome III criteria for constipation has rarely been reported. This study aimed to estimate the prevalence of OC in patients with FAP and to compare the effectiveness of prokinetic drugs and laxatives for FAP and OC. Pediatric outpatients (n = 212; aged 4-15 years) who satisfied the Rome III criteria for childhood FAP were divided into 2 groups based on Leech scores: group 1 < 8; group 2 ≥ 8. Group 2 received either prokinetic drugs or laxatives and pain severity was assessed after 2 weeks, 1 month, and 3 months. A total 52.4% (111/212) of patients had OC in this study. More patients who received laxatives had reduced pain scores compared with those who received prokinetic drugs. Those treated with laxatives in group 2 had a better response than those treated with prokinetic drugs throughout the study period (P < 0.001, P < 0.001, and P = 0.002 after 2 weeks, 1 month, and 3 months, respectively). OC was frequently encountered in children with FAP. Laxatives can be more effective than prokinetic drugs for relieving symptoms of FAP in children with a Leech score ≥ 8 and suspected OC.

Ambient measurement of fluorescent aerosol particles with a WIBS in the Yangtze River Delta of China: potential impacts of combustion-related aerosol particles

NASA Astrophysics Data System (ADS)

Yu, Xiawei; Wang, Zhibin; Zhang, Minghui; Kuhn, Uwe; Xie, Zhouqing; Cheng, Yafang; Pöschl, Ulrich; Su, Hang

2016-09-01

Fluorescence characteristics of aerosol particles in a polluted atmosphere were studied using a wideband integrated bioaerosol spectrometer (WIBS-4A) in Nanjing, Yangtze River Delta area of China. We observed strong diurnal and day-to-day variations of fluorescent aerosol particles (FAPs). The average number concentrations of FAPs (1-15 µm) detected in the three WIBS measurement channels (FL1: 0.6 cm-3, FL2: 3.4 cm-3, FL3: 2.1 cm-3) were much higher than those observed in forests and rural areas, suggesting that FAPs other than bioaerosols were detected. We found that the number fractions of FAPs were positively correlated with the black carbon mass fraction, especially for the FL1 channel, indicating a large contribution of combustion-related aerosols. To distinguish bioaerosols from combustion-related FAPs, we investigated two classification schemes for use with WIBS data. Our analysis suggests a strong size dependence for the fractional contributions of different types of FAPs. In the FL3 channel, combustion-related particles seem to dominate the 1-2 µm size range while bioaerosols dominate the 2-5 µm range. The number fractions of combustion-related particles and non-combustion-related particles to total aerosol particles were ˜ 11 and ˜ 5 %, respectively.

HRV biofeedback for pediatric irritable bowel syndrome and functional abdominal pain: a clinical replication series.

PubMed

Stern, Mark J; Guiles, Robert A F; Gevirtz, Richard

2014-12-01

Irritable bowel syndrome (IBS) and Functional Abdominal Pain (FAP) are among the most commonly reported Functional Gastrointestinal Disorders. Both have been associated with varying autonomic dysregulation. Heart Rate Variability Biofeedback (HRVB) has recently begun to show efficacy in the treatment of both IBS and FAP. The purpose of this multiple clinical replication series was to analyze the clinical outcomes of utilizing HRVB in a clinical setting. Archival data of twenty-seven consecutive pediatric outpatients diagnosed with IBS or FAP who received HRVB were analyzed. Clinical outcomes were self-report and categorized as full or remission with patient satisfaction, or no improvement. Qualitative reports of patient experiences were also noted. Full remission was achieved by 69.2 % and partial remission was achieved by 30.8 % of IBS patients. Full remission was achieved by 63.6 % and partial remission was achieved by 36.4 % of FAP patients. No patients in either group did not improve to a level of patient satisfaction or >50 %. Patient's commonly reported feeling validated in their discomfort as a result of psychophysiological education. Results suggest that HRVB is a promising intervention for pediatric outpatients with IBS or FAP. Randomized controlled trials are necessary to accurately determine clinical efficacy of HRVB in the treatment of IBS and FAP.

Through-plane conductivities of membranes for nonaqueous redox flow batteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, Travis Mark; Small, Leo J.; Pratt, III, Harry D.

In this study, nonaqueous redox flow batteries (RFB) leverage nonaqueous solvents to enable higher operating voltages compared to their aqueous counterparts. Most commercial components for flow batteries, however, are designed for aqueous use. One critical component, the ion-selective membrane, provides ionic conductance between electrodes while preventing crossover of electroactive species. Here we evaluate the area-specific conductances and through-plane conductivities of commercially available microporous separators (Celgard 2400, 2500) and anion exchange membranes (Neosepta AFX, Neosepta AHA, Fumasep FAP-450, Fumasep FAP-PK) soaked in acetonitrile, propylene carbonate, or two imidazolium-based ionic liquids. Fumasep membranes combined with acetonitrile-based electrolyte solutions provided the highest conductancemore » values and conductivities by far. When tested in ionic liquids, all anion exchange membranes displayed conductivities greater than those of the Celgard microporous separators, though the separators’ decreased thickness-enabled conductances on par with the most conductive anion exchange membranes. Ionic conductivity is not the only consideration when choosing an anion exchange membrane; testing of FAP-450 and FAP-PK membranes in a nonaqueous RFB demonstrated that the increased mechanical stability of PEEK-supported FAP-PK minimized swelling, in turn decreasing solvent mediated crossover and enabling greater electrochemical yields (40% vs. 4%) and Coulombic efficiencies (94% vs. 90%) compared to the unsupported, higher conductance FAP-450.« less

miR-204 reverses temozolomide resistance and inhibits cancer initiating cells phenotypes by degrading FAP-α in glioblastoma.

PubMed

Yang, Yun-Na; Zhang, Xiang-Hua; Wang, Yan-Ming; Zhang, Xi; Gu, Zheng

2018-05-01

Malignant gliomas are treated with temozolomide (TMZ) at present, but often exhibit resistance to this agent. Cancer-initiating cells (CICs) have been suggested to lead to TMZ resistance. The mechanisms underlying CICs-based TMZ resistance are not fully understood. MicroRNAs (miRNAs) have been demonstrated to serve important roles in tumorigenesis and TMZ resistance. In the present study, a sphere forming assay and western blot analysis were performed to detect the formation of CICs and fibroblast activation protein α (FAP-α) protein expression. It was revealed that TMZ resistance promoted the formation of CICs and upregulated FAP-α expression in glioblastoma cells. Over-expressing FAP-α was also demonstrated to promote TMZ resistance and induce the formation of CICs in U251MG cells. In addition, using a reverse transcription-quantitative polymerase chain reaction, it was observed that miR-204 was downregulated in U251MG-resistant (-R) cells. miR-204 expression negatively correlated with the FAP-α levels in human glioblastoma tissues, and it may inhibit the formation of CICs and reverse TMZ resistance in U251MG-R cells. Therefore, it was concluded that miR-204 reversed temozolomide resistance and inhibited CICs phenotypes by degrading FAP-α in glioblastoma.

Through-plane conductivities of membranes for nonaqueous redox flow batteries

DOE PAGES

Anderson, Travis Mark; Small, Leo J.; Pratt, III, Harry D.; ...

2015-08-13

In this study, nonaqueous redox flow batteries (RFB) leverage nonaqueous solvents to enable higher operating voltages compared to their aqueous counterparts. Most commercial components for flow batteries, however, are designed for aqueous use. One critical component, the ion-selective membrane, provides ionic conductance between electrodes while preventing crossover of electroactive species. Here we evaluate the area-specific conductances and through-plane conductivities of commercially available microporous separators (Celgard 2400, 2500) and anion exchange membranes (Neosepta AFX, Neosepta AHA, Fumasep FAP-450, Fumasep FAP-PK) soaked in acetonitrile, propylene carbonate, or two imidazolium-based ionic liquids. Fumasep membranes combined with acetonitrile-based electrolyte solutions provided the highest conductancemore » values and conductivities by far. When tested in ionic liquids, all anion exchange membranes displayed conductivities greater than those of the Celgard microporous separators, though the separators’ decreased thickness-enabled conductances on par with the most conductive anion exchange membranes. Ionic conductivity is not the only consideration when choosing an anion exchange membrane; testing of FAP-450 and FAP-PK membranes in a nonaqueous RFB demonstrated that the increased mechanical stability of PEEK-supported FAP-PK minimized swelling, in turn decreasing solvent mediated crossover and enabling greater electrochemical yields (40% vs. 4%) and Coulombic efficiencies (94% vs. 90%) compared to the unsupported, higher conductance FAP-450.« less

miR-204 reverses temozolomide resistance and inhibits cancer initiating cells phenotypes by degrading FAP-α in glioblastoma

PubMed Central

Yang, Yun-Na; Zhang, Xiang-Hua; Wang, Yan-Ming; Zhang, Xi; Gu, Zheng

2018-01-01

Malignant gliomas are treated with temozolomide (TMZ) at present, but often exhibit resistance to this agent. Cancer-initiating cells (CICs) have been suggested to lead to TMZ resistance. The mechanisms underlying CICs-based TMZ resistance are not fully understood. MicroRNAs (miRNAs) have been demonstrated to serve important roles in tumorigenesis and TMZ resistance. In the present study, a sphere forming assay and western blot analysis were performed to detect the formation of CICs and fibroblast activation protein α (FAP-α) protein expression. It was revealed that TMZ resistance promoted the formation of CICs and upregulated FAP-α expression in glioblastoma cells. Over-expressing FAP-α was also demonstrated to promote TMZ resistance and induce the formation of CICs in U251MG cells. In addition, using a reverse transcription-quantitative polymerase chain reaction, it was observed that miR-204 was downregulated in U251MG-resistant (-R) cells. miR-204 expression negatively correlated with the FAP-α levels in human glioblastoma tissues, and it may inhibit the formation of CICs and reverse TMZ resistance in U251MG-R cells. Therefore, it was concluded that miR-204 reversed temozolomide resistance and inhibited CICs phenotypes by degrading FAP-α in glioblastoma. PMID:29725461

First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy

PubMed Central

Adams, David; Suhr, Ole B.; Hund, Ernst; Obici, Laura; Tournev, Ivailo; Campistol, Josep M.; Slama, Michel S.; Hazenberg, Bouke P.; Coelho, Teresa

2016-01-01

Purpose of review Early and accurate diagnosis of transthyretin familial amyloid polyneuropathy (TTR-FAP) represents one of the major challenges faced by physicians when caring for patients with idiopathic progressive neuropathy. There is little consensus in diagnostic and management approaches across Europe. Recent findings The low prevalence of TTR-FAP across Europe and the high variation in both genotype and phenotypic expression of the disease means that recognizing symptoms can be difficult outside of a specialized diagnostic environment. The resulting delay in diagnosis and the possibility of misdiagnosis can misguide clinical decision-making and negatively impact subsequent treatment approaches and outcomes. Summary This review summarizes the findings from two meetings of the European Network for TTR-FAP (ATTReuNET). This is an emerging group comprising representatives from 10 European countries with expertise in the diagnosis and management of TTR-FAP, including nine National Reference Centres. The current review presents management strategies and a consensus on the gold standard for diagnosis of TTR-FAP as well as a structured approach to ongoing multidisciplinary care for the patient. Greater communication, not just between members of an individual patient's treatment team, but also between regional and national centres of expertise, is the key to the effective management of TTR-FAP. PMID:26734952

Chemoprevention with special reference to inherited colorectal cancer.

PubMed

Lynch, Patrick M

2008-01-01

Familial Adenomatous Polyposis (FAP) is a model for the adenoma-carcinoma sequence in several respects. One important area in which FAP serves as a model is chemoprevention. Early prevention trials mainly utilized micronutrients and were largely unsuccessful in preventing or causing regression of adenomas. A new era was ushered in by the recognition that antiarthritic doses of a nonsteroidal anti-inflammatory agent (NSAID), sulindac, could actually induce regression of colorectal adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal adenomas, but sulindac appears to lack significant benefit in regressing duodenal adenomas or preventing initial occurrence of adenomas in APC mutation carriers. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some duodenal activity as well. Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of NSAID research in chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic adenoma prevention trials. Whether NSAIDs will have a significant future in FAP chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial adenomas, a problem with even greater societal impact. The historical development of chemoprevention in FAP will be presented, with an emphasis on issues of trial design.

Symptom Profiles in Patients With Irritable Bowel Syndrome or Functional Abdominal Pain Compared With Healthy Controls.

PubMed

Varni, James W; Shulman, Robert J; Self, Mariella M; Nurko, Samuel; Saps, Miguel; Saeed, Shehzad A; Bendo, Cristiane B; Patel, Ashish S; Dark, Chelsea Vaughan; Zacur, George M; Pohl, John F

2015-09-01

Patient-reported outcome (PRO) measures of gastrointestinal symptoms are recommended to determine treatment effects for irritable bowel syndrome (IBS) and functional abdominal pain (FAP). Study objectives were to compare the symptom profiles of pediatric patients with IBS or FAP with healthy controls and with each other using the PedsQL Gastrointestinal Symptoms and Gastrointestinal Worry Scales, and to establish clinical interpretability of PRO scale scores through identification of minimal important difference (MID) scores. Gastrointestinal Symptoms and Worry Scales were completed in a 9-site study by 154 pediatric patients and 161 parents (162 families; IBS n = 46, FAP n = 119). Gastrointestinal Symptoms Scales measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood in poop, and diarrhea were administered along with Gastrointestinal Worry Scales. A matched sample of 447 families with healthy children completed the scales. Gastrointestinal Symptoms and Worry Scales distinguished between patients with IBS or FAP compared with healthy controls (P < 0.001), with larger effect sizes (>1.50) for symptoms indicative of IBS or FAP, demonstrating a broad multidimensional gastrointestinal symptom profile and clinical interpretability with MID scores for individual PRO scales. Patients with IBS manifested more symptoms of constipation, gas and bloating, and diarrhea than patients with FAP. Patients with IBS or FAP manifested a broad gastrointestinal symptom profile compared with healthy controls with large differences, indicating the critical need for more effective interventions to bring patient functioning within the range of healthy functioning.

Autonomic nervous system function in young children with functional abdominal pain or irritable bowel syndrome.

PubMed

Jarrett, Monica; Heitkemper, Margaret; Czyzewski, Danita; Zeltzer, Lonnie; Shulman, Robert J

2012-05-01

Adults with irritable bowel syndrome (IBS) have been reported to have alterations in autonomic nervous system function as measured by vagal activity via heart rate variability. Whether the same is true for children is unknown. We compared young children 7 to 10 years of age with functional abdominal pain (FAP) or IBS to healthy children (HC) and explored the relationship of vagal activity and sympathovagal balance to psychological distress and stool type. Children completed questionnaires, kept a 2-week pain/stool diary, and wore a 24-hour Holter monitor to assess vagal activity. Group comparisons on vagal activity were controlled for age and body mass index. Indicators of vagal activity and sympathovagal balance did not differ between FAP/IBS children (70 girls, 30 boys) and HC (44 girls, 18 boys). Psychological distress measures were generally higher in FAP/IBS than HC, primarily in girls. Exploratory analyses suggest a potential negative correlation between vagal activity and psychological distress in FAP/IBS girls but not boys. In contrast to reports in women, no differences were found in vagal activity between FAP/IBS and HC. Preliminary findings suggest that in girls with FAP/IBS there is an inverse relationship between vagal activity and psychological distress. The results from this study suggest a possible relationship between emotional state and vagal activity in prepubertal girls (but not boys) with FAP/IBS. Age and/or duration of symptoms may explain our contrasting findings versus adults with IBS. Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.

Commentary on fast atmospheric pulsations. Technical report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vampola, A.L.

A recent paper proposed that Fast Atmospheric Light Pulsations (FAPs), which have been observed at L=1.5-2.2 in the northern hemisphere, are optical signatures of >2-MeV electrons associated with Lightning-induced Electron Precipitation (LEP) events produced by lightning strokes in the southern hemisphere. FAPs cannot be produced by >2-MeV electrons in the inner radiation belt because the upper limit for fluxes of such particles is only about 0.2% of the value that was used in the analysis and would lead to an unrealistically short electron lifetime. The discrepancy comes from using an electron model, AE-2, which included the Starfish fission electrons. Latermore » inner-zone electron environment models show the inner-zone to have negligible fluxes of electrons in excess of 2 MeV. The use of a model in which southern hemisphere lightning strokes result in northern hemisphere FAPs via a cyclotron mode interaction between magnetospheric electrons and lightning generated waves is also untenable because it would result in FAP intensities two orders of magnitude greater in the southern hemisphere than in the northern hemisphere, leading to a further two orders of magnitude reduction in estimated inner-zone electron lifetimes. The estimated light intensity of FAPs is within acceptable bounds compared to the lifetime of inner zone electrons if all electrons above 100 keV contribute to the light production, if southern hemisphere FAP intensity is no greater than the FAP intensity observed in the northern hemisphere, and if the light-production efficiency is of the order of .001.« less

A teat papillomatosis case in a Damascus goat (Shami goat) in Hatay province, Turkey: a new putative papillomavirus?

PubMed

Dogan, Fırat; Dorttas, Selvi Deniz; Bilge Dagalp, Seval; Ataseven, Veysel Soydal; Alkan, Feray

2018-06-01

Papillomaviruses (PVs) are epitheliotropic viruses that cause benign proliferative lesions in the skin (warts or papillomas) and mucous membranes of their natural hosts. Recently, new PVs have been found in many animal species. The most common current approach for identifying novel PV types is based on PCR, using various consensus or degenerated primer (broad-range primers), designed on the basis of the multiple alignment of nucleotide or amino acid sequences of a large number of different human papillomaviruses (HPV). PVs have been classified according to the sequence similarity of one of their capsid proteins, L1, without taking into account other regions of the genome and without considering the phenotypic characteristics of the viral infection. In this study, we performed molecular detection and typing of a PV in a goat with teat papillomatosis. Firstly, PCR was performed using the FAP59/FAP64 and MY09/MY11 primer pairs for the L1 gene region. The PV DNA was found to be positive only with the FAP59/FAP64 primer pair. PV DNA was then tested with three primer sets in four different combinations (L2Bf/FAP64, L2Bf/L1Br, FAP59/FAP64, L1Bf/LCRBr) for the gene region encoding the L1, L2 and LCR proteins. The goat teat papilloma sample was amplified using FAP59/FAP64 primers and two primer pairs (L2Bf/FAP64 and L2Bf/L1Br). We obtained products matching approximately 604 bp of the L1 region of the virus. PV DNA was used for typing using sequence analysis/PCR with some type-specific primers for bovids, caprids and cervids. The results of the sequence analysis suggested one new putative PV type with sequence identity ranging from 46.45 to 80.09% to other known papillomaviruses, including Capra hircus papillomavirus (ChPV-2), bovine papillomavirus (BPV) 6, 7, 10, 11 and 12, Rangifer tarandus papillomavirus 3 (RtPV-3) and BPV-7Z (Alpine wild ruminant papillomavirus; Cervus elaphus papillomavirus). We therefore propose that this is the first identification of a new putative type, MG523274 (HTY-goat-TR2016), in a goat with teat papillomatosis. It is essential to identify PV types in different animal species and investigate their prevalence/distribution and clinical consequences in order to develop appropriate prophylactic and/or therapeutic procedures and to determine the interspecies transmission potential and evolution of PVs.

Probing Tumor Microenvironment With In Vivo Phage Display

DTIC Science & Technology

2014-10-01

C). (C) Dot plots showing mCherry expression on the X axis and fibroblast activation protein ( FAP ) or rabbit isotype control staining in the Y...by flow cytometry-based cell sorting using an antibody against fibroblast activation protein ( FAP ). During the optimization steps, flow cytometry...expression of αvβ3 and αvβ5 integrins, neuropilin-1 (NRP-1), and fibroblast activation protein ( FAP ) in hb6011 CAFs was analyzed by flow cytometry

Fluorapatite crystal growth from modified seawater solutions

NASA Astrophysics Data System (ADS)

Van Cappellen, Philippe; Berner, Robert A.

Seeded precipitation experiments were conducted in a pH/fluoride-stat system to study the crystal growth of fluorapatite ( FAP ) in carbonate-free NaCl-CaCl 2-NaF-Na 2HPO 4 solutions, at seawater calcium concentration, chlorinity, and pH. With increasing supersaturation, the dependence of the growth rate on the relative supersaturation changes from parabolic to exponential. This is interpreted as reflecting a transition in the crystal growth mechanism from growth at dislocation-induced surface steps to surface nucleation-controlled growth. The analysis of the kinetic data leads to a mineral-aqueous solution interfacial tension for FAP of 289 mJ/m 2. The Arrhenius activation energy of the growth reaction in the temperature range 12 to 35°C is 47 kJ/mol. The inhibition of FAP growth by Mg 2+ ions was investigated over a range of total dissolved Mg of 0 to 60 mM. At dissolved magnesium concentrations typical of marine pore waters (40-60 mM), the rate of FAP growth is 15 to 20 times slower than in the absence of Mg 2+, for the same degree of supersaturation, at 25 °C and pH = 8. The inhibitory effect can be explained by the blocking of growth sites at the surface of FAP crystals by adsorbed Mg 2+ ions. A simple Langmuir adsorption model for the retardation effect of Mg 2+ is supported by the results. The effect of pH on FAP growth was tested for pH values from 7 to 8.5. In this range, growth of FAP is catalyzed by hydrogen ions. The apparent growth rate constant is proportional to ( aH+) m where m, the rate order with respect to H +, is a non-integral number which depends on pH. At identical degrees of supersaturation, the growth rate of FAP at pH = 7 is nearly twice that at pH = 8. When corrected for bottom water temperatures, pore water pH, and the retardation of Mg 2+, the experimental growth rates predict that during burial in modern phosphatic sediments, apatite particles grow to sizes on the order of 0.1-10 μrn. The relatively slow growth kinetics of FAP are consistent with the observed small particle sizes of marine sedimentary apatite.

The importance of a large sample cohort for studies on modifier genes influencing disease severity in FAP patients.

PubMed

Talseth-Palmer, Bente A; Wijnen, Juul T; Andreassen, Eva K; Barker, Daniel; Jagmohan-Changur, Shantie; Tops, Carli M; Meldrum, Cliff; Spigelman, Allan; Hes, Frederik J; Van Wezel, Tom; Vasen, Hans Fa; Scott, Rodney J

2013-12-29

Familial adenomatous polyposis (FAP) is usually characterised by the appearance of hundreds-to-thousands of adenomas throughout the colon and rectum and if left untreated the condition will develop into CRC with close to 100% penetrance. Germline mutations in the APC gene, which plays an integral role in the Wnt-signalling pathway, have been found to be responsible for 70-90% of FAP cases. Several studies suggest that modifier genes may play an important role in the development of CRC and possible modifiers for FAP have been suggested. Interestingly, a study has found that SNPs within ATP5A1 is associated with raised levels of ATP5A1 expression and high expression levels may facilitate CRC development. We aimed to determine if SNPs in ATP5A1 modify the risk of developing CRC/adenomas in FAP patients. Genomic DNA from 139 Australian FAP patients with a germline APC mutation underwent genotyping at the Australian Genome Research Facility (AGRF) utilising iPLEX GOLD chemistry with Sequenom MassArray on an Autoflex Spectrometer for 16 SNPs in the ATP5A1 gene. Association between ages of diagnosis/risk of CRC/adenomas was tested with Kaplan-Meier estimator analysis, logistic regression and cox proportional hazard regression. An association between age of diagnosis of CRC and genotypes was observed for SNP rs2578189 (p = 0.0014), with individuals harbouring the variant genotype developing CRC 29 years earlier than individuals harbouring the wildtype genotype. Individuals harbouring the variant genotype of SNP rs2578189 were also at increased risk of CRC (HR = 13.79, 95% CI = 2.36-80.64, p = 0.004). We used an independent Dutch FAP cohort (n = 427) to validate our results; no association between SNP rs2578189 and CRC was observed. These results highlight the difficulties in studying a disease that has a high degree of intervention and also emphasize the importance of large sample sizes when searching for modifier genes in patients with an inherited predisposition to disease. To fully determine if there are genetic modifiers of disease in FAP we would encourage people that are interested in collaborating in future studies into the role of modifier genes in disease expression in FAP to join forces.

Clinical outcomes of gastric polyps and neoplasms in patients with familial adenomatous polyposis

PubMed Central

Nakamura, Keiko; Nonaka, Satoru; Nakajima, Takeshi; Yachida, Tatsuo; Abe, Seiichiro; Sakamoto, Taku; Suzuki, Haruhisa; Yoshinaga, Shigetaka; Oda, Ichiro; Matsuda, Takahisa; Sekine, Shigeki; Kanemitsu, Yukihide; Katai, Hitoshi; Saito, Yutaka; Hirota, Seiichi

2017-01-01

Background and study aims Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene, characterized by the presence of more than 100 adenomatous polyps in the colorectum. The upper gastrointestinal tract is an extracolonic site for malignancy in patients with FAP. The frequency of death in Japanese patients with FAP because of gastric cancer is 2.8 % and that because of colon cancer is 60.6 %. Few studies have reported upper gastrointestinal diseases in patients with FAP. In the present study, we investigated the clinical outcomes of patients with FAP diagnosed with gastric neoplasms. Patients and methods We enrolled 80 patients with FAP who underwent esophagogastroduodenoscopy from October 1997 to December 2011. We investigated patient characteristics, endoscopic findings of gastric lesions, treatment outcomes, and long-term courses. Results Fundic gland polyposis was observed in 51 patients (64 %) and gastric neoplasms in 22 patients (28 %), including 20 with non-invasive and 2 with invasive neoplasm. Of the 26 neoplasms, 11 were treated by endoscopic resection (ER) and 4 by surgical resection. Metachronous gastric neoplasms were observed in 7 patients (15 lesions) and treated by ER, except for in 1 patient. No patients died of gastric lesions during a median follow-up period of 6.5 years (range, 0 – 14). Conclusion Because gastric lesions including gastric cancers in patients with FAP did not cause any deaths, they can be considered to have favorable prognoses. Early detection of gastric neoplasms through an appropriate follow-up interval may have contributed to these good outcomes. PMID:28271094

Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary.

PubMed

Papp, Janos; Kovacs, Marietta Eva; Matrai, Zoltan; Orosz, Enikő; Kásler, Miklós; Børresen-Dale, Anne-Lise; Olah, Edith

2016-01-01

Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome with considerable genetic and phenotypic heterogeneity, defined by the development of multiple adenomas throughout the colorectum. FAP is caused either by monoallelic mutations in the adenomatous polyposis coli gene APC, or by biallelic germline mutations of MUTYH, this latter usually presenting with milder phenotype. The aim of the present study was to characterize the genotype and phenotype of Hungarian FAP patients. Mutation screening of 87 unrelated probands from FAP families (21 of them presented as the attenuated variant of the disease, showing <100 polyps) was performed using DNA sequencing and multiplex ligation-dependent probe amplification. Twenty-four different pathogenic mutations in APC were identified in 65 patients (75 %), including nine cases (37.5 %) with large genomic alterations. Twelve of the point mutations were novel. In addition, APC-negative samples were also tested for MUTYH mutations and we were able to identify biallelic pathogenic mutations in 23 % of these cases (5/22). Correlations between the localization of APC mutations and the clinical manifestations of the disease were observed, cases with a mutation in the codon 1200-1400 region showing earlier age of disease onset (p < 0.003). There were only a few, but definitive dissimilarities between APC- and MUTYH-associated FAP in our cohort: the age at onset of polyposis was significantly delayed for biallelic MUTYH mutation carriers as compared to patients with an APC mutation. Our data represent the first comprehensive study delineating the mutation spectra of both APC and MUTYH in Hungarian FAP families, and underscore the overlap between the clinical characteristics of APC- and MUTYH-associated phenotypes, necessitating a more appropriate clinical characterization of FAP families.

Visceral sensation and irritable bowel syndrome; with special reference to comparison with functional abdominal pain syndrome.

PubMed

Nozu, Tsukasa; Okumura, Toshikatsu

2011-04-01

Stress-induced visceral hypersensitivity may play an important role in the pathogenesis of irritable bowel syndrome (IBS) but not in functional abdominal pain syndrome (FAPS). We examined rectal sensation in those patients. Experiment 1: Rectal thresholds of pain (PT) and maximum tolerance were assessed by barostat with ramp distention before and after repetitive rectal painful distention (RRD). Experiment 2, PT was measured in basal state and after intravenous CRF (100 µg) or vehicle, together with or without RRD. Experiment 3: Three phasic distentions at physiological range were randomly loaded. The subjects were asked to mark the visual analogue scale (VAS) in reference to subjective intensity of sensation. Experiment 1: Majority of IBS patients showed rectal hypersensitivity before RRD in contrast to FAPS. All IBS patients developed hypersensitivity after RRD, however, none of the FAPS patients did. RRD significantly reduced both thresholds in IBS (n=7) but did not change in controls (n=14) and FAPS (n=6). Experiment 2: PT was not modified by RRD in placebo group (n=6), while it was significantly reduced in CRF-treated group (n=5). On the other hand, CRF (n=5) or vehicle (n=5) without RRD did not alter PT. Experiment 3: The VAS ratings were increased in IBS (n=7) but significantly decreased in FAPS (n=6) as compared to controls (n=14). RRD-induced rectal hypersensitivity seems to be reliable marker for IBS, and CRF may contribute to this response. FAPS patients may have hyposensitivity to non-noxious physiological distention, suggesting FAPS has different pathogenesis from IBS. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

A distinct variant of papillary thyroid carcinoma indicating familial adenomatous polyposis (FAP): a case report and brief review.

PubMed

Liyanapathirana, Nishantha; Seneviratne, Sanjeewa Anuruddha; Samarasekera, Dharmabandhu Nandadeva

2015-12-17

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited intestinal polyposis syndrome with an incidence of about 1/8300 births and accounts for about 1% of all colorectal cancers. It has a spectrum of extra-intestinal manifestations including thyroid carcinoma which occur in 1-2% of affected. The cribriform morular variant (CMV) is a rare but distinct histological subtype of papillary thyroid carcinoma (PTC) associated with FAP. Most of the reported cases describe the above entity in the background of well-established FAP. We report a case where both entities presenting simultaneously in a previously undiagnosed patient with FAP without a family history of polyposis. A 24 year old Asian female presented to the surgical clinic with a goitre of eight months duration and recent onset of altered bowel habits with features of anaemia. She was previously healthy and there was no family history of adenomatous polyposis, colorectal carcinoma or thyroid neoplasms. Colonoscopy revealed large bowel polyposis and fine needle aspiration of thyroid revealed a smear suspicious for malignancy. She underwent total thyroidectomy which revealed CMV PTC. Histology was characterized by a prominent cribriform pattern of growth with interspersed cell clusters arranged as morules along with papillary structures which are the key features of this subtype. Diagnosis of CMV warrants ruling out of underlying FAP, irrespective of family history or gastrointestinal symptoms.

Involvement of Macrophages in the Pathogenesis of Familial Amyloid Polyneuropathy and Efficacy of Human iPS Cell-Derived Macrophages in Its Treatment

PubMed Central

Komohara, Yoshihiro; Takamatsu, Koutaro; Kakuma, Tatsuyuki; Tasaki, Masayoshi; Misumi, Yohei; Ueda, Mitsuharu; Ito, Takaaki; Senju, Satoru; Ando, Yukio

2016-01-01

We hypothesized that tissue-resident macrophages in familial amyloid polyneuropathy (FAP) patients will exhibit qualitative or quantitative abnormalities, that may accelerate transthyretin (TTR)-derived amyloid deposition. To evaluate this, we examined the number and subset of tissue-resident macrophages in heart tissue from amyloid-deposited FAP and control patients. In both FAP and control patients, tissue-resident macrophages in heart tissue were all Iba+/CD163+/CD206+ macrophages. However, the number of macrophages was significantly decreased in FAP patients compared with control patients. Furthermore, the proportion of intracellular TTR in CD14+ monocytes was reduced in peripheral blood compared with healthy donors. Based on these results, we next examined degradation and endocytosis of TTR in human induced pluripotent stem (iPS) cell-derived myeloid lineage cells (MLs), which function like macrophages. iPS-MLs express CD163 and CD206, and belong to the inhibitory macrophage category. In addition, iPS-MLs degrade both native and aggregated TTR in a cell-dependent manner in vitro. Further, iPS-MLs endocytose aggregated, and especially polymerized, TTR. These results suggest that decreased tissue-localized macrophages disrupt clearance of TTR-derived amyloid deposits, leading to progression of a pathological condition in FAP patients. To improve this situation, clinical application of pluripotent stem cell-derived MLs may be useful as an approach for FAP therapy. PMID:27695122

Impact of antibodies against amyloidogenic transthyretin (ATTR) on phenotypes of patients with familial amyloidotic polyneuropathy (FAP) ATTR Valine30Methionine.

PubMed

Obayashi, Konen; Tasaki, Masayoshi; Jono, Hirofumi; Ueda, Mitsuharu; Shinriki, Satoru; Misumi, Yohei; Yamashita, Taro; Oshima, Toshinori; Nakamura, Teruya; Ikemizu, Shinji; Anan, Intissar; Suhr, Ole; Ando, Yukio

2013-04-18

This study investigated whether a relationship exists between the presence of de novo antibodies and the clinical manifestations of familial amyloidotic polyneuropathy (FAP). Serum samples were collected from 25 Japanese and 6 Swedish FAP amyloidogenic transthyretin (ATTR) Valine30Methionine (V30M) patients, 4 asymptomatic Japanese ATTR V30M gene carriers, and 24 Japanese healthy volunteers. Study methods included enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. Three Japanese and 5 Swedish patients had significantly higher levels of antibodies against ATTR than did healthy volunteers and asymptomatic gene carriers (P<0.05). All 8 patients with higher antibody levels were late-onset cases. The ratio of wild-type TTR to ATTR V30M in serum from the high-antibody group was higher than that of the low-antibody group. ELISA results revealed two epitopes at positions 24-35 and 105-115 of ATTR V30M. We found a significant positive correlation between levels of the antibody at positions 24-35 and the age at FAP onset (r=0.751, P<0.05). An age-dependent increase in the occurrence of antibodies was observed in these patients with an epitope at positions 24-35. These findings may help explain the differences in early- and late-onset FAP and/or the progression of FAP. Copyright © 2013 Elsevier B.V. All rights reserved.

7 CFR 1753.2 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... perform engineering services. FAP (force account proposal)—The borrower's detailed plans submitted to RUS... employees under an RUS approved FAP, with the borrower furnishing all materials, equipment, tools, and...

7 CFR 1753.2 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... perform engineering services. FAP (force account proposal)—The borrower's detailed plans submitted to RUS... employees under an RUS approved FAP, with the borrower furnishing all materials, equipment, tools, and...

7 CFR 1753.2 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

... perform engineering services. FAP (force account proposal)—The borrower's detailed plans submitted to RUS... employees under an RUS approved FAP, with the borrower furnishing all materials, equipment, tools, and...

7 CFR 1753.2 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

... perform engineering services. FAP (force account proposal)—The borrower's detailed plans submitted to RUS... employees under an RUS approved FAP, with the borrower furnishing all materials, equipment, tools, and...

Evidence of a reverse side-chain effect of tris(pentafluoroethyl)trifluorophosphate [FAP]-based ionic liquids against pathogenic bacteria.

PubMed

Weyhing-Zerrer, Nadine; Kalb, Roland; Oßmer, Rolf; Rossmanith, Peter; Mester, Patrick

2018-02-01

Increased interest in ionic liquids (ILs) is due to their designable and tunable unique physicochemical properties, which are utilized for a wide variety of chemical and biotechnological applications. ILs containing the tris(pentafluoroethyl)trifluorophosphate ([FAP]) anion have been shown to have excellent hydrolytic, electrochemical and thermal stability and have been successfully used in various applications. In the present study the influence of the cation on the toxicity of the [FAP] anion was investigated. Due to the properties of [FAP] ILs, the IL-toxicity of seven cations with [FAP] compared to [Cl] was examined by determination of minimum inhibitory (MIC) and minimum bactericidal concentrations (MBC) on six Gram-positive and six Gram-negative clinically-relevant bacteria. For the first time, to our knowledge, the results provide evidence for a decrease in toxicity with increasing alkyl side-chain length, indicating that the combination of both ions is responsible for this 'reverse side-chain effect'. These findings could portend development of new non-toxic ILs as green alternatives to conventional organic solvents. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis and characterization of fluorapatite-titania (FAp-TiO 2) nanocomposite via mechanochemical process

NASA Astrophysics Data System (ADS)

Ebrahimi-Kahrizsangi, Reza; Nasiri-Tabrizi, Bahman; Chami, Akbar

2010-09-01

In this paper, synthesis of bionanocomposite of fluorapatite-titania (FAp-TiO 2) was studied by using one step mechanochemical process. Characterization of the products was accomplished by X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, energy dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. Based on XRD patterns and FT-IR spectroscopy, correlation between the structural features of the nanostructured FAp-TiO 2 and the process conditions was discussed. Variations in crystallite size, lattice strain, and volume fraction of grain boundary were investigated during milling and the following heat treatment. Crystallization of the nanocomposite occurred after thermal treatment at 650 °C. Morphological features of powders were influenced by the milling time. The resulting FAp-20 wt.%TiO 2 nanocomposite powder exhibited an average particle size of 15 nm after 20 h of milling. The results show that the one step mechanosynthesis technique is an effective route to prepare FAp-based nanocomposites with excellent morphological and structural features.

Abdominal Pain

MedlinePlus

... and Recurrent or Functional Abdominal Pain (RAP or FAP) What is abdominal pain? Abdominal pain , or stomachache, ... recurrent abdominal pain (RAP) or functional abdominal pain (FAP)? If your health care provider has ruled out ...

Dento-osseous anomalies associated to familial adenomatous polyposis mimicking florid cemento-osseous dysplasia.

PubMed

Almeida, Fabiana Tolentino; Leite, André Ferreira; de Souza Figueiredo, Paulo Tadeu; Melo, Nilce Santos; Sousa, João Batista; Almeida, Rômulo; Acevedo, Ana Carolina; Silva Guerra, Eliete Neves

2012-12-01

Familial adenomatous polyposis (FAP) is a colorectal cancer syndrome characterized by the development of multiple polyps of the colon and rectum with high risk of malignant transformation. The extraintestinal manifestations such as dento-osseous changes are associated with FAP. This is a case report of a 36-year-old female patient who was referred for dental treatment with the initial diagnosis of florid cemento-osseous dysplasia (FCOD). However, the association of the imaging dento-osseous findings with the medical history confirmed the diagnosis of FAP. The paper illustrates the clinical characteristics and imaging findings associated with FAP, and also discusses misdiagnosis based exclusively on imaging features. Copyright © 2012 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21*

PubMed Central

Dunshee, Diana Ronai; Bainbridge, Travis W.; Kljavin, Noelyn M.; Zavala-Solorio, Jose; Schroeder, Amy C.; Chan, Ruby; Corpuz, Racquel; Wong, Manda; Zhou, Wei; Deshmukh, Gauri; Ly, Justin; Sutherlin, Daniel P.; Ernst, James A.; Sonoda, Junichiro

2016-01-01

FGF21 is a stress-induced hormone with potent anti-obesity, insulin-sensitizing, and hepatoprotective properties. Although proteolytic cleavage of recombinant human FGF21 in preclinical species has been observed previously, the regulation of endogenously produced FGF21 is not well understood. Here we identify fibroblast activation protein (FAP) as the enzyme that cleaves and inactivates human FGF21. A selective chemical inhibitor, immunodepletion, or genetic deletion of Fap stabilized recombinant human FGF21 in serum. In addition, administration of a selective FAP inhibitor acutely increased circulating intact FGF21 levels in cynomolgus monkeys. On the basis of our findings, we propose selective FAP inhibition as a potential therapeutic approach to increase endogenous FGF21 activity for the treatment of obesity, type 2 diabetes, non-alcoholic steatohepatitis, and related metabolic disorders. PMID:26797127

Low-toxic Mn-doped ZnSe@ZnS quantum dots conjugated with nano-hydroxyapatite for cell imaging

NASA Astrophysics Data System (ADS)

Zhou, Ronghui; Li, Mei; Wang, Shanling; Wu, Peng; Wu, Lan; Hou, Xiandeng

2014-11-01

Fluorescent bio-imaging has received significant attention in a myriad of research disciplines, and QDs are playing an increasingly important role in these areas. Doped QDs, an important alternative to conventional heavy metal-containing QDs are employed for biomedical applications. However, since QDs are exogenous substances to the biological environment, the biocompatibility of QDs is expected to be challenging in some cases. Herein, nano fluorine-doped hydroxyapatite (FAp, a well-known biocompatible material) was introduced to endow biocompatibility to Cd-free Mn-doped ZnSe@ZnS QDs. Thus, a nano-FAp-QD conjugate was developed and the biocompatibility, as well as potential cell imaging application, was investigated. To construct the proposed conjugate, Cd-free highly luminescent Mn-doped ZnSe@ZnS QDs and monodispersed nano-FAp were first prepared in high-temperature organic media. For facilitating the conjugation, hydrophobic nano-FAp was made water soluble via o-phosphoethanolamine (PEA) coating, which further provides conjugating sites for QDs to anchor. Cytotoxicity studies indicated the developed conjugate indeed possesses good compatibility and low toxicity to cells. The nano-FAp-QDs conjugate was successfully employed for cancer cell staining for at least 24 h, demonstrating the potential usefulness of this material in future biomedical research.Fluorescent bio-imaging has received significant attention in a myriad of research disciplines, and QDs are playing an increasingly important role in these areas. Doped QDs, an important alternative to conventional heavy metal-containing QDs are employed for biomedical applications. However, since QDs are exogenous substances to the biological environment, the biocompatibility of QDs is expected to be challenging in some cases. Herein, nano fluorine-doped hydroxyapatite (FAp, a well-known biocompatible material) was introduced to endow biocompatibility to Cd-free Mn-doped ZnSe@ZnS QDs. Thus, a nano-FAp-QD conjugate was developed and the biocompatibility, as well as potential cell imaging application, was investigated. To construct the proposed conjugate, Cd-free highly luminescent Mn-doped ZnSe@ZnS QDs and monodispersed nano-FAp were first prepared in high-temperature organic media. For facilitating the conjugation, hydrophobic nano-FAp was made water soluble via o-phosphoethanolamine (PEA) coating, which further provides conjugating sites for QDs to anchor. Cytotoxicity studies indicated the developed conjugate indeed possesses good compatibility and low toxicity to cells. The nano-FAp-QDs conjugate was successfully employed for cancer cell staining for at least 24 h, demonstrating the potential usefulness of this material in future biomedical research. Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c4nr04473h

MYH-Associated Polyposis

MedlinePlus

... to other hereditary conditions of familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP). In other ... a mutation in the APC gene associated with FAP and AFAP. It may also be considered if ...

UV-Induced Triggering of a Biomechanical Initiation Switch Within Collagen Promotes Development of a Melanoma-Permissive Microenvironment in the Skin

DTIC Science & Technology

2014-11-01

associated with basement membranes, these M21 melanoma tumors were co- stained for fibroblasts expressing fibroblast activation protein ( FAP ) and a well...characterized marker of blood vessels CD-31 (5,6). As shown in figure 7B below, elevated levels of FAP -expressing -tumor associated fibroblasts were...by staining with Mab D93 in frozen section of tumor tissue from each condition. B). Example of co-distribution of FAP expressing cancer associated

Radon Spectrum and Its Application for Small Moving Target Detection

DTIC Science & Technology

2015-04-01

cumulative distribution function) starts separating from the exact distribution only at the very end of the upper tail, normally in the 610−= faP or...131059.1 −×= PNtotal (15) According to (15), for instance, to determine the threshold for 610−= faP , a total 91059.1 × samples shall...is the incomplete Gamma function9 Suppose we require a false-alarm rate of 610−= faP for the original data, therefore after non-coherent multi

A comprehensive update on current fixation options for two-part proximal humerus fractures: a biomechanical investigation.

PubMed

Yoon, Richard S; Dziadosz, Daniel; Porter, David A; Frank, Matthew A; Smith, Wade R; Liporace, Frank A

2014-03-01

Recent advancements in implant technology offer updated options for surgical management that have been rapidly adopted into clinical practice. The objective of this study is to biomechanically test and compare the current fixation options available for surgical fixation of two-part proximal humerus fractures and establish load to failure and stiffness values. Sixteen match-paired (32 total) fresh-frozen, cadaveric specimens were randomized to receive 1 of 4 fixation constructs following creation of an AO/OTA Type 11A3 (two-part) proximal humerus fractures. Fixation constructs tested consisted of 3.5 mm fixed angle plate (3.5-FAP), 4.5 mm fixed angle plate (4.5-FAP), humeral intramedullary nail (IMN), and a humeral intramedullary nail with a fixed angle blade (IMN-FAB). Specimen bone density was measured to ensure no adequate, non-osteoporotic bone. Constructs were tested for stiffness and ultimate load to failure and compared via one-way ANOVA analysis with subsequent post hoc Tukey HSD multiple group comparison statistical analysis. The IMN-FAB construct was significantly stiffer than the 3.5-FAP construct (123.8 vs. 23.9, p<0.0001), the 4.5-FAP construct (123.8 vs. 33.3, p<0.0001) and the IMN construct (123.8 vs. 60.1, p=0.005). The IMN-FAB construct reported a significantly higher load to failure than the 3.5-FAB construct (4667.3 N vs. 1756.9 N, p<0.0001), and the 4.5-FAP construct (4667.3 N vs. 2829.4 N, p=0.019, Table 2). The IMN construct had a significantly higher load to failure than the 3.5-FAP construct (3946.8 vs. 1756.9, p=0.001, Table 2). Biomechanical testing of modern fixation options for two-part proximal humerus fracture exhibited that the stiffest and highest load to failure construct was the IMN-FAB followed by the IMN, 3.5-FAP and then the 4.5-FAP constructs. However, prospective clinical trials with longer-term follow-up are required for definitive assessment of the ideal fixation construct for surgical management of two-part proximal humerus fractures. Copyright © 2013 Elsevier Ltd. All rights reserved.

Gut-directed hypnotherapy in children with irritable bowel syndrome or functional abdominal pain (syndrome): a randomized controlled trial on self exercises at home using CD versus individual therapy by qualified therapists.

PubMed

Rutten, Juliette M T M; Vlieger, Arine M; Frankenhuis, Carla; George, Elvira K; Groeneweg, Michael; Norbruis, Obbe F; Tjon a Ten, Walther; Van Wering, Herbert; Dijkgraaf, Marcel G W; Merkus, Maruschka P; Benninga, Marc A

2014-06-04

Irritable bowel syndrome (IBS) and functional abdominal pain (syndrome) (FAP(S)) are common pediatric disorders, characterized by chronic or recurrent abdominal pain. Treatment is challenging, especially in children with persisting symptoms. Gut-directed hypnotherapy (HT) performed by a therapist has been shown to be effective in these children, but is still unavailable to many children due to costs, a lack of qualified child-hypnotherapists and because it requires a significant investment of time by child and parent(s). Home-based hypnotherapy by means of exercises on CD has been shown effective as well, and has potential benefits, such as lower costs and less time investment. The aim of this randomized controlled trial (RCT) is to compare cost-effectiveness of individual HT performed by a qualified therapist with HT by means of CD recorded self-exercises at home in children with IBS or FAP(S). 260 children, aged 8-18 years with IBS or FAP(S) according to Rome III criteria are included in this currently conducted RCT with a follow-up period of one year. Children are randomized to either 6 sessions of individual HT given by a qualified therapist over a 3-month period or HT through self-exercises at home with CD for 3 months.The primary outcome is the proportion of patients in which treatment is successful at the end of treatment and after one year follow-up. Treatment success is defined as at least 50% reduction in both abdominal pain frequency and intensity scores. Secondary outcomes include adequate relief, cost-effectiveness and effects of both therapies on depression and anxiety scores, somatization scores, QoL, pain beliefs and coping strategies. If the effectiveness of home-based HT with CD is comparable to, or only slightly lower, than HT by a therapist, this treatment may become an attractive form of therapy in children with IBS or FAP(S), because of its low costs and direct availability. Dutch Trial Register number NTR2725 (date of registration: 1 February 2011).

Gut-directed hypnotherapy in children with irritable bowel syndrome or functional abdominal pain (syndrome): a randomized controlled trial on self exercises at home using CD versus individual therapy by qualified therapists

PubMed Central

2014-01-01

Background Irritable bowel syndrome (IBS) and functional abdominal pain (syndrome) (FAP(S)) are common pediatric disorders, characterized by chronic or recurrent abdominal pain. Treatment is challenging, especially in children with persisting symptoms. Gut-directed hypnotherapy (HT) performed by a therapist has been shown to be effective in these children, but is still unavailable to many children due to costs, a lack of qualified child-hypnotherapists and because it requires a significant investment of time by child and parent(s). Home-based hypnotherapy by means of exercises on CD has been shown effective as well, and has potential benefits, such as lower costs and less time investment. The aim of this randomized controlled trial (RCT) is to compare cost-effectiveness of individual HT performed by a qualified therapist with HT by means of CD recorded self-exercises at home in children with IBS or FAP(S). Methods/Design 260 children, aged 8-18 years with IBS or FAP(S) according to Rome III criteria are included in this currently conducted RCT with a follow-up period of one year. Children are randomized to either 6 sessions of individual HT given by a qualified therapist over a 3-month period or HT through self-exercises at home with CD for 3 months. The primary outcome is the proportion of patients in which treatment is successful at the end of treatment and after one year follow-up. Treatment success is defined as at least 50% reduction in both abdominal pain frequency and intensity scores. Secondary outcomes include adequate relief, cost-effectiveness and effects of both therapies on depression and anxiety scores, somatization scores, QoL, pain beliefs and coping strategies. Discussion If the effectiveness of home-based HT with CD is comparable to, or only slightly lower, than HT by a therapist, this treatment may become an attractive form of therapy in children with IBS or FAP(S), because of its low costs and direct availability. Trial registration Dutch Trial Register number NTR2725 (date of registration: 1 February 2011) PMID:24894077

Drug Combo Decreases Colorectal Polyps in People with FAP

Cancer.gov

In people with familial adenomatous polyposis, or FAP, a combination treatment of erlotinib (Tarceva) and sulindac (Aflodac) decreased the number of precancerous colorectal polyps, according to recently published clinical trial results.

7 CFR 1753.58 - Closeout documents.

Code of Federal Regulations, 2013 CFR

2013-01-01

... followed in the preparation of closeout documents for the FAP. (2) The period between the completion of... documents required to close the FAP are listed in the following table. The following is a brief description...

7 CFR 1753.58 - Closeout documents.

Code of Federal Regulations, 2012 CFR

2012-01-01

... followed in the preparation of closeout documents for the FAP. (2) The period between the completion of... documents required to close the FAP are listed in the following table. The following is a brief description...

7 CFR 1753.58 - Closeout documents.

Code of Federal Regulations, 2014 CFR

2014-01-01

... followed in the preparation of closeout documents for the FAP. (2) The period between the completion of... documents required to close the FAP are listed in the following table. The following is a brief description...

7 CFR 1753.58 - Closeout documents.

Code of Federal Regulations, 2010 CFR

2010-01-01

... followed in the preparation of closeout documents for the FAP. (2) The period between the completion of... documents required to close the FAP are listed in the following table. The following is a brief description...

7 CFR 1753.58 - Closeout documents.

Code of Federal Regulations, 2011 CFR

2011-01-01

... followed in the preparation of closeout documents for the FAP. (2) The period between the completion of... documents required to close the FAP are listed in the following table. The following is a brief description...

Optimization of the cooling profile to achieve crack-free Yb:S-FAP crystals

NASA Astrophysics Data System (ADS)

Fang, H. S.; Qiu, S. R.; Zheng, L. L.; Schaffers, K. I.; Tassano, J. B.; Caird, J. A.; Zhang, H.

2008-08-01

Yb:S-FAP [Yb 3+:Sr 5(PO 4) 3F] crystals are an important gain medium for diode-pumped laser applications. Growth of 7.0 cm diameter Yb:S-FAP crystals utilizing the Czochralski (CZ) method from SrF 2-rich melts often encounters cracks during the post-growth cool-down stage. To suppress cracking during cool-down, a numerical simulation of the growth system was used to understand the correlation between the furnace power during cool-down and the radial temperature differences within the crystal. The critical radial temperature difference, above which the crystal cracks, has been determined by benchmarking the simulation results against experimental observations. Based on this comparison, an optimal three-stage ramp-down profile was implemented, which produced high-quality, crack-free Yb:S-FAP crystals.

Skin fibroblasts from individuals hemizygous for the familial adenopolyposis susceptibility gene show delayed crisis in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, S.; Kazim, D.; Kraveka, J.

Normal human fibroblast cells have not been reported to escape crisis--that is they die after about 24 doublings in culture. The authors have been studying the growth properties of skin fibroblast cells from persons in families with familial adenopolyposis of the colon (FAP). An individual hemizygous at the FAP locus will develop hyperplasia of the colonic epithelium followed by colonic polyps, both at an early age. Polyps themselves still retain a single functional FAP allele. A mutation or deletion in this allele in a polyp is hypothesized to lead to further loss of growth control; thus, a tumor is formed.more » They found that the in vitro life-span of skin fibroblast cells from FAP individuals and from some asymptomatic children were markedly extended when compared with normal individuals.« less

Laser, optical and thermomechanical properties of Yb-doped fluorapatite

DOE Office of Scientific and Technical Information (OSTI.GOV)

Payne, S.A.; Smith, L.K.; DeLoach, L.D.

The laser performance of Yb-doped fluorapatite (Ca[sub 5](PO[sub 4])[sub 3]F or FAP), is assessed by employing a Ti:sapphire laser operating at 905 nm as the pump source. The authors have measured slope efficiencies to be as high as 79%; the residual decrement from the quantum defect-limited efficiency of 87% is accounted for by the presence of passive loss at the 1,043-nm laser wavelength. The important spectral properties of Yb:FAP were evaluated, including the absorption and emission cross sections, excited-state lifetime, and ground-state energy-level splitting. The emission and absorption cross sections of Yb[sup 3+] in FAP are found to be substantiallymore » larger than those of other Yb-doped media. The thermal, physical, and optical properties of the FAP host are reported as well.« less

Effective optical path length for tandem diffuse cubic cavities as gas absorption cell

NASA Astrophysics Data System (ADS)

Yu, J.; Gao, Q.; Zhang, Y. G.; Zhang, Z. G.; Wu, S. H.

2014-12-01

Tandem diffuse cubic cavities designed by connecting two single diffuse cubic-shaped cavities, A and B, with an aperture (port fraction fap) in the middle of the connecting baffle was developed as a gas absorption cell. The effective optical path length (EOPL) was evaluated by comparing the oxygen absorption signal in the cavity and in air based on tunable diode laser absorption spectroscopy (TDLAS). Experimental results manifested an enhancement of EOPL for the tandem diffuse cubic cavities as the decrease of fap and can be expressed as the sum of EOPL of two single cubic cavities at fap < 0.01, which coincided well with theoretical analysis. The simulating EOPL was smaller than experimental results at fap > 0.01, which indicated that back scattering light from cavity B to cavity A cannot be ignored at this condition.

Human microRNA expression in sporadic and FAP-associated desmoid tumors and correlation with beta-catenin mutations.

PubMed

Cavallini, Aldo; Rotelli, Maria Teresa; Lippolis, Catia; Piscitelli, Domenico; Digennaro, Rosa; Covelli, Claudia; Carella, Nicola; Accetturo, Matteo; Altomare, Donato Francesco

2017-06-27

Desmoid tumors (DT) are rare, benign, fibroblastic neoplasm with challenging histological diagnosis. DTs can occur sporadically or associated with the familial adenomatous polyposis coli (FAP). Most sporadic DTs are associated with β-catenin gene (CTNNB1) mutations, while mutated APC gene causes FAP disease. microRNAs (miRNAs) are involved in many human carcinogenesis.The miRNA profile was analyzed by microarray in formalin-fixed, paraffin-embedded (FFPE) specimens of 12 patients (8 sporadic, 4 FAP-associated) and 4 healthy controls. One hundred and one mRNAs resulted dysregulated, of which 98 in sporadic DTs and 8 in FAP-associated DTs, 5 were shared by both tumors. Twenty-six miRNAs were then validated by RT-qPCR in 23 sporadic and 7 FAP-associated DT samples matched with healthy controls. The qPCR method was also used to evaluate the CTNNB1 mutational status in sporadic DTs. The correlation between sporadic DTs and miRNA expression showed that miR-21-3p increased in mutated versus wild-type DTs, while miR-197-3p was decreased. The mRNA expression of Tetraspanin3 and Serpin family A member 3, as miR-21-3p targets, and L1 Cell Adhesion Molecule, as miR-197-3p target, was also evaluate. CTNNB1 mutations associated to miRNA dysregulation could affect the genesis and the progression of this disease and help histological diagnosis of sporadic DTs.

A Patient With Desmoid Tumors and Familial FAP Having Frame Shift Mutation of the APC Gene.

PubMed

Sadighi, Sanambar; Ghaffari-Moghaddam, Mahsa; Saffari, Mojtaba; Mohagheghi, Mohammad Ali; Shirkoohi, Reza

2017-02-01

Desmoids tumors, characterized by monoclonal proliferation of myofibroblasts, could occur in 5-10% of patients with familial adenomatous polyposis (FAP) as an extra-colonic manifestation of the disease. FAP can develop when there is a germ-line mutation in the adenomatous polyposis coli gene. Although mild or attenuated FAP may follow mutations in 5΄ extreme of the gene, it is more likely that 3΄ extreme mutations haveamore severe manifestation of thedisease. A 28-year-old woman was admitted to the Cancer Institute of Iran with an abdominal painful mass. She had strong family history of FAP and underwent prophylactic total colectomy. Pre-operative CT scans revealed a large mass. Microscopic observation showed diffuse fibroblast cell infiltration of the adjacent tissue structures. Peripheral blood DNA extraction followed by adenomatous polyposis coli gene exon by exon sequencing was performed to investigate the mutation in adenomatous polyposis coli gene. Analysis of DNA sequencing demonstrated a mutation of 4 bpdeletions at codon 1309-1310 of the exon 16 of adenomatous polyposis coli gene sequence which was repeated in 3 members of the family. Some of them had desmoid tumor without classical FAP history. Even when there is no familial history of adenomatous polyposis, the adenomatous polyposis coli gene mutation should be investigated in cases of familial desmoids tumors for a suitable prevention. The 3΄ extreme of the adenomatous polyposis coli gene is still the best likely location in such families.

Application of Mobile-ip to Space and Aeronautical Networks

NASA Technical Reports Server (NTRS)

Leung, Kent; Shell, Dan; Ivancic, William D.; Stewart, David H.; Bell, Terry L.; Kachmar, Brian A.

2001-01-01

The National Aeronautics and Space Administration (NASA) is interested in applying mobile Internet protocol (mobile-ip) technologies to its space and aeronautics programs. In particular, mobile-ip will play a major role in the Advanced Aeronautic Transportation Technology (AAT-F), the Weather Information Communication (WINCOMM), and the Small Aircraft Transportation System (SATS) aeronautics programs. This paper describes mobile-ip and mobile routers--in particular, the features, capabilities, and initial performance of the mobile router are presented. The application of mobile-router technology to NASA's space and aeronautics programs is also discussed.

Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial.

PubMed

Burke, Carol A; Dekker, Evelien; Samadder, N Jewel; Stoffel, Elena; Cohen, Alfred

2016-08-02

Molecular studies suggest inhibition of colorectal mucosal polyamines (PAs) may be a promising approach to prevent colorectal cancer (CRC). Inhibition of ornithine decarboxylase (ODC) using low-dose eflornithine (DFMO, CPP-1X), combined with maximal PA export using low-dose sulindac, results in greatly reduced levels of normal mucosal PAs. In a clinical trial, this combination (compared with placebo) reduced the 3-year incidence of subsequent high-risk adenomas by >90 %. Familial Adenomatous Polyposis (FAP) is characterized by marked up-regulation of ODC in normal intestinal epithelial and adenoma tissue, and therefore PA reduction might be a potential strategy to control progression of FAP-related intestinal polyposis. CPP FAP-310, a randomized, double-blind, Phase III trial was designed to examine the safety and efficacy of sulindac and DFMO (alone or in combination) for preventing a clinically relevant FAP-related progression event in individuals with FAP. Eligible adults with FAP will be randomized to: CPP-1X 750 mg and sulindac 150 mg, CPP-1X placebo and sulindac 150 mg, or CPP-1X 750 mg and sulindac placebo once daily for 24 months. Patients will be stratified based on time-to-event prognosis into one of the three treatment arms: best (ie, longest time to first FAP-related event [rectal/pouch polyposis]), intermediate (duodenal polyposis) and worst (pre-colectomy). Stage-specific, "delayed time to" FAP-related events are the primary endpoints. Change in polyp burden (upper and/or lower intestine) is a key secondary endpoint. The trial is ongoing. As of February 1, 2016, 214 individuals have been screened; 138 eligible subjects have been randomized to three treatment groups at 15 North American sites and 6 European sites. By disease strata, 26, 80 and 32 patients are included for assessment of polyp burden in the rectum/pouch, duodenal polyposis and pre-colectomy groups, respectively. Median age is 40 years; 59 % are men. The most common reasons for screening failure include minimal polyp burden (n = 22), withdrawal of consent (n = 9) and extensive polyposis requiring immediate surgical intervention (n = 9). Enrollment is ongoing. This trial is registered at ClinicalTrials.gov ( NCT01483144 ; November 21, 2011) and the EU Clinical Trials Register( EudraCT 2012-000427-41 ; May 15, 2014).

Factors Influencing Interdisciplinary Team Member Agreement With Social Worker Assessments of Domestic Violence Incidents in the United States Air Force

DTIC Science & Technology

2002-08-01

General Accounting Office (GAO) noted, "the programs were little more than administrative mechanisms to formalize the existing structure" (Daley, 1999...p. 57). The USAF formalized the DoD Directive by establishing the Air Force Family Advocacy Program (FAP) later that year through Air Force...highly formalized authority structure has served the military well and allows for consistency despite frequent turnover of a mobile personnel force. The

Quality of life following liver transplantation: a comparative study between Familial Amyloid Neuropathy and liver disease patients

PubMed Central

2009-01-01

Background It has been demonstrated in many studies that quality of life can be improved after liver transplantation in patients with liver disease. Nevertherless quality of life improvement in specific groups of transplantated patients such as those with Familial Amyloid Polineuropathy hasn't yet been explored. The present study aimed to compare the change in quality of life following liver transplantation between patients with Familial Amyloid Polineuropathy (FAP) and patients with liver disease. Results Patient's mental quality of life showed an improvement in all liver disease patients, and a worsening in FAP patients, resulting in a significant difference between the two groups. Regarding physical quality of life, although a similar improvement was seen in both groups, FAP patients had significantly less improvement than the sub-group of decompensated liver disease (Child-Pugh B and C). Conclusion It is concluded that liver transplantation has a less beneficial impact in FAP patient's physical quality of life, probably because they are not so much disabled by their disease at the moment of liver transplantation. The lesser improvement in mental quality of life of FAP patients may be due to their particular psychological profile and greater expectations towards transplantation. PMID:19604387

Automatic facial animation parameters extraction in MPEG-4 visual communication

NASA Astrophysics Data System (ADS)

Yang, Chenggen; Gong, Wanwei; Yu, Lu

2002-01-01

Facial Animation Parameters (FAPs) are defined in MPEG-4 to animate a facial object. The algorithm proposed in this paper to extract these FAPs is applied to very low bit-rate video communication, in which the scene is composed of a head-and-shoulder object with complex background. This paper addresses the algorithm to automatically extract all FAPs needed to animate a generic facial model, estimate the 3D motion of head by points. The proposed algorithm extracts human facial region by color segmentation and intra-frame and inter-frame edge detection. Facial structure and edge distribution of facial feature such as vertical and horizontal gradient histograms are used to locate the facial feature region. Parabola and circle deformable templates are employed to fit facial feature and extract a part of FAPs. A special data structure is proposed to describe deformable templates to reduce time consumption for computing energy functions. Another part of FAPs, 3D rigid head motion vectors, are estimated by corresponding-points method. A 3D head wire-frame model provides facial semantic information for selection of proper corresponding points, which helps to increase accuracy of 3D rigid object motion estimation.

APC promoter 1B deletion in seven American families with familial adenomatous polyposis.

PubMed

Snow, A K; Tuohy, T M F; Sargent, N R; Smith, L J; Burt, R W; Neklason, D W

2015-10-01

Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome caused by mutations in the adenomatous polyposis coli (APC) gene. Clinical genetic testing fails to identify disease causing mutations in up to 20% of clinically apparent FAP cases. Following the inclusion of multiplex ligation-dependent probe amplification (MLPA) probes specific for APC promoter 1B, seven probands were identified with a deletion of promoter 1B. Using haplotype analysis spanning the APC locus, the seven families appear to be identical by descent from a common founder. The clinical phenotype of 19 mutation carriers is classical FAP with colectomy at an average age of 24. The majority of cases had a large number of duodenal and gastric polyps. Measurements of allele-specific expression of APC mRNA using TaqMan assay confirmed that relative expression in the allele containing the promoter 1B deletion was reduced 42-98%, depending on tissue type. This study confirms the importance of APC promoter deletions as a cause of FAP and identifies a founder mutation in FAP patients from the United States. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[A Case in Which a Patient Was Operated for Intra-Abdominal Desmoid Tumors after Total Colectomy in FAP].

PubMed

Hoshi, Minako; Ikeda, Kimimasa; Higashiguchi, Kimiya; Kobayashi, Teruyuki; Sakai, Kenji; Koyama, Taichi; Doi, Takasi; Taniguchi, Hirokazu; Murakami, Masakazu; Kurokawa, Eiji; Nakamichi, Itsuko

2015-11-01

The patient was a 22-year-old woman with FAP, who had undergone laparoscopic total colectomy 3 years previously. She presented to our hospital with a high fever and abdominal pain. Large hard tumors were palpated in the right lower abdomen and pelvis. Blood examination showed an inflammatory response. CT scan revealed 17 cm diameter solid tumors. At surgery, 2 tumors arising from the mesentery of the small intestine were found, neither of which invaded any organs. We performed tumor extirpation with partial resection of the duodenum, ileum, right fallopian tube and rectum. A jejunal stoma was formed, leaving a length of remnant intestine of about 120 cm. The histopathological diagnosis was given as desmoid tumor with infection. The patient was discharged from the hospital on the 9th postoperative day. Desmoid tumor is the second most common cause of death in FAP patients. Although desmoids can also occur in the extremities, most FAP patients develop intra-abdominal tumors. Despite being histologically benign, they are locally infiltrative and can cause death through invasion and destruction of adjacent vital structures and organs. Here, we report a case of desmoid tumors with FAP with reference to the literature.

APC+/− alters colonic fibroblast proteome in FAP

PubMed Central

Dixon, Maketa P.; Blagoi, Elena L.; Nicolas, Emmanuelle; Seeholzer, Steven H.; Cheng, David; He, Yin A.; Coudry, Renata A.; Howard, Sharon D.; Riddle, Dawn M.; Cooper, Harry S.; Boman, Bruce M.; Conrad, Peggy; Crowell, James A.; Bellacosa, Alfonso; Knudson, Alfred; Yeung, Anthony T.; Kopelovich, Levy

2011-01-01

Here we compared the proteomes of primary fibroblast cultures derived from morphologically normal colonic mucosa of familial adenomatous polyposis (FAP) patients with those obtained from unaffected controls. The expression signature of about 19% of total fibroblast proteins separates FAP mutation carriers from unaffected controls (P < 0.01). More than 4,000 protein spots were quantified by 2D PAGE analysis, identifying 368 non-redundant proteins and 400 of their isoforms. Specifically, all three classes of cytoskeletal filaments and their regulatory proteins were altered as were oxidative stress response proteins. Given that FAP fibroblasts showed heightened sensitivity to transformation by KiMSV and SV40 including elevated levels of the p53 protein, events controlled in large measure by the Ras suppressor protein-1 (RSU-1) and oncogenic DJ-1, here we show decreased RSU1 and augmented DJ-1 expression in both fibroblasts and crypt-derived epithelial cells from morphologically normal colonic mucosa of FAP gene-carriers. The results indicate that heterozygosity for a mutant APC tumor suppressor gene alters the proteomes of both colon-derived normal fibroblasts in a gene-specific manner, consistent with a “one-hit” effect. PMID:21411865

Adenomas of the common bile duct in familial adenomatous polyposis

PubMed Central

Yan, Mao-Lin; Pan, Jun-Yong; Bai, Yan-Nan; Lai, Zhi-De; Chen, Zhong; Wang, Yao-Dong

2015-01-01

Familial adenomatous polyposis (FAP) or Gardner’s syndrome is often accompanied by adenomas of the stomach and duodenum. We experienced a case of adenomas of the common bile duct in a 40-year-old woman with FAP presenting with acute cholangitis. Only 8 cases of adenomas or adenocarcinoma of the common bile duct have been reported in the literature in patients with FAP or Gardner’s syndrome. Those patients presented with acute cholangitis or pancreatitis. Local excision or Whipple procedure may be the reasonable surgical option. PMID:25780319

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in France

PubMed Central

Mariani, Louise‐Laure; Lozeron, Pierre; Théaudin, Marie; Mincheva, Zoia; Signate, Aissatou; Ducot, Beatrice; Algalarrondo, Vincent; Denier, Christian; Adam, Clovis; Nicolas, Guillaume; Samuel, Didier; Slama, Michel S.; Lacroix, Catherine; Misrahi, Micheline; Adams, David

2015-01-01

Objective To compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP. Methods We compared 84 French patients with a control group of 110 Portuguese patients carrying the Val30Met mutation also living in France, all referred to and followed at the French National FAP Reference Center from 1988 to 2010. Clinical examination, functional and walking disability scores, nerve conduction studies, and muscle biopsies are reported. We also conducted a comprehensive literature review to further determine the range of phenotypic expression. Results By comparison with Portuguese Val30Met FAP, French Ile107Val, Ser77Tyr, and LateVal30Met FAP showed more rapid and severe disease progression; onset of gait disorders was 3 times more rapid (p < 0.0001) and the rate of modified Norris test decline was up to 40 times faster in Ile107Val patients (p < 0.0001). Median survival was much shorter in Ile107Val and in Val30Met mutation with late onset (>50 years; LateMet30) FAP (p = 0.0005). Other distinctive features relative to the Portuguese patients included atypical clinical presentations, demyelination on nerve conduction studies (p = 0.0005), and difficult identification of amyloid deposits in nerve and muscle biopsies. Interpretation Ile107Val and LateMet30 mutations are associated with the most debilitating and severe FAP ever described, with rapid onset of tetraparesis and shorter median survival. It could be explained by frequent large‐fiber involvement and associated demyelination and more severe axonal loss. These findings have major implications for genetic counseling and patient management as new therapeutic options are being assessed in clinical trials (TTR gene silencing). Ann Neurol 2015;78:901–916 PMID:26369527

Free antibiotic and vaccination programmes in community pharmacies of Miami-Dade County, FL, USA.

PubMed

Gauthier, Timothy P; Suda, Katie J; Mathur, Sunil Kumar; Harriman, David; Pham, Jenny; Aragon, Laura; Abbo, Lilian M; Hooton, Thomas M

2015-02-01

Some community pharmacies provide prescribed oral antibiotics for free to incentivize customers. This can influence prescribing practices and may increase inappropriate antibiotic use. Thus, pleas to incorporate education and/or vaccinations into these initiatives have been made by the CDC and IDSA. This study aims to investigate the prevalence and characteristics of free antibiotic programmes (FAPs) and free vaccination programmes (FVPs) offered by community pharmacies within a major US county. Additionally, we evaluated the association between FAP location and proximate socioeconomic status. A telephone survey was administered to all community pharmacies in operation and located in Miami-Dade County, FL, USA (n=668). Population characteristics at the five-digit ZIP code level were acquired from the 2010 US Census and American Communities Survey. An independent t-test, Kruskal-Wallis and logistic regression were used for statistical analysis. A total of 660 community pharmacies agreed to the telephone survey (response rate=98.8%). FAPs were present in 6.8% of pharmacies (n=45) and none incorporated an educational component targeted at patients or prescribers. Ciprofloxacin and amoxicillin were offered by all FAPs and 84.4% provided up to a 14 day supply (n=38). Thirty-four of 72 ZIP codes had an FAP and those with a programme had larger populations and higher incomes (P≤0.05). Family income≥$75,000 (P=0.0002) was an independent predictor of FAP availability. None of the surveyed pharmacies offered a FVP. Frequently provided by chain pharmacies and located in areas of higher income, FAPs within Miami-Dade County offer broad-spectrum antibiotics for long durations without additional education to patients or prescribers. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Epigallocatechin-3-gallate as a potential therapeutic drug for TTR-related amyloidosis: "in vivo" evidence from FAP mice models.

PubMed

Ferreira, Nelson; Saraiva, Maria João; Almeida, Maria Rosário

2012-01-01

Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disease caused by the extracellular deposition of mutant transthyretin (TTR), with special involvement of the peripheral nervous system (PNS). Currently, hepatic transplantation is considered the most efficient therapy to halt the progression of clinical symptoms in FAP since more than 95% of TTR is produced by the liver. However, less invasive and more reliable therapeutic approaches have been proposed for FAP therapy, namely based on drugs acting as inhibitors of amyloid formation or as amyloid disruptors. We have recently reported that epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, is able to inhibit TTR aggregation and fibril formation, "in vitro" and in a cellular system, and is also able to disrupt pre-formed amyloid fibrils "in vitro". In the present study, we assessed the effect of EGCG subchronic administration on TTR amyloidogenesis "in vivo", using well characterized animal models for FAP. Semiquantitative immunohistochemistry (SQ-IHC) and Western blot analysis of mice tissues after treatment demonstrated that EGCG inhibits TTR toxic aggregates deposition in about 50% along the gastrointestinal tract (GI) and peripheral nervous system (PNS). Moreover EGCG treatment considerably lowered levels of several biomarkers associated with non-fibrillar TTR deposition, namely endoplasmic reticulum (ER)-stress, protein oxidation and apoptosis markers. Treatment of old FAP mice with EGCG resulted not only in the decrease of non-fibrillar TTR deposition but also in disaggregation of amyloid deposits. Consistently, matrix metalloproteinase (MMP)-9 and serum amyloid P component (SAP), both markers of amyloid deposition, were also found reduced in treated old FAP mice. The dual effect of EGCG both as TTR aggregation inhibitor and amyloid fibril disruptor together with the high tolerability and low toxicity of EGCG in humans, point towards the potential use of this compound, or optimized derivatives, in the treatment of TTR-related amyloidoses.

Monitoring acute equine visceral pain with the Equine Utrecht University Scale for Composite Pain Assessment (EQUUS-COMPASS) and the Equine Utrecht University Scale for Facial Assessment of Pain (EQUUS-FAP): A scale-construction study.

PubMed

van Loon, Johannes P A M; Van Dierendonck, Machteld C

2015-12-01

Although recognition of equine pain has been studied extensively over the past decades there is still need for improvement in objective identification of pain in horses with acute colic. This study describes scale construction and clinical applicability of the Equine Utrecht University Scale for Composite Pain Assessment (EQUUS-COMPASS) and the Equine Utrecht University Scale for Facial Assessment of Pain (EQUUS-FAP) in horses with acute colic. A cohort follow-up study was performed using 50 adult horses (n = 25 with acute colic, n = 25 controls). Composite pain scores were assessed by direct observations, Visual Analog Scale (VAS) scores were assessed from video clips. Colic patients were assessed at arrival, and on the first and second mornings after arrival. Both the EQUUS-COMPASS and EQUUS-FAP scores showed high inter-observer reliability (ICC = 0.98 for EQUUS-COMPASS, ICC = 0.93 for EQUUS-FAP, P <0.001), while a moderate inter-observer reliability for the VAS scores was found (ICC = 0.63, P <0.001). The cut-off value for differentiation between healthy and colic horses for the EQUUS-COMPASS was 5, and for differentiation between conservatively treated and surgically treated or euthanased patients it was 11. For the EQUUS-FAP, cut-off values were 4 and 6, respectively. Internal sensitivity and specificity were good for both EQUUS-COMPASS (sensitivity 95.8%, specificity 84.0%) and EQUUS-FAP (sensitivity 87.5%, specificity 88.0%). The use of the EQUUS-COMPASS and EQUUS-FAP enabled repeated and objective scoring of pain in horses with acute colic. A follow-up study with new patients and control animals will be performed to further validate the constructed scales that are described in this study. Copyright © 2015 Elsevier Ltd. All rights reserved.

Interplay between Ret and Fap-1 regulates CD95-mediated apoptosis in medullary thyroid cancer cells.

PubMed

Nicolini, Valentina; Cassinelli, Giuliana; Cuccuru, Giuditta; Bongarzone, Italia; Petrangolini, Giovanna; Tortoreto, Monica; Mondellini, Piera; Casalini, Patrizia; Favini, Enrica; Zaffaroni, Nadia; Zunino, Franco; Lanzi, Cinzia

2011-10-01

Emerging evidence suggests that Ret oncoproteins expressed in medullary thyroid cancer (MTC) might evade the pro-apoptotic function of the dependence receptor proto-Ret by directly impacting the apoptosis machinery. Identification of the molecular determinants of the interplay between Ret signaling and apoptosis might provide a relevant contribution to the optimization of Ret-targeted therapies. Here, we describe the cross-talk between Ret-M918T oncogenic mutant responsible for type 2B multiple endocrine syndrome (MEN2B), and components of death receptor-mediated extrinsic apoptosis pathway. In the human MEN2B-type MTC cell line MZ-CRC-1 expressing Ret-M918T, Ret was found associated with Fap-1, known as inhibitor of the CD95 death receptor trafficking to the cell membrane, and with procaspase-8, the initiator pro-form caspase in the extrinsic apoptosis pathway. Cell treatment with the anti-tumor Ret kinase inhibitor RPI-1 inhibited tyrosine phosphorylation of procaspase-8, likely inducing its local activation, followed by downregulation of both Ret and Fap-1, and translocation of CD95 into lipid rafts. According to the resulting increase of CD95 cell surface expression, the CD95 agonist antibody CH11 enhanced RPI-1-induced cell growth inhibition and apoptosis. RET RNA interference downregulated Fap-1 protein in MZ-CRC-1 cells, whereas exogenous RET-M918T upregulated Fap-1 in HEK293 cells. Overall, these data indicate that the Ret oncoprotein exerts opposing controls on Fap-1 and CD95, increasing Fap-1 expression and decreasing CD95 cell surface expression. The functional interplay of the Ret mutant with the extrinsic apoptosis pathway provides a mechanism possibly contributing to MTC malignant phenotype and a rational basis for novel therapeutic strategies combining Ret inhibitors and CD95 agonists. Copyright © 2011 Elsevier Inc. All rights reserved.

Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy

PubMed Central

Barroso, Fabio; González‐Duarte, Alejandra; Conceição, Isabel; Obici, Laura; Keohane, Denis; Amass, Leslie

2016-01-01

ABSTRACT Transthyretin familial amyloid polyneuropathy (TTR‐FAP) is a rare, severe, and irreversible, adult‐onset, hereditary disorder caused by autosomal‐dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR‐FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease‐modifying treatment options for a wider spectrum of patients with TTR‐FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation‐specific predictive genetic testing in first‐degree relatives of index patients diagnosed with TTR‐FAP and the structured clinical follow‐up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353–360, 2016 PMID:27273296

Antiasthmic effect of fermented Artemisia princeps in asthmic mice induced by ovalbumin.

PubMed

Bae, Eun-Ah; Min, Sung-Won; Lee, Bomi; Kim, Nam-Jae; Baek, Nam-In; Han, Eun-Joo; Chung, Hae-Gon; Kim, Dong-Hyun

2007-09-01

Artemisia princeps Pampanini (AP) was fermented with Bifidobacterium infantis K-525 and its antiasthmic effect investigated. AP and fermented AP (FAP) reduced the IgE level in the blood of ovalbumin-induced asthmic mice. Moreover, FAP reduced the IgE, proinflammatory cytokine IL-6, and IL-4 levels in the trachea, as well as in the lung of the experimental asthmic mice, whereas AP only reduced the IgE and IL-6 levels in the lungs. Nonetheless, AP and FAP both inhibited the mRNA expression of IL-6 and TNF-alpha in IgE-induced RBL-2H3 cells. The in vivo antiasthmic effect of FAP was more potent than that of AP. Therefore, these findings suggest that the enhanced antiasthmic effect of AP after bifidus fermentation was possibly due to the regulation of the proinflammatory cytokine biosynthesis of IL-6 and TNF-alpha.

Functional abdominal pain syndrome.

PubMed

Clouse, Ray E; Mayer, Emeran A; Aziz, Qasim; Drossman, Douglas A; Dumitrascu, Dan L; Mönnikes, Hubert; Naliboff, Bruce D

2006-04-01

Functional abdominal pain syndrome (FAPS) differs from the other functional bowel disorders; it is less common, symptoms largely are unrelated to food intake and defecation, and it has higher comorbidity with psychiatric disorders. The etiology and pathophysiology are incompletely understood. Because FAPS likely represents a heterogeneous group of disorders, peripheral neuropathic pain mechanisms, alterations in endogenous pain modulation systems, or both may be involved in any one patient. The diagnosis of FAPS is made on the basis of positive symptom criteria and a longstanding history of symptoms; in the absence of alarm symptoms, an extensive diagnostic evaluation is not required. Management is based on a therapeutic physician-patient relationship and empirical treatment algorithms using various classes of centrally acting drugs, including antidepressants and anticonvulsants. The choice, dose, and combination of drugs are influenced by psychiatric comorbidities. Psychological treatment options include psychotherapy, relaxation techniques, and hypnosis. Refractory FAPS patients may benefit from a multidisciplinary pain clinic approach.

Management of functional abdominal pain and irritable bowel syndrome in children and adolescents.

PubMed

Chiou, Eric; Nurko, Samuel

2010-06-01

Functional abdominal pain (FAP) and irritable bowel syndrome (IBS) are among the most commonly diagnosed medical problems in pediatrics. Symptom-based Rome III criteria for FAP and IBS have been validated and help the clinician in making a positive diagnosis. The majority of patients with mild complaints improve with reassurance and time. For a distinct subset of patients with more severe and disabling illness, finding effective treatment for these disorders remains a challenge. Over the years, a wide range of therapies have been proposed and studied. The lack of a single, proven intervention highlights the complex interplay of biopsychosocial factors probably involved in the development of childhood FAP and IBS, and the need for a multidisciplinary, integrated approach. This article reviews the current literature on the efficacy of pharmacologic, dietary and psychosocial interventions for FAP and IBS in children and adolescents.

Functional abdominal pain and irritable bowel syndrome in children and adolescents

PubMed Central

Chiou, Eric; Nurko, Samuel

2011-01-01

Functional abdominal pain (FAP) and irritable bowel syndrome (IBS) are both associated with recurrent abdominal pain and are among the most commonly diagnosed medical problems in pediatrics. The majority of patients with mild complaints improve with reassurance and time. For a distinct subset of patients with more severe and disabling illness, finding effective treatment for these disorders remains a challenge. Based on the biopsychosocial model of functional disease, the Rome III criteria have helped frame FAP and IBS in terms of being a positive diagnosis and not a diagnosis of exclusion. However, the lack of a single, proven intervention highlights the complex interplay of pathologic mechanisms likely involved in the development of childhood FAP and IBS and the need for a multidisciplinary, integrated approach. This article discusses the epidemiology, proposed mechanisms, clinical approach and therapeutic options for the management of FAP and IBS in children and adolescents. PMID:21731470

Laser and spectroscopic properties of Sr[sub 5](PO[sub 4])[sub 3]F:Yb

DOE Office of Scientific and Technical Information (OSTI.GOV)

DeLoach, L.D.; Payne, S.A.; Smith, L.K.

Sr[sub 5](PO[sub 4])[sub 3]F (S-FAP) has been investigated as a new Yb-doped laser crystal belonging to the apatite structural family. The spectroscopy of the Yb[sup 3+] ion and the laser properties of the medium have been investigated. The maximum absorption cross section of Yb in S-FAP is 8.6 [times] 10[sup [minus]20] cm[sup 2], and the maximum emission cross section is 7.3 [times] 10[sup [minus]20] cm[sup 2]. The measured emission lifetime of Yb[sup 3+] is 1.26 ms. An Yb:S-FAP laser has been demonstrated with a Ti:sapphire laser pump operating at 899 nm. The Yb:S-FAP laser was measured to have slope efficienciesmore » as high as 71%. The spectroscopy and laser studies are reported, as well as certain thermal, mechanical, and optical properties.« less

Optimization of the cooling profile to achieve crack-free Yb:S-FAP crystals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, H; Qiu, S; Kheng, L

Yb:S-FAP [Yb{sup 3+}:Sr{sub 5}(PO{sub 4}){sub 3}F] crystals are an important gain medium for diode-pumped laser applications. Growth of 7.0 cm diameter Yb:S-FAP crystals utilizing the Czochralski (CZ) method from SrF{sub 2}-rich melts often encounter cracks during the post growth cool down stage. To suppress cracking during cool down, a numerical simulation of the growth system was used to understand the correlation between the furnace power during cool down and the radial temperature differences within the crystal. The critical radial temperature difference, above which the crystal cracks, has been determined by benchmarking the simulation results against experimental observations. Based on thismore » comparison, an optimal three-stage ramp-down profile was implemented and produced high quality, crack-free Yb:S-FAP crystals.« less

Temporal metatranscriptomic patterning in phototrophic Chloroflexi inhabiting a microbial mat in a geothermal spring

PubMed Central

Klatt, Christian G; Liu, Zhenfeng; Ludwig, Marcus; Kühl, Michael; Jensen, Sheila I; Bryant, Donald A; Ward, David M

2013-01-01

Filamentous anoxygenic phototrophs (FAPs) are abundant members of microbial mat communities inhabiting neutral and alkaline geothermal springs. Natural populations of FAPs related to Chloroflexus spp. and Roseiflexus spp. have been well characterized in Mushroom Spring, where they occur with unicellular cyanobacteria related to Synechococcus spp. strains A and B′. Metatranscriptomic sequencing was applied to the microbial community to determine how FAPs regulate their gene expression in response to fluctuating environmental conditions and resource availability over a diel period. Transcripts for genes involved in the biosynthesis of bacteriochlorophylls (BChls) and photosynthetic reaction centers were much more abundant at night. Both Roseiflexus spp. and Chloroflexus spp. expressed key genes involved in the 3-hydroxypropionate (3-OHP) carbon dioxide fixation bi-cycle during the day, when these FAPs have been thought to perform primarily photoheterotrophic and/or aerobic chemoorganotrophic metabolism. The expression of genes for the synthesis and degradation of storage polymers, including glycogen, polyhydroxyalkanoates and wax esters, suggests that FAPs produce and utilize these compounds at different times during the diel cycle. We summarize these results in a proposed conceptual model for temporal changes in central carbon metabolism and energy production of FAPs living in a natural environment. The model proposes that, at night, Chloroflexus spp. and Roseiflexus spp. synthesize BChl, components of the photosynthetic apparatus, polyhydroxyalkanoates and wax esters in concert with fermentation of glycogen. It further proposes that, in daytime, polyhydroxyalkanoates and wax esters are degraded and used as carbon and electron reserves to support photomixotrophy via the 3-OHP bi-cycle. PMID:23575369

Food assistance programmes are indirectly associated with anaemia status in children <5 years old in Mexico.

PubMed

Shamah-Levy, Teresa; Méndez-Gómez-Humarán, Ignacio; Gaona-Pineda, Elsa B; Cuevas-Nasu, Lucia; Villalpando, Salvador

2016-09-01

Anaemia in children is a public health concern in Mexico; Federal food assistance programmes are being implemented to prevent it. We undertook this research to investigate the indirect association between food assistance programmes (FAP) and anaemia through dietary and socio-economic conditions of beneficiary children. A structural equation model (SEM) was constructed to assess associations among FAP, dietary and socio-economic conditions, as well as anaemia. A cross-sectional comparative study was conducted based on a sample of 1214 households with children <5 years old, beneficiaries of two FAP: Prospera and rescue from malnutrition with amaranth (RMA) and a comparison group in San Luis Potosí, Mexico. The SEM and a decomposition effect analysis revealed the existence of a significant indirect association of FAP on the prevalence of anaemia via dietary and socio-economic conditions in children under 5 years old. The Prospera assistance programme showed a significant indirect positive association with the prevalence of anaemia (standard coefficient=0·027, P<0·031), and the RMA programme showed a significant indirect negative association with the prevalence of anaemia (standard coefficient=-0·029, P=0·047). There was a direct association between FAP and dietary and socio-economic conditions. FAP could indirectly modify the prevalence of anaemia in young children with a direct improvement on dietary and socio-economic conditions. The unexpected finding of the association between RMA, dietary and socio-economic conditions and the prevalence of anaemia reflects differences in the focus of the programmes.

Circulating FGF21 proteolytic processing mediated by fibroblast activation protein

PubMed Central

Zhen, Eugene Y.; Jin, Zhaoyan; Ackermann, Bradley L.; Thomas, Melissa K.; Gutierrez, Jesus A.

2015-01-01

Fibroblast growth factor 21 (FGF21), a hormone implicated in the regulation of glucose homoeostasis, insulin sensitivity, lipid metabolism and body weight, is considered to be a promising therapeutic target for the treatment of metabolic disorders. Despite observations that FGF21 is rapidly proteolysed in circulation rending it potentially inactive, little is known regarding mechanisms by which FGF21 protein levels are regulated. We systematically investigated human FGF21 protein processing using mass spectrometry. In agreement with previous reports, circulating human FGF21 was found to be cleaved primarily after three proline residues at positions 2, 4 and 171. The extent of FGF21 processing was quantified in a small cohort of healthy human volunteers. Relative abundance of FGF21 proteins cleaved after Pro-2, Pro-4 and Pro-171 ranged from 16 to 30%, 10 to 25% and 10 to 34%, respectively. Dipeptidyl peptidase IV (DPP-IV) was found to be the primary protease responsible for N-terminal cleavages after residues Pro-2 and Pro-4. Importantly, fibroblast activation protein (FAP) was implicated as the protease responsible for C-terminal cleavage after Pro-171, rendering the protein inactive. The requirement of FAP for FGF21 proteolysis at the C-terminus was independently demonstrated by in vitro digestion, immunodepletion of FAP in human plasma, administration of an FAP-specific inhibitor and by human FGF21 protein processing patterns in FAP knockout mouse plasma. The discovery that FAP is responsible for FGF21 inactivation extends the FGF21 signalling pathway and may enable novel approaches to augment FGF21 actions for therapeutic applications. PMID:26635356

Cancer in an unexpected site post pouch surgery for familial adenomatous polyposis (FAP).

PubMed

Alwahbi, Omar A; Abduljabbar, Alaa S; Anwer, Lucman A

2018-01-01

Familial Adenomatous Polyposis (FAP) is a hereditary condition characterized by multiple colorectal adenomatous polyps. FAP is the most common adenomatous polyposis syndrome. Restorative proctocolectomy is the most commonly performed surgical procedure performed for patients suffering from FAP with different options for anastomosis, namely ileorectal anastomosis (IRA) or ileal pouch anal anastomosis (IPAA). The occurrence of adenomas is a common finding during follow up and surveillance post surgery for these patients. Although there are a few cases of carcinoma that were namely at the anal transitional zone (ATZ), there are only a few cases of ileal pouch related adenocarcinoma reported. This work has been reported in line with the SCARE criteria (Agha et al., 2016) [1]. We report a case of a 34-year-old man diagnosed with FAP who underwent proctocolectomy with IPAA, and subsequently referred to our center, who, despite appropriate measures and surveillance, developed adenocarcinoma in the ileal pouch. Restorative proctocolectomy for Familial Adenomatous Polyposis (FAP) is the mainstay of treatment. There are different surgical options, each with its own set of advantages and disadvantages. The most favored option is proctocolectomy with ileal pouch anal anastomosis (IPAA) due to because it involves resection of the rectum. Despite these interventions, adenomas and/or carcinomas have been reported on follow up post surgery. Although the risk of developing adenomas or carcinomas in the ileal pouch post proctocolectomy with IPAA is low it should not be neglected as cancer occurrence or recurrence is unpredictable even with appropriate measures. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

77 FR 61825 - Notice of Final Federal Agency Actions on Proposed Highway in Illinois

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-11

.... 139(l)(1). The actions relate to a proposed highway project, Willow Road (FAP 305) between Illinois... in the State of Illinois: reconstruct and widen Willow Road (FAP 305) from Illinois Route 43...

Clinical characterization and mutation spectrum in Hispanic families with adenomatous polyposis syndromes.

PubMed

Cruz-Correa, Marcia; Diaz-Algorri, Yaritza; Mendez, Vanessa; Vazquez, Pedro Juan; Lozada, Maria Eugenia; Freyre, Katerina; Lathroum, Liselle; Gonzalez-Pons, Maria; Hernandez-Marrero, Jessica; Giardiello, Francis; Rodriguez-Quilichini, Segundo

2013-09-01

Several genetically defined hereditary colorectal cancer (CRC) syndromes are associated with colonic polyposis including familial adenomatous polyposis (FAP) and MUTYH adenomatous polyposis (MAP). Limited data exists on the clinical characterization and genotypic spectrum of polyposis syndromes among Hispanics. To describe the phenotype and genotype of Puerto Rican Hispanic patients with FAP and MUTYH and compare with other ethnic and racial groups. Probands were identified from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). Recruited individuals completed risk factors, medical, and family history questionnaires and underwent genetic testing for genotype analysis. Frequency analysis, Chi square, Fisher's exact and Wilcoxon rank-sum tests were used for statistical analysis methods. A total of 31 FAP (from 19 families) and 13 MAP (from 13 families) Hispanic patients recruited from the PURIFICAR were evaluated. Among the FAP cases, mean age at diagnosis was 27.6 (range 9-71 years); 67.7 % cases had more than 100 polyps and 41.9 % had upper gastrointestinal polyps. Among the 19 FAP families, there were 77 affected FAP individuals and 26 colorectal cancer cases. Genetic mutations were available for 42.2 % of FAP families; all mutations identified were unique. Surgeries were reported in 31 cases; 14 (45.2 %) prophylactic surgeries and 6 (19.4 %) therapeutic surgeries for management of CRC. Among MAP cases, mean age at diagnosis was 53 (range 34-76 years). Genetic analysis revealed homozygous biallelic mutations (G382D) in 53.8 %, compound heterozygous mutations (G382/Y165C) in 23 %, and non-G382/Y165C monoallelic mutations in 23 %. Familial cancer registries should be promoted as vehicles for detection, education and follow up of families at-risk of acquiring familial cancers. PURIFICAR is the first and only familial cancer registry in Puerto Rico providing these services to families affected with familial cancer syndromes promoting education, testing and surveillance of at-risk family members, and focusing on cancer prevention efforts. The fact that only 40 % of FAP patients had access to genetic testing stresses the need to promote the establishment of policies supporting genetic testing coverage by medical insurance companies in order to provide patients with the highest standard of care to prevent cancer. Furthermore, our results suggest that Hispanics may have uncommon mutations in adenomatous polyposis related genes, which emphasize the need for full gene sequencing to establish genetic diagnosis.

NASA's aeronautics research and technology base

NASA Technical Reports Server (NTRS)

1979-01-01

NASA's research technology base in aeronautics is assessed in terms of: (1) US aeronautical technology needs and requirements in the future; (2) objectives of the aeronautics program; (3) magnitude and scope of the program; and (4) research and technology performed by NASA and other research organizations.

76 FR 77992 - Combined Notice of Filings #2

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-15

.... Description: ISO New England Inc. submits tariff filing per 35: Revisions to ISO-NE FAP Compliance Order--Part...: Revisions to ISO-NE FAP Compliance Filing--Part 2 of 2 to be effective 5/1/2012. Filed Date: 12/8/11...

SPANXB2 and Prostate Cancer Progression

DTIC Science & Technology

2014-12-01

FAP  and  α-­‐ SMA   are   markers   of...100 150 200 IL-11 Fo ld c ha ng e of E xp re ss io n 19 I 19 I-P C3 19 I-P C3 -2 R 19 I-R W PE ** 0 500 1000 1500 FAP Fo ld c ha ng e of E xp re...more  “  reactive”  A  :  Markers  of   Reactive  stromal  genes  including   FAP ,  α-­‐SMA  (  ACTA2),  VIM,

Nonampullary duodenal adenoma: Current understanding of its diagnosis, pathogenesis, and clinical management

PubMed Central

Lim, Chul-Hyun; Cho, Young-Seok

2016-01-01

Nonampullary duodenal adenomas are relatively common in familial adenomatous polyposis (FAP), but nonampullary sporadic duodenal adenomas (SDAs) are rare. Emerging evidence shows that duodenal adenomas, regardless of their anatomic location and whether they are sporadic or FAP-related, share morphologic and molecular features with colorectal adenomas. The available data suggest that duodenal adenomas develop to duodenal adenocarcinomas via similar mechanisms. The optimal approach for management of duodenal adenomas remains to be determined. The techniques for endoscopic resection of duodenal adenoma include snare polypectomy, endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and argon plasma coagulation ablation. EMR may facilitate removal of large duodenal polyps. Although several studies have reported cases of successful ESD for duodenal adenomas, the procedure is technically difficult to perform safely because of the anatomical properties of the duodenum. Although current clinical practice recommends endoscopic resection of all large duodenal adenomas in patients with FAP, endoscopic treatment is usually insufficient to guarantee a polyp-free duodenum. Surgery is indicated for FAP patients with severe polyposis or nonampullary SDAs or FAP-related polyps not amenable to endoscopic resection. Further studies are needed to develop newer endoscopic techniques to guide diagnostic and therapeutic decisions for future management of nonampullary duodenal adenomas. PMID:26811631

Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials.

PubMed

Suanprasert, N; Berk, J L; Benson, M D; Dyck, P J B; Klein, C J; Gollob, J A; Bettencourt, B R; Karsten, V; Dyck, P J

2014-09-15

Protein stabilization and oligonucleotide therapies are being tested in transthyretin amyloid polyneuropathy (TTR FAP) trials. From retrospective analysis of 97 untreated TTR FAP patients, we test the adequacy of Neuropathy Impairment Score+7 tests (NIS+7) and modifications to comprehensively score impairments for use in such therapeutic trials. Our data confirms that TTR FAP usually is a sensorimotor polyneuropathy with autonomic features which usually is symmetric, length dependent, lower limb predominant and progressive. NIS+7 adequately assesses weakness and muscle stretch reflexes without ceiling effects but not sensation loss, autonomic dysfunction or nerve conduction abnormalities. Three modifications of NIS+7 are suggested: 1) use of Smart Somatotopic Quantitative Sensation Testing (S ST QSTing); 2) choice of new autonomic assessments, e.g., sudomotor testing of distributed anatomical sites; and 3) use of only compound muscle action potential amplitudes (of ulnar, peroneal and tibial nerves) and sensory nerve action potentials of ulnar and sural nerve - than the previously recommended attributes suggested for the sensitive detection of diabetic sensorimotor polyneuropathy. These modifications of NIS+7 if used in therapeutic trials should improve characterization and quantification of sensation and autonomic impairment in TTR FAP and provide better nerve conduction tests. Copyright © 2014 Elsevier B.V. All rights reserved.

Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia

PubMed Central

Roberts, Edward W.; Deonarine, Andrew; Jones, James O.; Denton, Alice E.; Feig, Christine; Lyons, Scott K.; Espeli, Marion; Kraman, Matthew; McKenna, Brendan; Wells, Richard J.B.; Zhao, Qi; Caballero, Otavia L.; Larder, Rachel; Coll, Anthony P.; O’Rahilly, Stephen; Brindle, Kevin M.; Teichmann, Sarah A.; Tuveson, David A.

2013-01-01

Fibroblast activation protein-α (FAP) identifies stromal cells of mesenchymal origin in human cancers and chronic inflammatory lesions. In mouse models of cancer, they have been shown to be immune suppressive, but studies of their occurrence and function in normal tissues have been limited. With a transgenic mouse line permitting the bioluminescent imaging of FAP+ cells, we find that they reside in most tissues of the adult mouse. FAP+ cells from three sites, skeletal muscle, adipose tissue, and pancreas, have highly similar transcriptomes, suggesting a shared lineage. FAP+ cells of skeletal muscle are the major local source of follistatin, and in bone marrow they express Cxcl12 and KitL. Experimental ablation of these cells causes loss of muscle mass and a reduction of B-lymphopoiesis and erythropoiesis, revealing their essential functions in maintaining normal muscle mass and hematopoiesis, respectively. Remarkably, these cells are altered at these sites in transplantable and spontaneous mouse models of cancer-induced cachexia and anemia. Thus, the FAP+ stromal cell may have roles in two adverse consequences of cancer: their acquisition by tumors may cause failure of immunosurveillance, and their alteration in normal tissues contributes to the paraneoplastic syndromes of cachexia and anemia. PMID:23712428

The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing.

PubMed

Kou, Xiaoxing; Xu, Xingtian; Chen, Chider; Sanmillan, Maria Laura; Cai, Tao; Zhou, Yanheng; Giraudo, Claudio; Le, Anh; Shi, Songtao

2018-03-14

Mesenchymal stem cells (MSCs) are capable of secreting exosomes, extracellular vesicles, and cytokines to regulate cell and tissue homeostasis. However, it is unknown whether MSCs use a specific exocytotic fusion mechanism to secrete exosomes and cytokines. We show that Fas binds with Fas-associated phosphatase-1 (Fap-1) and caveolin-1 (Cav-1) to activate a common soluble N -ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE)-mediated membrane fusion mechanism to release small extracellular vesicles (sEVs) in MSCs. Moreover, we reveal that MSCs produce and secrete interleukin-1 receptor antagonist (IL-1RA) associated with sEVs to maintain rapid wound healing in the gingiva via the Fas/Fap-1/Cav-1 cascade. Tumor necrosis factor-α (TNF-α) serves as an activator to up-regulate Fas and Fap-1 expression via the nuclear factor κB pathway to promote IL-1RA release. This study identifies a previously unknown Fas/Fap-1/Cav-1 axis that regulates SNARE-mediated sEV and IL-1RA secretion in stem cells, which contributes to accelerated wound healing. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

FAP Associated Papillary Thyroid Carcinoma: A Peculiar Subtype of Familial Nonmedullary Thyroid Cancer.

PubMed

Cetta, Francesco

2015-01-01

Familial Nonmedullary Thyroid Carcinoma (FNMTC) makes up to 5-10% of all thyroid cancers, also including those FNMTC occurring as a minor component of familial cancer syndromes, such as Familial Adenomatous Polyposis (FAP). We give evidence that this extracolonic manifestation of FAP is determined by the same germline mutation of the APC gene responsible for colonic polyps and cancer but also shows some unusual features (F : M ratio = 80 : 1, absence of LOH for APC in the thyroid tumoral tissue, and indolent biological behaviour, despite frequent multicentricity and lymph nodal involvement), suggesting that the APC gene confers only a generic susceptibility to thyroid cancer, but perhaps other factors, namely, modifier genes, sex-related factors, or environmental factors, are also required for its phenotypic expression. This great variability is against the possibility of classifying all FNMTC as a single entity, not only with a unique or prevalent causative genetic factor, but also with a unique or common biological behavior and a commonly dismal prognosis. A new paradigm is also suggested that could be useful (1) for a proper classification of FAP associated PTC within the larger group of FNMTC and (2) for making inferences to sporadic carcinogenesis, based on the lesson from FAP.

The role of Mycobacterium avium complex fibronectin attachment protein in adherence to the human respiratory mucosa.

PubMed

Middleton, A M; Chadwick, M V; Nicholson, A G; Dewar, A; Groger, R K; Brown, E J; Wilson, R

2000-10-01

Mycobacterium avium complex (MAC) are opportunistic respiratory pathogens that infect non-immunocompromised patients with established lung disease, although they can also cause primary infections. The ability to bind fibronectin is conserved among many mycobacterial species. We have investigated the adherence of a sputum isolate of MAC to the mucosa of organ cultures constructed with human tissue and the contribution of M. avium fibronectin attachment protein (FAP) to the process. MAC adhered to fibrous, but not globular mucus, and to extracellular matrix (ECM) in areas of epithelial damage, but not to intact extruded cells and collagen fibres. Bacteria occasionally adhered to healthy unciliated epithelium and to cells that had degenerated exposing their contents, but never to ciliated cells. The results obtained with different respiratory tissues were similar. Two ATCC strains of MAC gave similar results. There was a significant reduction (P < 0.05) in the number of bacteria adhering to ECM after preincubation of bacteria with fibronectin and after preincubation of the tissue with M. avium FAP in a concentration-dependant manner. The number of bacteria adhering to fibrous mucus was unchanged. Immunogold labelling demonstrated fibronectin in ECM as well as in other areas of epithelial damage, but only ECM bound FAP. A Mycobacterium smegmatis strain had the same pattern of adherence to the mucosa as MAC. When the FAP gene was deleted, the strain demonstrated reduced adherence to ECM, and adherence was restored when the strain was transfected with an M. avium FAP expression construct. We conclude that MAC adheres to ECM in areas of epithelial damage via FAP and to mucus with a fibrous appearance via another adhesin. Epithelial damage exposing ECM and poor mucus clearance will predispose to MAC airway infection.

Sequential cancer immunotherapy: targeted activity of dimeric TNF and IL-8

PubMed Central

Adrian, Nicole; Siebenborn, Uta; Fadle, Natalie; Plesko, Margarita; Fischer, Eliane; Wüest, Thomas; Stenner, Frank; Mertens, Joachim C.; Knuth, Alexander; Ritter, Gerd; Old, Lloyd J.; Renner, Christoph

2009-01-01

Polymorphonuclear neutrophils (PMNs) are potent effectors of inflammation and their attempts to respond to cancer are suggested by their systemic, regional and intratumoral activation. We previously reported on the recruitment of CD11b+ leukocytes due to tumor site-specific enrichment of TNF activity after intravenous administration of a dimeric TNF immunokine with specificity for fibroblast activation protein (FAP). However, TNF-induced chemo-attraction and extravasation of PMNs from blood into the tumor is a multistep process essentially mediated by interleukin 8. With the aim to amplify the TNF-induced and IL-8-mediated chemotactic response, we generated immunocytokines by N-terminal fusion of a human anti-FAP scFv fragment with human IL-8 (IL-872) and its N-terminally truncated form IL-83-72. Due to the dramatic difference in chemotaxis induction in vitro, we favored the mature chemokine fused to the anti-FAP scFv for further investigation in vivo. BALB/c nu/nu mice were simultaneously xenografted with FAP-positive or -negative tumors and extended chemo-attraction of PMNs was only detectable in FAP-expressing tissue after intravenous administration of the anti-FAP scFv-IL-872 construct. As TNF-activated PMNs are likewise producers and primary targets for IL-8, we investigated the therapeutic efficacy of co-administration of both effectors: Sequential application of scFv-IL-872 and dimeric IgG1-TNF fusion proteins significantly enhanced anti-tumor activity when compared either to a single effector treatment regimen or sequential application of non-targeted cytokines, indicating that the tumor-restricted sequential application of IL-872 and TNF is a promising approach for cancer therapy. PMID:19267427

Nausea in Children With Functional Abdominal Pain Predicts Poor Health Outcomes in Young Adulthood.

PubMed

Russell, Alexandra C; Stone, Amanda L; Walker, Lynn S

2017-05-01

Nausea is common among children with functional abdominal pain (FAP). We evaluated the relation of nausea to short- and long-term morbidity in pediatric patients with FAP. We performed a prospective study of 871 children with FAP (age, 8-17 y) seen in a pediatric gastroenterology practice; follow-up data were collected from 392 of the patients at 8.7 ± 3.3 years later. Participants were defined as having significant nausea if they reported nausea "a lot" or "a whole lot" within the past 2 weeks. Validated questionnaires assessed abdominal pain, gastrointestinal and somatic symptoms, and depression. Baseline measures, anxiety, and the Rome III criteria were assessed in the follow-up evaluation. At baseline, 44.8% of the patients reported significant nausea. Those with nausea reported worse abdominal pain, gastrointestinal symptoms, somatic symptoms, and depression than those without nausea (P < .001 for all). When the children had reached young adulthood, those with nausea in childhood continued to have more severe gastrointestinal (P < .001) and somatic symptoms (P = .003) than patients without nausea in childhood, as well as higher levels of anxiety (P = .02) and depression (P = .02). In the follow-up evaluation, somatic symptoms, depression, and anxiety remained significant after controlling for baseline abdominal pain severity. Pediatric patients with FAP and nausea have more severe short- and long-term gastrointestinal and somatic symptoms than patients with FAP without nausea, as well as reductions in mental health and daily function. Pediatric patients with FAP and nausea therefore need intensive treatment and follow-up evaluation. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

FAP-1-mediated activation of NF-kappaB induces resistance of head and neck cancer to Fas-induced apoptosis.

PubMed

Wieckowski, Eva; Atarashi, Yoshinari; Stanson, Joanna; Sato, Taka-Aki; Whiteside, Theresa L

2007-01-01

Molecular mechanisms responsible for tumor resistance to apoptosis often involve the Fas/FasL pathway. While squamous cell carcinomas of the head and neck (SCCHN) express both Fas and FasL, their resistance to self-induced apoptosis or apoptosis mediated by Fas agonistic antibody (CH-11Ab) was independent of the level of Fas surface expression or the presence of soluble Fas in supernatants of primary or metastatic SCCHN cell lines. By in vitro immunoselection, using PCI-15A cell line treated with successive cycles of CH-11 Ab, Fas-resistant sublines with the parental genotype were selected. Such sublines failed to cleave caspase-8 upon Fas engagement and were resistant to CH-11 Ab, although they remained sensitive to VP-16 or staurosporin. In the presence of cycloheximide, the selected SCCHN sublines become susceptible to CH-11 Ab, and showed cleavage of caspase-8, suggesting that apoptosis resistance was mediated by an inhibitory protein(s) acting upstream of caspase-8. Overexpression of Fas-associated phosphatase 1 (FAP-1), but not cellular FLICE-inhibitory protein (cFLIP) in SCCHN sublines was documented by Western blots and RT-PCR analyses. The FAP-1+ selected sublines also downregulated cell surface Fas. A high phosphorylation level of IkappaB kappa, NFkappaB activation and upregulation of Bcl-2 expression were observed in the FAP-1+ sublines. Treatment with the phosphatase inhibitor, orthovanadate, or silencing of FAP-1 with siRNA abolished their resistance to apoptosis, suggesting that FAP-1 phosphatase activity could be responsible for NF-kappaB activation and resistance of SCCHN cells to Fas-mediated apoptosis. 2006 Wiley-Liss, Inc.

Comparison between ultrasound-guided compression and para-aneurysmal saline injection in the treatment of postcatheterization femoral artery pseudoaneurysms.

PubMed

ElMahdy, Mahmoud Farouk; Kassem, Hussien Heshmat; Ewis, Essam Baligh; Mahdy, Soliman Gharieb

2014-03-01

Management of postcatheterization femoral artery pseudoaneurysm (FAP) is problematic. Ultrasound-guided compression (UGC) is painful and cumbersome. Thrombin injection is costly and may cause thromboembolism. Ultrasound-guided para-aneurysmal saline injection (PASI) has been described but was never compared against other treatment methods of FAP. We aimed at comparing the success rate and complications of PASI versus UGC. We randomly assigned 80 patients with postcatheterization FAPs to either UGC (40 patients) or PASI (40 patients). We compared the 2 procedures regarding successful obliteration of the FAP, incidence of vasovagal attacks, procedure time, discontinuation of antiplatelet and/or anticoagulants, and the Doppler waveform in the ipsilateral pedal arteries at the end of the procedure. There was no significant difference between patients in both groups regarding clinical and vascular duplex data. The mean durations of UGC and PASI procedures were 58.14 ± 28.45 and 30.33 ± 8.56 minutes, respectively (p = 0.045). Vasovagal attacks were reported in 10 (25%) and 2 patients (5%) treated with UGC and PASI, respectively (p = 0.05). All patients in both groups had triphasic Doppler waveform in the infrapopliteal arteries before and after the procedure. The primary and final success rates were 75%, 92.5%, 87.5%, and 95% for UGC and PASI, respectively (p = 0.43). In successfully treated patients, there was no reperfusion of the FAP in the follow-up studies (days 1 and 7) in both groups. In conclusion, ultrasound-guided PASI is an effective method for the treatment of FAP. Compared with UGC, PASI is faster, less likely to cause vasovagal reactions, and can be more convenient to patients and physicians. Copyright © 2014 Elsevier Inc. All rights reserved.

Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice.

PubMed

Penny, Hweixian Leong; Prestwood, Tyler R; Bhattacharya, Nupur; Sun, Fionna; Kenkel, Justin A; Davidson, Matthew G; Shen, Lei; Zuniga, Luis A; Seeley, E Scott; Pai, Reetesh; Choi, Okmi; Tolentino, Lorna; Wang, Jinshan; Napoli, Joseph L; Engleman, Edgar G

2016-11-01

Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APC Min/+ mice, a model that recapitulates FAP in most respects. We also investigated the impact of intestinal RA repletion and depletion on tumorigenesis and inflammation in APC Min/+ mice. Tumors from both FAP patients and APC Min/+ mice displayed striking alterations in RA metabolism that resulted in reduced intestinal RA. APC Min/+ mice placed on a vitamin A-deficient diet exhibited further reductions in intestinal RA with concomitant increases in inflammation and tumor burden. Conversely, restoration of RA by pharmacologic blockade of the RA-catabolizing enzyme CYP26A1 attenuated inflammation and diminished tumor burden. To investigate the effect of RA deficiency on the gut immune system, we studied lamina propria dendritic cells (LPDC) because these cells play a central role in promoting tolerance. APC Min/+ LPDCs preferentially induced Th17 cells, but reverted to inducing Tregs following restoration of intestinal RA in vivo or direct treatment of LPDCs with RA in vitro These findings demonstrate the importance of intestinal RA deficiency in tumorigenesis and suggest that pharmacologic repletion of RA could reduce tumorigenesis in FAP patients. Cancer Immunol Res; 4(11); 917-26. ©2016 AACR. ©2016 American Association for Cancer Research.

Fluorapatite crystal growth from modified seawater solutions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van Cappellen, P.; Berner, R.A.

Seeded precipitation experiments were conducted in a pH/fluoride-stat system to study the crystal growth of fluorapatite (FAP) in carbonate-free NaCl-CaCl{sub 2}-NaF-Na{sub 2}HPO{sub 4} solutions, at seawater calcium concentration, chlorinity, and pH. With increasing supersaturation, the dependence of the growth rate on the relative supersaturation changes from parabolic to exponential. This is interpreted as reflecting a transition in the crystal growth mechanism from growth at dislocation-induced surface steps to surface nucleation-controlled growth. The analysis of the kinetic data leads to a mineral-aqueous solution interfacial tension for FAP of 289 mJ/M{sup 2}. The Arrhenius activation energy of the growth reaction in themore » temperature range 12 to 35C is 47 kJ/mol. The effect of pH on FAP growth was tested for pH values from 7 to 8.5. In this range, growth of FAP is catalyzed by hydrogen ions. The apparent growth rate constant is proportional to (a{sub H{sup +}}){sup m} where m, the rate order with respect to H{sup +}, is a non-integral number which depends on pH. At identical degrees of supersaturation, the growth rate of FAP at pH = 7 is nearly twice that at pH = 8. When corrected for bottom water temperatures, pore water pH, and the retardation of Mg{sup 2+}, the experimental growth rates predict that during burial in modern phosphatic sediments, apatite particles grow to sizes on the order of 0.1-10{mu}m. The relatively slow growth kinetics of FAP are consistent with the observed small particle sizes of marine sedimentary apatite.« less

Questions & Answers about Aeronautics and Space.

ERIC Educational Resources Information Center

National Aeronautics and Space Administration, Washington, DC.

Answers to 27 questions about aeronautics, space, and the National Aeronautics and Space Administration (NASA) are provided in this pamphlet. Among the topics dealt with in these questions are: costs of the space program; NASA's role in aeronautics; benefits received from the space program; why the United States hasn't developed means of rescuing…

Culture-Sensitive Functional Analytic Psychotherapy

ERIC Educational Resources Information Center

Vandenberghe, L.

2008-01-01

Functional analytic psychotherapy (FAP) is defined as behavior-analytically conceptualized talk therapy. In contrast to the technique-oriented educational format of cognitive behavior therapy and the use of structural mediational models, FAP depends on the functional analysis of the moment-to-moment stream of interactions between client and…

Differentiated thyroid cancer associated with intestinal polyposis syndromes: a review.

PubMed

Harb, William J; Sturgis, Erich M

2009-11-01

Intestinal polyposis syndromes, such as familial adenomatous polyposis (FAP) and Cowden's syndrome, are often associated with extraintestinal manifestations, and while many of these manifestations are benign, malignant extraintestinal manifestations, such as differentiated thyroid cancers, do occur. Although differentiated thyroid cancers (ie, papillary and follicular thyroid carcinomas) are associated with multiple syndromes, they are most commonly associated with intestinal polyposis syndromes. In the general population, the probability of developing thyroid cancer by age 65 years is only .5%. However, 1% to 2% of patients with FAP develop papillary thyroid carcinoma, the most common extraintestinal malignancy in patients with FAP. Also, up to 10% of patients with Cowden's syndrome will develop follicular thyroid carcinoma. The purpose of this review was to provide an overview of FAP, Cowden's syndrome, and Peutz-Jeghers syndrome, to discuss in detail the associations between intestinal polyposis syndromes and differentiated thyroid cancers, and to provide suggestions for screening and managing these diseases. (c) 2009 Wiley Periodicals, Inc. Head Neck, 2009.

Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy.

PubMed

Schmidt, Hartmut H-J; Barroso, Fabio; González-Duarte, Alejandra; Conceição, Isabel; Obici, Laura; Keohane, Denis; Amass, Leslie

2016-09-01

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, severe, and irreversible, adult-onset, hereditary disorder caused by autosomal-dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR-FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease-modifying treatment options for a wider spectrum of patients with TTR-FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation-specific predictive genetic testing in first-degree relatives of index patients diagnosed with TTR-FAP and the structured clinical follow-up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353-360, 2016. © 2016 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

Preliminary evidence for increased parasympathetic activity during social inclusion and exclusion in adolescents with functional abdominal pain.

PubMed

Gulewitsch, Marco Daniel; Jusyte, Aiste; Mazurak, Nazar; Weimer, Katja; Schönenberg, Michael

2017-07-01

Peer victimization (e.g. social exclusion) has been shown to be associated with physical health problems such as functional somatic complaints and especially symptoms of pain. To date, no study has investigated the mechanisms underlying this association in clinical pediatric samples. The aim of this study was to evaluate the parasympathetic activity during a social exclusion experience in adolescents with functional abdominal pain (FAP). Twenty adolecents with FAP and 21 matched healthy participants were compared regarding parameters of parasympathetic activation before, during, and after participating in the Cyberball-game, a well-established paradigm to induce social exclusion. Adolescents with FAP showed an increase in parasympathetic activation during both consecutive phases of the Cyberball game (inclusion as well as exclusion condition) whereas the healthy control group remained stable. There were no differences in subjective experience of in- and exclusion between the groups. The parasympathetic activation pattern may indicate altered processing of social stimuli in adolescents with FAP. Copyright © 2017 Elsevier Inc. All rights reserved.

Sweat pore reactivity as a surrogate measure of sympathetic nervous system activity in trauma-exposed individuals with and without posttraumatic stress disorder.

PubMed

Familoni, Babajide O; Gregor, Kristin L; Dodson, Thomas S; Krzywicki, Alan T; Lowery, Bobby N; Orr, Scott P; Suvak, Michael K; Rasmusson, Ann M

2016-09-01

Stress analysis by FLIR (forward-looking infrared) evaluation (SAFE) has been demonstrated to monitor sweat pore activation (SPA) as a novel surrogate measure of sympathetic nervous system (SNS) activity in a normal population. SNS responses to a series of 15 1-s, 82 dB, white noise bursts were measured by skin conductance (SC) and SAFE monitoring of SPA on the fingers (FiP) and face (FaP) in 10 participants with posttraumatic stress disorder (PTSD) and 16 trauma-exposed participants without PTSD (Mage  = 48.92 ± 12.00 years; 26.9% female). Within participants, SC and FiP responses across trials were strongly correlated (r = .92, p < .001). Correlations between SC and FaP (r = .76, p = .001) and between FiP and FaP (r = .47, p = .005) were smaller. The habituation of SNS responses across the 15 trials was substantial (SC: d = -2.97; FiP: d = -2.34; FaP: d = -1.02). There was a strong correlation between habituation effects for SC and FiP (r = .76, p < .001), but not for SC and FaP (r = .15, p = .45) or FiP and FaP (r = .29, p = .16). Participants with PTSD showed larger SNS responses to the first loud noise than those without PTSD. PTSD reexperiencing symptoms assessed by the PTSD Checklist on the day of testing were associated with the SNS responses to the first loud noise measured by SC (d = 1.19) and FiP (d = .99), but not FaP (d = .10). This study confirms convergence of SAFE and SC as valid measures of SNS activity. SAFE FiP and SC responses were highly predictive of self-rated PTSD reexperiencing symptoms. SAFE may offer an attractive alternative for applications in PTSD and similar populations. © 2016 Society for Psychophysiological Research. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Yb:FAP and related materials, laser gain medium comprising same, and laser systems using same

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krupke, William F.; Payne, Stephen A.; Chase, Lloyd L.

An ytterbium doped laser material remarkably superior to all others, including Yb:YAG, comprises Ytterbium doped apatite (Yb:Ca.sub.5 (PO.sub.4).sub.3 F) or Yb:FAP, or ytterbium doped crystals that are structurally related to FAP. The new laser material is used in laser systems pumped by diode pump sources having an output near 0.905 microns or 0.98 microns, such as InGaAs and AlInGaAs, or other narrowband pump sources near 0.905 microns or 0.98 microns. The laser systems are operated in either the conventional or ground state depletion mode.

Yb:FAP and related materials, laser gain medium comprising same, and laser systems using same

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krupke, W.F.; Payne, S.A.; Chase, L.L.

An ytterbium doped laser material remarkably superior to all others, including Yb:YAG, comprises ytterbium doped apatite (Yb:Ca[sub 5](PO[sub 4])[sub 3]F) or Yb:FAP, or ytterbium doped crystals that are structurally related to FAP. The new laser material is used in laser systems pumped by diode pump sources having an output near 0.905 microns or 0.98 microns, such as InGaAs and AlInGaAs, or other narrowband pump sources near 0.905 microns or 0.98 microns. The laser systems are operated in either the conventional or ground state depletion mode. 9 figures.

Yb:FAP and related materials, laser gain medium comprising same, and laser systems using same

DOEpatents

Krupke, W.F.; Payne, S.A.; Chase, L.L.; Smith, L.K.

1994-01-18

An ytterbium doped laser material remarkably superior to all others, including Yb:YAG, comprises ytterbium doped apatite (Yb:Ca[sub 5](PO[sub 4])[sub 3]F) or Yb:FAP, or ytterbium doped crystals that are structurally related to FAP. The new laser material is used in laser systems pumped by diode pump sources having an output near 0.905 microns or 0.98 microns, such as InGaAs and AlInGaAs, or other narrowband pump sources near 0.905 microns or 0.98 microns. The laser systems are operated in either the conventional or ground state depletion mode. 9 figures.

Coordinated Optimization of Aircraft Routes and Locations of Ground Sensors

DTIC Science & Technology

2014-09-17

d U γ P p w dw    r sr s , (6) where γ is the detection threshold determined from the following equa- tion for some given faP : ( )( ) ,fa N γ...normal with the mean Uμ 7 and variance Uσ  2 3 . Suppose, the threshold for the false alarm is faP  410 . Then, from equation (7), .γ6 7190 ; and...functions; and the joint probability of false alarm would be ( , ) faP     s s 4 4 81 2 10 10 10 whereas the joint probabil- ity of detection would

Yb:FAP and related materials, laser gain medium comprising same, and laser systems using same

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krupke, W.F.; Payne, S.A.; Chase, L.L.

An ytterbium doped laser material remarkably superior to all others, including Yb:YAG, comprises ytterbium doped apatite (Yb:Ca{sub 5}(PO{sub 4}){sub 3}F) or Yb:FAP, or ytterbium doped crystals structurally related to FAP. The new laser material is used in laser systems pumped by diode pump sources having an output near 0.905 microns or 0.98 microns, such as InGaAs and AlInGaAs, or other narrowband pump sources near 0.905 microns or 0.98 microns. The laser systems are operated in either the conventional or ground state depletion mode.

Psychological implications of living with familial adenomatous polyposis.

PubMed

Claes, E; Renson, M; Delespesse, A; De Hoe, V; Haelterman, G; Kartheuser, A; Van Cutsem, E

2011-09-01

Psychosocial implications of living with FAP remain largely unexplored. This article reviews available literature on three topics: 1) Implications of living with FAP 2) genetic testing and reproductive decision-making and 3) family communication. Papers published until 2009 about psychosocial and behavioral issues in FAP were identified. Psychometric data indicate that FAP patients and at-risk relatives as a group do not exhibit clinical symptoms of mental health problems after clinical or genetic diagnosis. However, some subgroups revealed to be more vulnerable to distress. Also, concerns related to the disease and its consequences were reported. While interest in prenatal diagnosis or preimplantation genetic diagnosis seems to be high it is important to study actual uptake because this may reveal to be much lower. Family members are an important source of information and the few available data suggest that family communication is problematic. The findings described have several shortcomings. They were obtained from only a few studies often conducted using specific or mixed study groups, originating from the 90ties and mostly cross-sectional in nature. For clinical practice, it is important to have more research data on how FAP patients at different ages cope with the disease, on the impact of genetic testing on reproductive decision-making and on family communication. Results reported here need to be confirmed by additional research and new themes need to be explored.

Role of Alpha-Smooth Muscle Actin and Fibroblast Activation Protein Alpha in Ovarian Neoplasms.

PubMed

da Silva, Ana Carolinne; Jammal, Millena Prata; Etchebehere, Renata Margarida; Murta, Eddie Fernando Candido; Nomelini, Rosekeila Simões

2018-04-05

Studies show that tumor growth is not just determined by the presence of malignant cells, since interactions between cancer cells and stromal microenvironment have important impacts on the cancer growth and progression. Cancer-associated fibroblasts play a prominent role in this process. The aims of the study were to investigate 2 cancer-associated fibroblasts markers, alpha-smooth muscle actin (α-SMA), and fibroblast activation protein alpha (FAP) in the stromal microenvironment of benign and malignant ovarian epithelial neoplasms, and to relate their tissue expression with prognostic factors in ovarian cancer. α-SMA and FAP were evaluated by immunohistochemistry in malignant (n = 28) and benign (n = 28) ovarian neoplasms. Fisher's exact test was used with a significance level lower than 0.05. FAP immunostaining was stronger in ovarian cancer when compared to benign neoplasms (p = 0.0366). There was no significant difference in relation to α-SMA expression between malignant and benign ovarian neoplasms as well as prognostic factors. In ovarian cancer, FAP stainings 2/3 was significantly related to histological grades 2 and 3 (p = 0.0183). FAP immunostaining is more intense in malignant neoplasms than in benign ovarian neoplasms, as well as in moderately differentiated and undifferentiated ovarian carcinomas compared to well-differentiated neoplasms, thus indicating that it can be used as a marker of worse prognosis. © 2018 S. Karger AG, Basel.

In vitro modelling of familial amyloidotic polyneuropathy allows quantitative detection of transthyretin amyloid fibril-like structures in hepatic derivatives of patient-specific induced pluripotent stem cells.

PubMed

Hoepfner, Jeannine; Kleinsorge, Mandy; Papp, Oliver; Alfken, Susanne; Heiringhoff, Robin; Pich, Andreas; Sauer, Vanessa; Zibert, Andree; Göhring, Gudrun; Schmidt, Hartmut; Sgodda, Malte; Cantz, Tobias

2017-07-26

The transthyretin protein is thermodynamically destabilised by mutations in the transthyretin gene, promoting the formation of amyloid fibrils in various tissues. Consequently, impaired autonomic organ function is observed in patients suffering from transthyretin-related familial amyloidotic polyneuropathy (FAP). The influence of individual genetic backgrounds on fibril formation as a potential cause of genotype-phenotype variations needs to be investigated in order to ensure efficient patient-specific therapies. We reprogrammed FAP patient fibroblasts to induced pluripotent stem (iPS) cells and differentiated these cells into transthyretin-expressing hepatocyte-like cells (HLCs). HLCs differentiated from FAP iPS cells and healthy control iPS cells secreted the transthyretin protein in similar concentrations. Mass spectrometry revealed the presence of mutant transthyretin protein in FAP HLC supernatants. In comparison to healthy control iPS cells, we demonstrated the formation of transthyretin amyloid fibril-like structures in FAP HLC supernatants using the amyloid-specific dyes Congo red and thioflavin T. These dyes were also applicable for the quantitative determination of in vitro formed transthyretin fibril-like structures. Moreover, we confirmed the inhibition of fibril formation by the TTR kinetic stabiliser diclofenac. Thioflavin T fluorescence intensity measurements even allowed the quantification of amyloid fibril-like structures in 96-well plate formats as a prerequisite for patient-specific drug screening approaches.

MDCT distinguishing features of focal aortic projections (FAP) in acute clinical settings.

PubMed

Valente, Tullio; Rossi, Giovanni; Lassandro, Francesco; Rea, Gaetano; Marino, Maurizio; Urciuolo, Salvatore; Tortora, Giovanni; Muto, Maurizio

2015-01-01

Focal aortic projections (FAP) are protrusion images of the contrast medium (focal contour irregularity, breaks in the intimal contour, outward lumen bulging or localized blood-filled outpouching) projecting beyond the aortic lumen in the aortic wall and are commonly seen on multidetector computed tomography (MDCT) scans of the chest and abdomen. FAP include several common and uncommon etiologies, which can be demonstrated both in the native aorta, mainly in acute aortic syndromes, and in the post-surgical aorta or after endovascular therapy. They are also found in some types of post-traumatic injuries and in impending rupture of the aneurysms. The expanding, routine use of millimetric or submillimetric collimation of current state-of-the-art MDCT scanners (16 rows and higher) all the time allows the identification and characterization of these small ulcer-like lesions or irregularities in the entire aorta, as either an incidental or expected finding, and provides detailed three-dimensional pictures of these pathologic findings. In this pictorial review, we illustrate the possible significance of FAP and the discriminating MDCT features that help to distinguish among different types of aortic protrusions and their possible evolution. Awareness of some related and distinctive radiologic features in FAP may improve our understanding of aortic diseases, provide further insight into the pathophysiology and natural history, and guide the appropriate management of these lesions.

Potential of activatable FAP-targeting immunoliposomes in intraoperative imaging of spontaneous metastases.

PubMed

Tansi, Felista L; Rüger, Ronny; Böhm, Claudia; Kontermann, Roland E; Teichgraeber, Ulf K; Fahr, Alfred; Hilger, Ingrid

2016-05-01

Despite intensive research and medical advances met, metastatic disease remains the most common cause of death in cancer patients. This results from late diagnosis, poor therapeutic response and undetected micrometastases and tumor margins during surgery. One approach to overcome these challenges involves fluorescence imaging, which exploits the properties of fluorescent probes for diagnostic detection of molecular structures at the onset of transformation and for intraoperative detection of metastases and tumor margins in real time. Considering these benefits, many contrast agents suitable for fluorescence imaging have been reported. However, most reports only demonstrate the detection of primary tumors and not the detection of metastases or their application in models of image-guided surgery. In this work, we demonstrate the influence of fibroblast activation protein (FAP) on the metastatic potential of fibrosarcoma cells and elucidate the efficacy of activatable FAP-targeting immunoliposomes (FAP-IL) for image-guided detection of the spontaneous metastases in mice models. Furthermore, we characterized the biodistribution and cellular localization of the liposomal fluorescent components in mice organs and traced their excretion over time in urine and feces. Taken together, activatable FAP-IL enhances intraoperative imaging of metastases. Their high accumulation in metastases, subsequent localization in the bile canaliculi and liver kupffer cells and suitable excretion in feces substantiates their potency as contrast agents for intraoperative imaging. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Family Advocacy Program (FAP)

DTIC Science & Technology

1992-06-23

PURPOSEiA ’. This Directive administratively reissues reference (a) to update: a. DoD policy on child abuse and neglect (hereafter referred to as...34 child abuse ") and spouse abuse. b. The Department of Defense YAP and Family Advocacy Committee (FAC). c. Responsibility for the establishment and...Notification of the local public child protective agency (in alleged child abuse cases only) in the United States and where covered by agreement overseas

Interpersonal Mindfulness Informed by Functional Analytic Psychotherapy: Findings from a Pilot Randomized Trial

ERIC Educational Resources Information Center

Bowen, Sarah; Haworth, Kevin; Grow, Joel; Tsai, Mavis; Kohlenberg, Robert

2012-01-01

Functional Analytic Psychotherapy (FAP; Kohlenberg & Tsai, 1991) aims to improve interpersonal relationships through skills intended to increase closeness and connection. The current trial assessed a brief mindfulness-based intervention informed by FAP, in which an interpersonal element was added to a traditional intrapersonal mindfulness…

FAPRS Manual: Manual for the Functional Analytic Psychotherapy Rating Scale

ERIC Educational Resources Information Center

Callaghan, Glenn M.; Follette, William C.

2008-01-01

The Functional Analytic Psychotherapy Rating Scale (FAPRS) is behavioral coding system designed to capture those essential client and therapist behaviors that occur during Functional Analytic Psychotherapy (FAP). The FAPRS manual presents the purpose and rules for documenting essential aspects of FAP. The FAPRS codes are exclusive and exhaustive…

Promoting Efficacy Research on Functional Analytic Psychotherapy

ERIC Educational Resources Information Center

Maitland, Daniel W. M.; Gaynor, Scott T.

2012-01-01

Functional Analytic Psychotherapy (FAP) is a form of therapy grounded in behavioral principles that utilizes therapist reactions to shape target behavior. Despite a growing literature base, there is a paucity of research to establish the efficacy of FAP. As a general approach to psychotherapy, and how the therapeutic relationship produces change,…

Women's empowerment and the development research agenda: a personal account from the Bangladesh Flood Action Plan.

PubMed

Hanchett, S

1997-01-01

This article presents a discussion of the bureaucratic and social context for research related to the Bangladesh Flood Action Plan (FAP) in 1991 and 1992. The author's context was confined to meetings and information as a foreign aid program researcher. Insider information was unavailable. The research focused on the rural population, but contact was limited to a government panel of male engineers specializing in water management. These men were forced to participate in a gender study related to flooding. The author argues that her position as a woman created an important venue for opening local channels of communication about gender among a middle class elite and policymakers. Gender is a contested image within Bangladesh society. Various external and internal factors will advance or retard the progress of involving women in local planning and policy. The rigidity of the bureaucracy must be relaxed enough to allow the flow of information from powerless groups such as women to the upper levels of the political hierarchy. Policymakers can be sensitized by the workshops and conversations that occurred in the FAP and which linked powerful people with appropriate local groups. This article describes the flood problems, the first workshop discussion, an informal briefing with local people, the study team, the study findings, the implications for women of the FAP, the final workshop, and the phases of research leading to women's empowerment. Empowerment of women depends on both high-level decisions and grassroots organizing. Feminist social researchers can influence the dialogue by establishing official information gathering priorities.

14 CFR 1203.900 - Establishment.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program Committee § 1203.900 Establishment. Pursuant to Executive Order 12958, “National Security Information,” and the National Aeronautics and Space Act of 1958, as amended, there is established...

14 CFR 1203.900 - Establishment.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program Committee § 1203.900 Establishment. Pursuant to Executive Order 12958, “National Security Information,” and the National Aeronautics and Space Act of 1958, as amended, there is established...

Free volume dependence of an ionic molecular rotor in Fluoroalkylphosphate (FAP) based ionic liquids

NASA Astrophysics Data System (ADS)

Singh, Prabhat K.; Mora, Aruna K.; Nath, Sukhendu

2016-01-01

The emission properties of Thioflavin-T (ThT), a cationic molecular rotor, have been investigated in two fluoroalkylphosphate ([FAP]) anion based ionic liquids, namely, 1-ethyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate and 1-(2-hydroxyethyl)-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate, over a wide temperature range. The micro-viscosities of ionic liquids around ThT, measured from the emission quantum yield, are found to be quite different from their bulk viscosities. The temperature dependence of the viscosity and the emission quantum yield reveals that, despite the very low shear viscosity of these ILs, the non-radiative torsional relaxation has a strong dependence on the free volume of these [FAP] anion based ILs.

14 CFR 1203.201 - Information security objectives.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Information security objectives. 1203.201 Section 1203.201 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program § 1203.201 Information security objectives. The objectives of...

14 CFR 1203.201 - Information security objectives.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Information security objectives. 1203.201 Section 1203.201 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program § 1203.201 Information security objectives. The objectives of...

Translating the Theoretical into Practical: A Logical Framework of Functional Analytic Psychotherapy Interactions for Research, Training, and Clinical Purposes

ERIC Educational Resources Information Center

Weeks, Cristal E.; Kanter, Jonathan W.; Bonow, Jordan T.; Landes, Sara J.; Busch, Andrew M.

2012-01-01

Functional analytic psychotherapy (FAP) provides a behavioral analysis of the psychotherapy relationship that directly applies basic research findings to outpatient psychotherapy settings. Specifically, FAP suggests that a therapist's in vivo (i.e., in-session) contingent responding to targeted client behaviors, particularly positive reinforcement…

Digitization of Nuclear Explosion Seismograms from the Former Soviet Union

DTIC Science & Technology

2015-03-30

others in terms of frequency-amplitude-phase ( fap ) response files. Approved for public release; distribution is unlimited. T ab le 1 . I ns tr um en...responses are given in terms of poles and zeros, or fap (frequency-amplitude-phase) in CSS 3.0 relational database tables, specifically via .sensor and

FAP Group Supervision: Reporting Educational Experiences at the University of Sao Paulo, Brazil

ERIC Educational Resources Information Center

Wielenska, Regina Christina; Oshiro, Claudia Kami Bastos

2012-01-01

The present article describes and analyzes educational experiences related to the teaching of FAP for psychology graduate students and psychiatry residents at the University of Sao Paulo. The first experience involved psychology graduate students and includes an example of the shaping process occurring within the supervisor-supervisee…

Functional bacterial amyloid increases Pseudomonas biofilm hydrophobicity and stiffness

PubMed Central

Zeng, Guanghong; Vad, Brian S.; Dueholm, Morten S.; Christiansen, Gunna; Nilsson, Martin; Tolker-Nielsen, Tim; Nielsen, Per H.; Meyer, Rikke L.; Otzen, Daniel E.

2015-01-01

The success of Pseudomonas species as opportunistic pathogens derives in great part from their ability to form stable biofilms that offer protection against chemical and mechanical attack. The extracellular matrix of biofilms contains numerous biomolecules, and it has recently been discovered that in Pseudomonas one of the components includes β-sheet rich amyloid fibrils (functional amyloid) produced by the fap operon. However, the role of the functional amyloid within the biofilm has not yet been investigated in detail. Here we investigate how the fap-based amyloid produced by Pseudomonas affects biofilm hydrophobicity and mechanical properties. Using atomic force microscopy imaging and force spectroscopy, we show that the amyloid renders individual cells more resistant to drying and alters their interactions with hydrophobic probes. Importantly, amyloid makes Pseudomonas more hydrophobic and increases biofilm stiffness 20-fold. Deletion of any one of the individual members of in the fap operon (except the putative chaperone FapA) abolishes this ability to increase biofilm stiffness and correlates with the loss of amyloid. We conclude that amyloid makes major contributions to biofilm mechanical robustness. PMID:26500638

Functional bacterial amyloid increases Pseudomonas biofilm hydrophobicity and stiffness.

PubMed

Zeng, Guanghong; Vad, Brian S; Dueholm, Morten S; Christiansen, Gunna; Nilsson, Martin; Tolker-Nielsen, Tim; Nielsen, Per H; Meyer, Rikke L; Otzen, Daniel E

2015-01-01

The success of Pseudomonas species as opportunistic pathogens derives in great part from their ability to form stable biofilms that offer protection against chemical and mechanical attack. The extracellular matrix of biofilms contains numerous biomolecules, and it has recently been discovered that in Pseudomonas one of the components includes β-sheet rich amyloid fibrils (functional amyloid) produced by the fap operon. However, the role of the functional amyloid within the biofilm has not yet been investigated in detail. Here we investigate how the fap-based amyloid produced by Pseudomonas affects biofilm hydrophobicity and mechanical properties. Using atomic force microscopy imaging and force spectroscopy, we show that the amyloid renders individual cells more resistant to drying and alters their interactions with hydrophobic probes. Importantly, amyloid makes Pseudomonas more hydrophobic and increases biofilm stiffness 20-fold. Deletion of any one of the individual members of in the fap operon (except the putative chaperone FapA) abolishes this ability to increase biofilm stiffness and correlates with the loss of amyloid. We conclude that amyloid makes major contributions to biofilm mechanical robustness.

mir-200c Regulates Induction of Apoptosis through CD95 by Targeting FAP-1

PubMed Central

Schickel, Robert; Park, Sun-Mi; Murmann, Andrea E.; Peter, Marcus E.

2010-01-01

SUMMARY Tumor progression shares many characteristics with the process of epithelial-to-mesenchymal transition (EMT). Cells that have undergone an EMT are known to have an increased resistance to apoptosis. CD95/Fas is an apoptosis-inducing receptor expressed on many tissues and tumor cells. During tumor progression CD95 is frequently downregulated, and tumor cells lose apoptosis sensitivity. miR-200 microRNAs repress both the EMT-inducing ZEB1 and ZEB2 transcription factors. We now demonstrate that miR-200c sensitizes cells to apoptosis mediated by CD95. We have identified the apoptosis inhibitor FAP-1 as a target for miR-200c. FAP-1 was demonstrated to be responsible for the reduced sensitivity to CD95-mediated apoptosis in cells with inhibited miR-200. The identification of FAP-1 as a miR-200c target provides a molecular mechanism to explain both the downregulation of CD95 expression and the reduction in sensitivity of cells to CD95-mediated apoptosis that is observed in the context of reduced miR-200 expression during tumor progression. PMID:20620960

Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors

PubMed Central

Zhang, Ying; Ertl, Hildegund C.J.

2016-01-01

The tumor stroma, which is essential to support growth and metastasis of malignant cells, provides targets for active immunotherapy of cancer. Previous studies have shown that depleting fibroblast activation protein (FAP)-expressing stromal cells reduces tumor progression and concomitantly increases tumor antigen (TA)-specific T cell responses. However the underlying pathways remain ill defined. Here we identify that immunosuppressive cells (ISCs) from tumor-bearing mice impose metabolic stress on CD8+T cells, which is associated with increased expression of the co-inhibitor PD-1. In two mouse melanoma models, depleting FAP+ stroma cells from the tumor microenvironment (TME) upon vaccination with an adenoviral-vector reduces frequencies and functions of ISCs. This is associated with changes in the cytokine/chemokine milieu in the TME and decreased activity of STAT6 signaling within ISCs. Decreases in ISCs upon FAP+stromal cell depletion is associated with reduced metabolic stress of vaccine-induced tumor infiltrating CD8+T cells and their delayed progression towards functional exhaustion, resulting in prolonged survival of tumor-bearing mice. PMID:26943036

Near-infrared counterparts to the Galactic Bulge Survey X-ray source population

NASA Astrophysics Data System (ADS)

Greiss, S.; Steeghs, D.; Jonker, P. G.; Torres, M. A. P.; Maccarone, T. J.; Hynes, R. I.; Britt, C. T.; Nelemans, G.; Gänsicke, B. T.

2014-03-01

We report on the near-infrared matches, drawn from three surveys, to the 1640 unique X-ray sources detected by Chandra in the Galactic Bulge Survey (GBS). This survey targets faint X-ray sources in the bulge, with a particular focus on accreting compact objects. We present all viable counterpart candidates and associate a false alarm probability (FAP) to each near-infrared match in order to identify the most likely counterparts. The FAP takes into account a statistical study involving a chance alignment test, as well as considering the positional accuracy of the individual X-ray sources. We find that although the star density in the bulge is very high, ˜90 per cent of our sources have an FAP <10 per cent, indicating that for most X-ray sources, viable near-infrared counterparts candidates can be identified. In addition to the FAP, we provide positional and photometric information for candidate counterparts to ˜95 per cent of the GBS X-ray sources. This information in combination with optical photometry, spectroscopy and variability constraints will be crucial to characterize and classify secure counterparts.

Vibrational sum-frequency generation spectroscopy of ionic liquid 1-butyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate at the air-water interface

NASA Astrophysics Data System (ADS)

Saha, Ankur; SenGupta, Sumana; Kumar, Awadhesh; Choudhury, Sipra; Naik, Prakash D.

2016-08-01

The structure and orientation of room temperature ionic liquid (RTIL) 1-butyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate [PF3(C2F5)3], commonly known as [bmim][fap], have been investigated at the air-[bmim][fap] and air-water interfaces, employing vibrational sum-frequency generation (VSFG) spectroscopy. The VSFG spectra in the CH stretch region suggest presence of the [bmim] cation at the interfaces. Studies reveal that the butyl chain protrudes out into air, and the imidazolium ring lies almost planar to the interface. The CH stretch intensities get enhanced at the air-water interface, mainly because of polar orientation of imidazolium cation induced by interfacial water molecules. The OH stretch intensities are also enhanced at the air-water interface due to polar orientation of interfacial water molecules induced by [bmim][fap]. The Brewster angle microscopy suggests self aggregation of [bmim][fap] in the presence of water, and the aggregation becomes extensive showing dense surface domains with time. However, the surface pressure is almost unaffected due to aggregation.

Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors.

PubMed

Zhang, Ying; Ertl, Hildegund C J

2016-04-26

The tumor stroma, which is essential to support growth and metastasis of malignant cells, provides targets for active immunotherapy of cancer. Previous studies have shown that depleting fibroblast activation protein (FAP)-expressing stromal cells reduces tumor progression and concomitantly increases tumor antigen (TA)-specific T cell responses. However the underlying pathways remain ill defined. Here we identify that immunosuppressive cells (ISCs) from tumor-bearing mice impose metabolic stress on CD8+T cells, which is associated with increased expression of the co-inhibitor PD-1. In two mouse melanoma models, depleting FAP+ stroma cells from the tumor microenvironment (TME) upon vaccination with an adenoviral-vector reduces frequencies and functions of ISCs. This is associated with changes in the cytokine/chemokine milieu in the TME and decreased activity of STAT6 signaling within ISCs. Decreases in ISCs upon FAP+stromal cell depletion is associated with reduced metabolic stress of vaccine-induced tumor infiltrating CD8+T cells and their delayed progression towards functional exhaustion, resulting in prolonged survival of tumor-bearing mice.

Air Breathing Propulsion Controls and Diagnostics Research at NASA Glenn Under NASA Aeronautics Research Mission Programs

NASA Technical Reports Server (NTRS)

Garg, Sanjay

2015-01-01

The Intelligent Control and Autonomy Branch (ICA) at NASA (National Aeronautics and Space Administration) Glenn Research Center (GRC) in Cleveland, Ohio, is leading and participating in various projects in partnership with other organizations within GRC and across NASA, the U.S. aerospace industry, and academia to develop advanced controls and health management technologies that will help meet the goals of the NASA Aeronautics Research Mission Directorate (ARMD) Programs. These efforts are primarily under the various projects under the Advanced Air Vehicles Program (AAVP), Airspace Operations and Safety Program (AOSP) and Transformative Aeronautics Concepts Program (TAC). The ICA Branch is focused on advancing the state-of-the-art of aero-engine control and diagnostics technologies to help improve aviation safety, increase efficiency, and enable operation with reduced emissions. This paper describes the various ICA research efforts under the NASA Aeronautics Research Mission Programs with a summary of motivation, background, technical approach, and recent accomplishments for each of the research tasks.

Measurements for assessing the exposure from 3G femtocells.

PubMed

Boursianis, Achilles; Vanias, Pantelis; Samaras, Theodoros

2012-06-01

Femtocells are low-power access points, which combine mobile and broadband technologies. The main operation of a femtocell is to function as a miniature base station unit in an indoor environment and to connect to the operator's network through a broadband phone line or a coaxial cable line. This study provides the first experimental measurements and results in Greece for the assessment of exposure to a femtocell access point (FAP) indoors. Using a mobile handset with the appropriate software, power level measurements of the transmitted (Tx) and the received by the mobile handset signal were performed in two different and typical (home and office) environments. Moreover, radiofrequency electric field strength and frequency selective measurements with a radiation meter (SRM-3000) were carried out in the proximity of the FAP installation point. The cumulative distribution functions of the Tx power at most cases (except one) show that in 90% of all points the power of the mobile phone was lower by at least 7 dB during FAP operation. At a distance of ∼1 m from the FAP (in its main beam), power flux density measurements show that there is very little difference between the two situations (FAP ON and OFF). As a conclusion, the use of femtocells indoors improves reception quality, reduces the Tx power of the user's mobile terminal and results in an indiscernible increase of the electromagnetic field in front of the unit, at values that are extremely low compared with reference levels of exposure guidelines.

Review article: the functional abdominal pain syndrome.

PubMed

Sperber, A D; Drossman, D A

2011-03-01

Functional abdominal pain syndrome (FAPS) is a debilitating disorder with constant or nearly constant abdominal pain, present for at least 6 months and loss of daily functioning. To review the epidemiology, pathophysiology and treatment of FAPS. A literature review using the keywords: functional abdominal pain, chronic abdominal pain, irritable bowel syndrome and functional gastrointestinal disorders. No epidemiological studies have focused specifically on FAPS. Estimates of prevalence range from 0.5% to 1.7% and tend to show a female predominance. FAPS pathophysiology appears unique in that the pain is caused primarily by amplified central perception of normal visceral input, rather than by enhanced peripheral stimulation from abdominal viscera. The diagnosis of FAPS is symptom-based in accordance with the Rome III diagnostic criteria. These criteria are geared to identify patients with severe symptoms as they require constant or nearly constant abdominal pain with loss of daily function and are differentiated from IBS based on their non-association with changes in bowel habit, eating or other gut-related events. As cure is not feasible, the aims of treatment are reduced suffering and improved quality of life. Treatment is based on a biopsychosocial approach with a therapeutic patient-physician partnership at its base. Therapeutic options include central nonpharmacological and pharmacological modalities and peripheral modalities. These can be combined to produce an augmentation effect. Although few studies have assessed functional abdominal pain syndrome or its treatment specifically, the treatment strategies outlined in this paper appear to be effective. © 2011 Blackwell Publishing Ltd.

Diode-pumped Yb:Sr{sub 5}(PO{sub 4}){sub 3}F laser performance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marshall, C.D.; Payne, S.A.; Smith, L.K.

The performance of the first diode-pumped Yb{sup 3+}-doped Sr{sub 5}(PO{sub 4}){sub 3}F (Yb:S-FAP) laser is discussed. We found the pumping dynamics and extraction cross-sections of Yb:S-FAP crystals to be similar to those previously inferred by purely spectroscopic techniques. The saturation fluence for pumping was measured to be 2.2 J/cm{sup 2} using three different methods based on either the spatial, temporal, or energy transmission properties of a Yb:S-FAP rod. The small signal gain implies an emission cross section of 6.0 x 10{sup -20} cm{sup 2} that falls within error bars of the previously reported value of 7.3 x 10{sup -20} cm{supmore » 2}, obtained from spectroscopic techniques. Up to 1.7 J/cm{sup 3} of stored energy density was achieved in a 6 x 6 x 44 mm Yb:S-FAP amplifier rod. An InGaAs diode array has been fabricated that has suitable specifications for pumping a 3 x 3 x 30 mm Yb:S-FAP rod. In a free running configuration diode-pumped slope efficiencies up to 43% were observed with output energies up to {approximately}0.5 J per 1 ms pulse. When the rod was mounted in a copper block for cooling, 13 W of average power was produced with power supply limited operation at 70 Hz and 500 {mu}s pulses.« less

Retention Elasticity and Projection Model for U.S. Navy Medical Corps Officers

DTIC Science & Technology

2013-03-01

Department of Defense DODFMR Department of Defense Financial Management Regulation FAP Financial Assistance Program FY Fiscal Year GMO General...deployers who were affected by the increased OPTEMPO. Bristol (2006) finds that increased OPTEMPO has a negative effect on GMO retention. A GMO who was... GMO ) and attrite before completion of obligation service. Furthermore, we do not have information on those who stayed in the Navy in FY2000 and who

14 CFR 1203.904 - Meetings.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Meetings. 1203.904 Section 1203.904 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program Committee § 1203.904 Meetings. (a) Meetings will be held at the call of the...

14 CFR 1203.904 - Meetings.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Meetings. 1203.904 Section 1203.904 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program Committee § 1203.904 Meetings. (a) Meetings will be held at the call of the...

14 CFR 1203.903 - Ad hoc committees.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Ad hoc committees. 1203.903 Section 1203.903 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program Committee § 1203.903 Ad hoc committees. The Chairperson is authorized...

14 CFR 1203.903 - Ad hoc committees.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Ad hoc committees. 1203.903 Section 1203.903 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program Committee § 1203.903 Ad hoc committees. The Chairperson is authorized to...

14 CFR 1260.124 - Program income.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Program income. 1260.124 Section 1260.124 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION GRANTS AND COOPERATIVE AGREEMENTS Uniform... and Trademark Amendments (35 U.S.C. 18) apply to inventions made under an experimental, developmental...

[NASA] in the 21st Century

NASA Technical Reports Server (NTRS)

Horn, Thomas J.

2006-01-01

This viewgraph presentation reviews the NASA programs in support of Aeronautical and Space research. This research involves imagining the future of air travel. There are three major Aeronautics technology programs: (1) Fundamental Aeronautics, (2) Aviation Safety and (3) Airspace Systems. The aim of exploring the depths of the universe through earth based and space based assets. Other Space programs include the plans for exploration of the moon and Mars.

Aeronautics in NACA and NASA

NASA Technical Reports Server (NTRS)

1991-01-01

Initiated in 1915, the National Advisory Committee for Aeronautics/National Aeronautics and Space Administration (NACA/NASA) aeronautical programs have been the keystone of a sustained U.S. Government, industry, and university research effort which has been a primary factor in the development of our remarkable air transportation systems, the country's largest positive trade balance component, and the world's finest military Air Force. This overview summarizes the flow of events, and the major trends, that have led from the NACA origins to the present NASA Aeronautics program, and indicates some important directions for the years ahead.

Young Children with Functional Abdominal Pain (FAP) and Irritable Bowel Syndrome (IBS) Followed in Tertiary vs. Primary Care: Differences in Outcomes

USDA-ARS?s Scientific Manuscript database

Despite the fact that the American Academy of Pediatrics suggests that general pediatricians (PED) manage children with FAP/IBS without alarm signs many children are cared for by pediatric gastroenterologists (GI). In a longitudinal examination of physical symptoms, healthcare use, quality of life (...

Molecular mapping of the mutant fap4(A24) allele for elevated palmitate concentration in soybean

USDA-ARS?s Scientific Manuscript database

Soybean [Glycine max L. Merr.] oil with an elevated palmitate concentration is useful for some food and industrial applications. The objective of this study was to map the genetic location of the fap4(A24) allele that controls an increase in palmitate concentration and to identify molecular marker...

Gastrointestinal (GI) permeability is associated with trait anxiety in children with functional abdominal pain (FAP) and Irritable Bowel Syndrome (IBS)

USDA-ARS?s Scientific Manuscript database

FAP and IBS affect 10-15% of school age children and bear many physiological similarities to irritable bowel syndrome (IBS) in adults (e.g., functional pain, visceral hyperalgesia). Animal models of IBS have suggested a relationship between neonatal stress and increased GI permeability later in life...

An Ap-Structure with Finslerian Flavor I:. the Principal Idea

NASA Astrophysics Data System (ADS)

Wanas, M. I.

A geometric structure (FAP-structure), having both absolute parallelism and Finsler properties, is constructed. The building blocks of this structure are assumed to be functions of position and direction. A nonlinear connection emerges naturally and is defined in terms of the building blocks of the structure. Two linear connections, one of Berwald type and the other of the Cartan type, are defined using the nonlinear connection of the FAP. Both linear connections are nonsymmetric and consequently admit torsion. A metric tensor is defined in terms of the building blocks of the structure. The condition for this metric to be a Finslerian one is obtained. Also, the condition for an FAP-space to be an AP-one is given.

The Mercury Laser System: An Average power, gas-cooled, Yb:S-FAP based system with frequency conversion and wavefront correction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bibeau, C; Bayramian, A; Armstrong, P

We report on the operation of the Mercury laser with fourteen 4 x 6 cm{sup 2} Yb:S-FAP amplifier slabs pumped by eight 100 kW peak power diode arrays. The system was continuously run at 55 J and 10 Hz for several hours, (2 x 10{sup 5} cumulative shots) with over 80% of the energy in a 6 times diffraction limited spot at 1.047 um. Improved optical quality was achieved in Yb:S-FAP amplifiers with magneto-rheological finishing, a deterministic polishing method. In addition, average power frequency conversion employing YCOB was demonstrated at 50% conversion efficiency or 22.6 J at 10 Hz.

Rapid detection of translation-terminating mutations at the adenomatous polyposis coli (APC) gene by direct protein truncation test

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van Der Luut, R.; Khan, P.M.; Van Leeuwen, C.

Familial adenomatous polyposis (FAP) is usually associated with protein truncating mutations in the adenomatous polyposis coli (APC) gene. The APC mutations are known to play a major role in colorectal carcinogensis. For the identification of protein truncating mutations of the APC gene, the authors developed a rapid, sensitive, and direct screening procedure. The technique is based on the in vitro transcription and translation of the genomic PCR products and is called the protein truncation test. Samples of DNA from individual FAP patients, members of a FAP family, colorectal tumors, and colorectal tumor-derived cell lines were used to show the effectivenessmore » of this method. 9 refs., 2 figs.« less

FAP finds FGF21 easy to digest.

PubMed

Gillum, Matthew P; Potthoff, Matthew J

2016-05-01

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates carbohydrate and lipid metabolism. In humans, circulating FGF21 is inactivated by proteolytic cleavage of its C-terminus, thereby preventing signalling through a receptor complex. The mechanism for this cleavage event and the factors contributing to the post-translational regulation of FGF21 activity has previously been unknown. In a recent issue of the Biochemical Journal, Zhen et al. have identified fibroblast activation protein (FAP) as the endopeptidase responsible for this site-specific cleavage of human FGF21 (hFGF21), and propose that inhibition of FAP may be a therapeutic strategy to increase endogenous levels of active FGF21. © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

A photophysical study of two fluorogen-activating proteins bound to their cognate fluorogens

NASA Astrophysics Data System (ADS)

Gaiotto, Tiziano; Nguyen, Hau B.; Jung, Jaemyeong; Gnanakaran, Gnana S.; Schmidt, Jurgen G.; Waldo, Geoffrey S.; Bradbury, Andrew M.; Goodwin, Peter M.

2011-03-01

We are exploring the use of fluorogen-activating proteins (FAPs) as reporters for single-molecule imaging. FAPs are single-chain antibodies selected to specifically bind small chromophoric molecules termed fluorogens. Upon binding to its cognate FAP the fluorescence quantum yield of the fluorogen increases giving rise to a fluorescent complex. Based on the seminal work of Szent-Gyorgyi et al. (Nature Biotechnology, Volume 26, Number 2, pp 235-240, 2008) we have chosen to study two fluorogen-activating single-chain antibodies, HL1.0.1-TO1 and H6-MG, bound to their cognate fluorogens, thiazole orange and malachite green derivatives, respectively. Here we use fluorescence correlation spectroscopy to study the photophysics of these fluorescent complexes.

Near Infrared Luminescence Properties of Mn(5+): Ca5(PO4)3F

NASA Technical Reports Server (NTRS)

Davis, Valetta R.; Hoemmerich, Uwe; Loutts, George B.

1997-01-01

We report a spectroscopic investigation of Mn(5+) doped Ca5(PO4)(sub 3)F or FAP. Mn(5+) doped crystals have recently attracted world wide attention for potential solid-state laser applications. Following optical excitation of Mn: FAP with the 600 nm output of a Nd: YAG OPO laser system, we observed a strong near infrared luminescence centered at around 1150 nm. The room temperature luminescence decay time was measured to be approximately 635 microseconds. We attribute the infrared luminescence to the(1)E yields (3)A2 transition of tetrahedrally coordinated Mn5+ ions located in a strong crystal field environment. Absorption, luminescence and lifetime data of Mn: FAP will be presented and discussed.

14 CFR 1221.105 - Establishment of NASA Program Identifiers.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Establishment of NASA Program Identifiers. 1221.105 Section 1221.105 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION THE NASA SEAL AND OTHER DEVICES, AND THE CONGRESSIONAL SPACE MEDAL OF HONOR NASA Seal, NASA Insignia, NASA...

14 CFR 1221.105 - Establishment of NASA Program Identifiers.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Establishment of NASA Program Identifiers. 1221.105 Section 1221.105 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION THE NASA SEAL AND OTHER DEVICES, AND THE CONGRESSIONAL SPACE MEDAL OF HONOR NASA Seal, NASA Insignia, NASA...

14 CFR 1221.105 - Establishment of NASA Program Identifiers.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Establishment of NASA Program Identifiers. 1221.105 Section 1221.105 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION THE NASA SEAL AND OTHER DEVICES, AND THE CONGRESSIONAL SPACE MEDAL OF HONOR NASA Seal, NASA Insignia, NASA...

14 CFR 1221.105 - Establishment of NASA Program Identifiers.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Establishment of NASA Program Identifiers. 1221.105 Section 1221.105 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION THE NASA SEAL AND OTHER DEVICES, AND THE CONGRESSIONAL SPACE MEDAL OF HONOR NASA Seal, NASA Insignia, NASA...

Aeronautics Research and Technology Program and specific objectives, fiscal year 1982

NASA Technical Reports Server (NTRS)

Olstad, W. B.

1981-01-01

The Aeronautics Research and Technology program is broken down into two program areas (research and technology base, and systems technology programs) which are further broken down into succeedingly more detailed activities to form a work breakdown structure for the aeronautics program: program area, program/discipline objective, specific objective, and research and technology objective and plan (RTOP). A detailed view of this work breakdown structure down to the specific objective level is provided, and goals or objectives at each of these levels are set forth. What is to be accomplished and why are addressed, but not how. The letter falls within the domain of the RTOP.

Wartime Tracking of Class I Surface Shipments from Production or Procurement to Destination

DTIC Science & Technology

1992-04-01

Armed Forces I ICAF-FAP National Defense University 6c. ADDRESS (City, State, ard ZIP Code ) 7b. ADDRESS (City, State, and ZIP Code ) Fort Lesley J...INSTRUMENT IDENTIFICATION NUMBER ORGANIZATION (If applicable) 9c. ADDRESS (City, State, and ZIP Code ) 10. SOURCE OF FUNDING NUMBERS PROGRAM PROJECT TASK...COSATI CODES 18. SUBJECT TERMS (Continue on reverse if necessary and identify by block number) FIELD GROUP SUB-GROUP 19. ABSTRACT (Continue on reverse

Child pain catastrophizing mediates the relation between parent responses to pain and disability in youth with functional abdominal pain.

PubMed

Cunningham, Natoshia R; Lynch-Jordan, Anne; Barnett, Kimberly; Peugh, James; Sil, Soumitri; Goldschneider, Kenneth; Kashikar-Zuck, Susmita

2014-12-01

Functional abdominal pain (FAP) in youth is associated with substantial impairment in functioning, and prior research has shown that overprotective parent responses can heighten impairment. Little is known about how a range of parental behaviors (overprotection, minimizing, and/or encouragement) in response to their child's pain interact with child coping characteristics (eg, catastrophizing) to influence functioning in youth with FAP. In this study, it was hypothesized that the relation between parenting factors and child disability would be mediated by children's levels of maladaptive coping (ie, pain catastrophizing). Seventy-five patients with FAP presenting to a pediatric pain clinic and their caregivers participated in the study. Youth completed measures of pain intensity (Numeric Rating Scale), pain catastrophizing (Pain Catastrophizing Scale), and disability (Functional Disability Inventory). Caregivers completed measures of parent pain catastrophizing (Pain Catastrophizing Scale), and parent responses to child pain behaviors (Adult Responses to Child Symptoms: Protection, Minimizing, and Encouragement/Monitoring subscales). Increased functional disability was significantly related to higher child pain intensity, increased child and parent pain catastrophizing, and higher levels of encouragement/monitoring and protection. Parent minimization was not related to disability. Child pain catastrophizing fully mediated the relation between parent encouragement/monitoring and disability and partially mediated the relation between parent protectiveness and disability. The impact of parenting behaviors in response to FAP on child disability is determined, in part, by the child's coping style. Findings highlight a more nuanced understanding of the parent-child interaction in determining pain-related disability levels, which should be taken into consideration in assessing and treating youth with FAP.

Stromal cell markers are differentially expressed in the synovial tissue of patients with early arthritis.

PubMed

Choi, Ivy Y; Karpus, Olga N; Turner, Jason D; Hardie, Debbie; Marshall, Jennifer L; de Hair, Maria J H; Maijer, Karen I; Tak, Paul P; Raza, Karim; Hamann, Jörg; Buckley, Christopher D; Gerlag, Danielle M; Filer, Andrew

2017-01-01

Previous studies have shown increased expression of stromal markers in synovial tissue (ST) of patients with established rheumatoid arthritis (RA). Here, ST expression of stromal markers in early arthritis in relationship to diagnosis and prognostic outcome was studied. ST from 56 patients included in two different early arthritis cohorts and 7 non-inflammatory controls was analysed using immunofluorescence to detect stromal markers CD55, CD248, fibroblast activation protein (FAP) and podoplanin. Diagnostic classification (gout, psoriatic arthritis, unclassified arthritis (UA), parvovirus associated arthritis, reactive arthritis and RA), disease outcome (resolving vs persistent) and clinical variables were determined at baseline and after follow-up, and related to the expression of stromal markers. We observed expression of all stromal markers in ST of early arthritis patients, independent of diagnosis or prognostic outcome. Synovial expression of FAP was significantly higher in patients developing early RA compared to other diagnostic groups and non-inflammatory controls. In RA FAP protein was expressed in both lining and sublining layers. Podoplanin expression was higher in all early inflammatory arthritis patients than controls, but did not differentiate diagnostic outcomes. Stromal marker expression was not associated with prognostic outcomes of disease persistence or resolution. There was no association with clinical or sonographic variables. Stromal cell markers CD55, CD248, FAP and podoplanin are expressed in ST in the earliest stage of arthritis. Baseline expression of FAP is higher in early synovitis patients who fulfil classification criteria for RA over time. These results suggest that significant fibroblast activation occurs in RA in the early window of disease.

Characterization of bifunctional L-glutathione synthetases from Actinobacillus pleuropneumoniae and Actinobacillus succinogenes for efficient glutathione biosynthesis.

PubMed

Yang, Jianhua; Li, Wei; Wang, Dezheng; Wu, Hui; Li, Zhimin; Ye, Qin

2016-07-01

Glutathione (GSH), an important bioactive substance, is widely applied in pharmaceutical and food industries. In this work, two bifunctional L-glutathione synthetases (GshF) from Actinobacillus pleuropneumoniae (GshFAp) and Actinobacillus succinogenes (GshFAs) were successfully expressed in Escherichia coli BL-21(DE3). Similar to the GshF from Streptococcus thermophilus (GshFSt), GshFAp and GshFAs can be applied for high titer GSH production because they are less sensitive to end-product inhibition (Ki values 33 and 43 mM, respectively). The active catalytic forms of GshFAs and GshFAp are dimers, consistent with those of GshFPm (GshF from Pasteurella multocida) and GshFSa (GshF from Streptococcus agalactiae), but are different from GshFSt (GshF from S. thermophilus) which is an active monomer. The analysis of the protein sequences and three dimensional structures of GshFs suggested that the binding sites of GshFs for substrates, L-cysteine, L-glutamate, γ-glutamylcysteine, adenosine-triphosphate, and glycine are highly conserved with only very few differences. With sufficient supply of the precursors, the recombinant strains BL-21(DE3)/pET28a-gshFas and BL-21(DE3)/pET28a-gshFap were able to produce 36.6 and 34.1 mM GSH, with the molar yield of 0.92 and 0.85 mol/mol, respectively, based on the added L-cysteine. The results showed that GshFAp and GshFAs are potentially good candidates for industrial GSH production.

Concordant parent-child reports of anxiety predict impairment in youth with functional abdominal pain

PubMed Central

Cunningham, Natoshia Raishevich; Cohen, Mitchell B.; Farrell, Michael K.; Mezoff, Adam G.; Lynch-Jordan, Anne; Kashikar-Zuck, Susmita

2014-01-01

Introduction Functional abdominal pain (FAP) is associated with significant anxiety and impairment. Prior investigations of child anxiety in youth with FAP are generally limited by small sample sizes, based on child report, and use lengthy diagnostic tools. It is unknown 1) if a brief anxiety screening tool is feasible, 2) whether parent and child reports of anxiety are congruent, and 3) whether parent and child agreement of child anxiety corresponds to increased impairment. The purpose of this investigation was to examine anxiety characteristics in youth with FAP using parent and child reports. Parent-child agreement of child anxiety symptoms was examined in relation to pain and disability. Materials and Methods One-hundred patients with FAP (8-18 years of age) recruited from pediatric gastroenterology clinics completed measures of pain intensity (Numeric Rating Scale), and disability (Functional Disability Inventory). Patients and caregivers both completed a measure of child anxiety characteristics (Screen for Child Anxiety and Related Disorders). Results Clinically significant anxiety symptoms were more commonly reported by youth (54%) than their parents (30%). Panic/somatic symptoms, generalized anxiety, and separation anxiety were most commonly endorsed by patients whereas generalized anxiety, separation anxiety, and school avoidance were most commonly reported by parents. The majority (65%) of parents and children agreed on presence (26%) or absence (39%) of clinically significant anxiety. Parent-child agreement of clinically significant anxiety was related to increased impairment. Discussion A brief screening instrument of parent and child reports of anxiety can provide clinically relevant information for comprehensive treatment planning in children with FAP. PMID:25714575

Assessing barriers to a rational chemoprevention trial design in young patients with familial adenomatous polyposis.

PubMed

Wood, Joanna P; Howells, Lynne M; Brown, Karen; Thomas, Anne L

2017-07-01

Familial adenomatous polyposis coli (FAP) is an autosomal dominant condition caused by a germline mutation in the adenomatous polyposis coli gene. Colonic adenomas form and almost all patients will develop colorectal cancer if they are not managed at an early stage. The safest preventive strategy is surgical resection of the colon, most commonly performed in late teenage years. There is a paucity of trials investigating the use of primary chemoprevention to delay polyp formation in paediatric FAP. There are extensive preclinical and early clinical data demonstrating that curcumin may be a safe and effective chemotherapeutic agent in reducing the polyp burden in this disease. We ultimately proposed to design and conduct a clinical study to assess whether curcumin treatment delays the need for surgery and/or prevents cancer in young patients with FAP. Research into clinical trial protocols has demonstrated that assessing patients' perceptions at the initial stage leads to better outcomes. We therefore conducted a questionnaire study of patients and parents of children affected by FAP to gain information to aid the protocol design. Results demonstrated that there are some FAP patients for whom this study is relevant and desirable. Those with a personal history of curcumin use reported that it was well tolerated. However, the response rate was poor (25%), indicating that there are potential difficulties ensuring adequate recruitment to the proposed trial. This report draws on lessons learnt from prior trials and the findings from the questionnaire to outline the challenges faced in designing such a study.

Influence of alkyl chain length and anion species on ionic liquid structure at the graphite interface as a function of applied potential

NASA Astrophysics Data System (ADS)

Li, Hua; Wood, Ross J.; Endres, Frank; Atkin, Rob

2014-07-01

Atomic force microscopy (AFM) force measurements elucidate the effect of cation alkyl chain length and the anion species on ionic liquid (IL) interfacial structure at highly ordered pyrolytic graphite (HOPG) surfaces as a function of potential. Three ILs are examined: 1-hexyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate ([HMIM] FAP), 1-ethyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate ([EMIM] FAP), and 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM] TFSA). The step-wise force-distance profiles indicate the ILs adopt a multilayered morphology near the surface. When the surface is biased positively or negatively versus Pt quasireference electrode, both the number of steps, and the force required to rupture each step increase, indicating stronger interfacial structure. At all potentials, push-through forces for [HMIM] FAP are the highest, because the long alkyl chain results in strong cohesive interactions between cations, leading to well-formed layers that resist the AFM tip. The most layers are observed for [EMIM] FAP, because the C2 chains are relatively rigid and the dimensions of the cation and anion are similar, facilitating neat packing. [EMIM] TFSA has the smallest push-through forces and fewest layers, and thus the weakest interfacial structure. Surface-tip attractive forces are measured for all ILs. At the same potential, the attractions are the strongest for [EMIM] TFSA and the weakest for [HMIM] FAP because the interfacial layers are better formed for the longer alkyl chain cation. This means interfacial forces are stronger, which masks the weak attractive forces.

Rare earth elements in apatite: Uptake from H{sub 2}O-bearing phosphate-fluoride melts and the role of volatile components

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fleet, M.E.; Pan, Yuanming

The partitioning of rare earth elements (REEs) between fluorapatite (FAp) and H{sub 2}O- bearing phosphate-fluoride melts has been studied at about 700 and 800{degrees}C and 0.10-0.15 GPa. REE uptake patterns, i.e., plots of D(REE:FAp/melt), are convex upwards and peak near Nd for single-REE substituted FAp at minor (0.03-0.25 wt% REE{sub 2}O{sub 3}) abundances, and binary (LREE + HREE)-substituted FAp, and hexa-REE-substituted FAp at minor to major (0.25-7.8 wt% REE{sub 2}O{sub 3}) abundances. Partition coefficients for minor abundances of REE and depolymerized phosphate melts are about 5, 8, and 1 for La, Nd, and Lu, respectively and broadly comparable to thosemore » for early fluorapatite in the fractionation of melts of basaltic composition. The Ca2 site exerts marked control on the selectivity of apatite for REE because it preferentially incorporates LREE and its effective size varies with substitution of the A-site volatile anion component (F, Cl, OH). Using simple crystal-chemical arguments, melt(or fluid)-normalized REE patterns are predicted to peak near Nd for fluorapatite and be more LREE-enriched for chlorapatite. These predictions are consistent with data from natural rocks and laboratory experiments. The wide variation in D(REE:apatite/melt) in nature (from <1 for whitlockite-bearing lunar rocks to about 100 for evolved alkalic rocks) is attributed largely to the influence of the volatile components. 49 refs., 8 figs., 3 tabs.« less

Gastric tumours in FAP.

PubMed

Walton, Sarah-Jane; Frayling, Ian M; Clark, Susan K; Latchford, Andrew

2017-07-01

Gastric cancer is not a recognised extra-colonic manifestation of FAP, except in countries with a high prevalence of gastric cancer. Data regarding gastric adenomas in FAP are sparse. The aim of this study was to review the clinical characteristics of gastric tumours occurring within an FAP population from the largest European polyposis registry. All patients that developed a gastric adenoma or carcinoma were identified from a prospectively maintained registry database. The primary outcome measure was the occurrence of gastric adenoma or adenocarcinoma. Secondary outcomes included APC mutation, tumour stage, management and survival. Eight patients developed gastric cancer and 21 an adenoma (median age 52 and 44 years, respectively). Regular oesophagogastroduodenoscopy surveillance was performed in 6/8 patients who developed cancer. Half were advanced T3/4 tumours and 6/8 had nodal or metastatic spread at diagnosis. All cancer cases died within a median of 13.5 months from diagnosis. Gastric adenomas were evenly distributed: 11/21 (52%) in the distal and 10/21 (48%) proximal stomach, whereas 5/8 (63%) cancers were located proximally. An association between gastric tumour and desmoid development was observed; 7/8 (88%) cancer and 11/21 (52%) adenoma cases had a personal or family history of desmoid. It would appear from this small, retrospective study that gastric cancer is not a prominent extra-colonic feature of FAP in the Western world. It seems to present at an advanced stage with a poor prognosis. There may be an association between gastric tumour and desmoid occurrence but a large multicentre cohort is necessary to investigate this further.

Diagnostic values of dual focus narrow band imaging and probe-based confocal laser endomicroscopy in FAP-related duodenal adenoma.

PubMed

Pittayanon, Rapat; Rerknimitr, Rungsun; Imraporn, Boonlert; Wisedopas, Naruemon; Kullavanijaya, Pinit

2015-10-01

Familial adenomatous polyposis (FAP) is associated with an increased risk of development of periampullary and nonampullary adenoma. Either routine biopsy or endoscopic removal of the lesion is generally required to identify the presence of adenoma. Because the risk of tissue sampling from the ampulla is high and nonampullary polyps are sometimes numerous, resection of all the lesions is time-consuming. This study aimed to evaluate the diagnostic values of duodenal adenoma by dual focus NBI (dNBI) and probe-based confocal endomicroscopy (pCLE) in FAP patients. The authors conducted a diagnostic study in a single tertiary-care referral center. Surveillance esophagogastroduodenoscopy with dNBI and pCLE was performed on 26 patients with FAP for real-time adenoma diagnosis by two different endoscopists; one used dNBI and the other pCLE. Histology from the matched lesion was used as the gold standard. A total of 55 matched biopsies (25 ampullas, 30 nonampullas) were performed. The sensitivity, specificity, post predictive value (PPV), negative predictive value (NPV), and accuracy of dNBI vs. pCLE from all duodenal lesions were 96.9 % vs. 93.8 %, 78.3 % vs. 81 %, 86.1 % vs. 88.2 %, 94.7 vs. 89.5 %, and 92.4 % vs. 88.6 %, respectively. For surveillance of periampullary and nonampullary adenoma in patients with FAP, the real-time readings provided a high degree of diagnostic value when histology was used as the gold standard. ( NCT02162173).

Quality Program Provisions for Aeronautical and Space System Contractors

NASA Technical Reports Server (NTRS)

1969-01-01

This publication sets forth quality program requirements for NASA aeronautical and space programs, systems, subsystems, and related services. These requirements provide for the effective operation of a quality program which ensures that quality criteria and requirements are recognized, definitized, and performed satisfactorily.

FY2005 Progress Summary and FY2006 Program Plan Statement of Work and Deliverables for Development of High Average Power Diode-Pumped Solid State Lasers, and Complementary Technologies, for Applications in Energy and Defense

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ebbers, C

The primary focus this year was to operate the system with two amplifiers populated with and pumped by eight high power diode arrays. The system was operated for extended run periods which enabled average power testing of components, diagnostics, and controls. These tests were highly successful, with a demonstrated energy level of over 55 joules for 4 cumulative hours at a repetition rate of 10 Hz (average power 0.55 kW). In addition, high average power second harmonic generation was demonstrated, achieving 227 W of 523.5 nm light (22.7 J, 10 Hz, 15 ns, 30 minutes) Plans to achieve higher energymore » levels and average powers are in progress. The dual amplifier system utilizes a 4-pass optical arrangement. The Yb:S-FAP slabs were mounted in aerodynamic aluminum vane structures to allow turbulent helium gas flow across the faces. Diagnostic packages that monitored beam performance were deployed during operation. The laser experiments involved injecting a seed beam from the front end into the system and making four passes through both amplifiers. Beam performance diagnostics monitored the beam on each pass to assess system parameters such as gain and nearfield intensity profiles. This year, an active mirror and wavefront sensor were procured and demonstrated in an off-line facility. The active mirror technology can correct for low order phase distortions at user specified operating conditions (such as repetition rates different than 10 Hz) and is a complementary technology to the static phase plates used in the system for higher order distortions. A picture of the laser system with amplifier No.2 (foreground) and amplifier No.1 (background) is shown in Fig. 1.0.1.1. The control system and diagnostics were recently enhanced for faster processing and allow remote operation of the system. The growth and fabrication of the Yb:S-FAP slabs constituted another major element of our program objectives. Our goal was to produce at least fourteen 4x6 cm2 crystalline slabs. These goals were met. Nine crystal boules were successfully grown to produce 14 slabs. In addition, we have prepared the way to scale the Yb:S-FAP crystals to the next growth diameter (10-inch diameter as opposed to 7-inch diameter). An outside contract was placed with Northrop-Grumman to scaleup the Yb:S-FAP crystal size. The following sections discuss the above accomplishments in more technical detail and are followed by plans and a budget request for FY2006.« less

Mapping the low palmitate fap1 mutation and validation of its effects on soybean oil and agronomic traits in three soybean populations

USDA-ARS?s Scientific Manuscript database

Soybean oil with reduced palmitic acid content is desirable to reduce the risks of coronary diseases and; breast, colon, and prostate cancer incidence associated with consumption of this fatty acid. The objectives of this study were: to identify the genomic location of the reduced palmitate fap1 mut...

14 CFR 1221.112 - Use of the NASA Program Identifiers.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Use of the NASA Program Identifiers. 1221.112 Section 1221.112 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION THE NASA SEAL AND OTHER DEVICES, AND THE CONGRESSIONAL SPACE MEDAL OF HONOR NASA Seal, NASA Insignia, NASA Logotype...

14 CFR 1221.112 - Use of the NASA Program Identifiers.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Use of the NASA Program Identifiers. 1221.112 Section 1221.112 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION THE NASA SEAL AND OTHER DEVICES, AND THE CONGRESSIONAL SPACE MEDAL OF HONOR NASA Seal, NASA Insignia, NASA Logotype...

14 CFR 1221.112 - Use of the NASA Program Identifiers.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Use of the NASA Program Identifiers. 1221.112 Section 1221.112 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION THE NASA SEAL AND OTHER DEVICES, AND THE CONGRESSIONAL SPACE MEDAL OF HONOR NASA Seal, NASA Insignia, NASA Logotype...

14 CFR 1221.112 - Use of the NASA Program Identifiers.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Use of the NASA Program Identifiers. 1221.112 Section 1221.112 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION THE NASA SEAL AND OTHER DEVICES, AND THE CONGRESSIONAL SPACE MEDAL OF HONOR NASA Seal, NASA Insignia, NASA Logotype...

Accurate perception of negative emotions predicts functional capacity in schizophrenia.

PubMed

Abram, Samantha V; Karpouzian, Tatiana M; Reilly, James L; Derntl, Birgit; Habel, Ute; Smith, Matthew J

2014-04-30

Several studies suggest facial affect perception (FAP) deficits in schizophrenia are linked to poorer social functioning. However, whether reduced functioning is associated with inaccurate perception of specific emotional valence or a global FAP impairment remains unclear. The present study examined whether impairment in the perception of specific emotional valences (positive, negative) and neutrality were uniquely associated with social functioning, using a multimodal social functioning battery. A sample of 59 individuals with schizophrenia and 41 controls completed a computerized FAP task, and measures of functional capacity, social competence, and social attainment. Participants also underwent neuropsychological testing and symptom assessment. Regression analyses revealed that only accurately perceiving negative emotions explained significant variance (7.9%) in functional capacity after accounting for neurocognitive function and symptoms. Partial correlations indicated that accurately perceiving anger, in particular, was positively correlated with functional capacity. FAP for positive, negative, or neutral emotions were not related to social competence or social attainment. Our findings were consistent with prior literature suggesting negative emotions are related to functional capacity in schizophrenia. Furthermore, the observed relationship between perceiving anger and performance of everyday living skills is novel and warrants further exploration. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Identification a nonsense mutation of APC gene in Chinese patients with familial adenomatous polyposis.

PubMed

Li, Haishan; Zhang, Lingling; Jiang, Quan; Shi, Zhenwang; Tong, Hanxing

2017-04-01

Familial adenomatous polyposis (FAP; Mendelian of Inherintance in Man ID, 175100) is a rare autosomal dominant disorder characterized by the development of numerous adenomatous polyps throughout the colon and rectum associated with an increased risk of colorectal cancer. FAP is at time accompanied with certain extraintestinal manifestations such as congenital hypertrophy of the retinal pigment epithelium, dental disorders and desmoid tumors. It is caused by mutations in the adenomatous polyposis coli ( APC ) gene. The present study reported on a Chinese family with FAP. Polymerase chain reaction and direct sequencing of the full coding sequence of the APC gene were performed to identify the mutation in this family. A nonsense mutation of the APC gene was identified in this pedigree. It is a heterozygous G>T substitution at position 2,971 in exon 15 of the APC gene, which formed a premature stop codon at amino acid residue 991 (p.Glu991*). The resulting truncated protein lacked 1,853 amino acids. The present study expanded the database on APC gene mutations in FAP and enriched the spectrum of known germline mutations of the APC gene. Prophylactic proctocolectomy may be considered as a possible treatment for carriers of the mutation.

Fluorogen-Activating-Proteins as Universal Affinity Biosensors for Immunodetection

PubMed Central

Gallo, Eugenio; Vasilev, Kalin V.; Jarvik, Jonathan

2014-01-01

Fluorogen-activating-proteins (FAPs) are a novel platform of fluorescence biosensors utilized for protein discovery. The technology currently demands molecular manipulation methods that limit its application and adaptability. Here, we highlight an alternative approach based on universal affinity reagents for protein detection. The affinity reagents were engineered as bi-partite fusion proteins, where the specificity moiety is derived from IgG-binding proteins –Protein-A or Protein-G – and the signaling element is a FAP. In this manner, primary antibodies provide the antigenic selectivity against a desired protein in biological samples, while FAP affinity reagents target the constant region (Fc) of antibodies and provide the biosensor component of detection. Fluorescence results using various techniques indicate minimal background and high target specificity for exogenous and endogenous proteins in mammalian cells. Additionally, FAP-based affinity reagents provide enhanced properties of detection previously absent using conventional affinity systems. Distinct features explored in this report include: (1) unfixed signal wavelengths (excitation and emission) determined by the particular fluorogen chosen, (2) real-time user controlled fluorescence on-set and off-set, (3) signal wavelength substitution while performing live analysis, and (4) enhanced resistance to photobleaching. PMID:24122476

Flow-oriented dynamic assembly algorithm in TCP over OBS networks

NASA Astrophysics Data System (ADS)

Peng, Shuping; Li, Zhengbin; He, Yongqi; Xu, Anshi

2008-11-01

OBS is envisioned as a promising infrastructure for the next generation optical network, and TCP is likely to be the dominant transport protocol in the next generation network. Therefore, it is necessary to evaluate the performance of TCP over OBS networks. The assembly at the ingress edge nodes will impact the network performance. There have been several Fixed Assembly Period (FAP) algorithms proposed. However, the assembly period in FAP is fixed, and it can not be adjusted according to the network condition. Moreover, in FAP, the packets from different TCP sources are assembled into one burst. In that case, if such a burst is dropped, the TCP windows of the corresponding sources will shrink and the throughput will be reduced. In this paper, we introduced a flow-oriented Dynamic Assembly Period (DAP) algorithm for TCP over OBS networks. Through comparing the previous and current burst lengths, DAP can track the variation of TCP window, and update the assembly period dynamically for the next assembly. The performance of DAP is evaluated over a single TCP connection and multiple connections, respectively. The simulation results show that DAP performs better than FAP at almost the whole range of burst dropping probability.

Exclusion of the APC gene as the cause of a variant form of familial adenomatous polyposis (FAP)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stella, A.; Resta, N.; Susca, F.

Familial adenomatous polyposis (FAP) is a premalignant disease inherited as an autosomal dominant trait, characterized by hundreds to thousands of polyps in the colorectal tract. Recently, the syndrome has been shown to be caused by mutations in the APC (adenomatous polyposis coli) gene located on chromosome 5q21. The authors studied two families that both presented a phenotype different from that of the classical form of FAP. The most important findings observed in these two kindreds are (a) low and variable number of colonic polyps (from 5 to 100) and (b) a slower evolution of the disease, with colon cancer occurringmore » at a more advanced age than in FAP in spite of the early onset of intestinal manifestations. To determine whether mutations of the APC gene are also responsible for this variant syndrome, linkage studies were performed by using a series of markers both intragenic and tightly linked to the APC gene. The results provide evidence for exclusion of the APC gene as the cause of the variant form of polyposis present in the two families described. 30 refs., 1 fig., 1 tab.« less

Mobile-ip Aeronautical Network Simulation Study

NASA Technical Reports Server (NTRS)

Ivancic, William D.; Tran, Diepchi T.

2001-01-01

NASA is interested in applying mobile Internet protocol (mobile-ip) technologies to its space and aeronautics programs. In particular, mobile-ip will play a major role in the Advanced Aeronautic Transportation Technology (AATT), the Weather Information Communication (WINCOMM), and the Small Aircraft Transportation System (SATS) aeronautics programs. This report presents the results of a simulation study of mobile-ip for an aeronautical network. The study was performed to determine the performance of the transmission control protocol (TCP) in a mobile-ip environment and to gain an understanding of how long delays, handoffs, and noisy channels affect mobile-ip performance.

eRapa Restores A Normal Life Span in a FAP Mouse Model

PubMed Central

Hasty, Paul; Livi, Carolina B.; Dodds, Sherry G.; Jones, Diane; Strong, Randy; Javors, Martin; Fischer, Kathleen E.; Sloane, Lauren; Murthy, Kruthi; Hubbard, Gene; Sun, Lishi; Hurez, Vincent; Curiel, Tyler J.; Sharp, Zelton Dave

2014-01-01

Mutation of a single copy of the adenomatous polyposis coli (APC) gene results in familial adenomatous polyposis (FAP), which confers an extremely high risk for colon cancer. ApcMin/+ mice exhibit multiple intestinal neoplasia (MIN) that causes anemia and death from bleeding by 6 months. Mechanistic target of rapamycin complex 1 (mTORC1) inhibitors were shown to improve ApcMin/+ mouse survival when administered by oral gavage or added directly to the chow, but these mice still died from neoplasia well short of a natural life span. The National Institute of Aging Intervention Testing Program showed that enterically targeted rapamycin (eRapa) extended life span for wild type genetically heterogeneous mice in part by inhibiting age-associated cancer. We hypothesized that eRapa would be effective in preventing neoplasia and extend survival of ApcMin/+ mice. We show that eRapa improved survival for ApcMin/+ mice in a dose-dependent manner. Remarkably, and in contrast to previous reports, most of the ApcMin/+ mice fed 42 ppm eRapa lived beyond the median life span reported for wild type syngeneic mice. Furthermore, chronic eRapa did not cause detrimental immune effects in mouse models of cancer, infection or autoimmunity; thus, assuaging concerns that chronic rapamycin treatment suppresses immunity. Our studies suggest that a novel formulation (enteric targeting) of a well-known and widely used drug (rapamycin) can dramatically improve its efficacy in targeted settings. eRapa or other mTORC1 inhibitors could serve as effective cancer preventatives for people with FAP without suppressing the immune system, thus reducing the dependency on surgery as standard therapy. PMID:24282255

Research And Development Contributions to Aviation Progress (RADCAP): Executive summary

NASA Technical Reports Server (NTRS)

1972-01-01

Positive contributions of military aeronautical research and development programs to civil aviation are reviewed and some possible future contributions of those military programs are assessed. A summary is presented of detailed results concerned with: (1) review of the progress that has been made in aviation since 1925 and the significant technological advances that have been made; (2) an examination of current and planned military aeronautical research and technology programs and an assessment of their relevancy to the aeronautical R and D needs of civil aviation; (3) the relationship of the development base generated by military programs to the needs of civil airliner design, development, and production; (4) information on aeronautical R and D funding; and (5) the findings and observations of the RADCAP study.

U.S. Aeronautical L-Band Satellite Technology Test Program : Interim Tests Results

DOT National Transportation Integrated Search

1975-06-01

The U.S. Aeronautical L-Band satellite test program was performed between September 1974 and April 1975 as part of an international ATS-6 L-Band satellite test program. The U.S. program consisted of both technology and ATC communications demonstratio...

A photophysical study of two fluorogen-activating proteins bound to their cognate fluorogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gaiotto, Tiziano; Nguyen, Hau B; Jung, Jaemyeong

We are exploring the feasibility of using recently developed flu orogen-activating proteins (FAPs) as reporters for single-molecule imaging. FAPs are single-chain antibodies choosen to specifically bind small chromophoric molecules termed f1uorogens. Upon binding to its cognate FAP the fluorescence quantum yield of the fluorogen can increase substantially giving rise to a fluorescent complex. Based on the seminal work of Szent-Gyorgyi et al. (Nature Biotechnology, Volume 26, Number 2, pp 235-240, 2008) we have chosen to study two fluorogen-activating single-chain antibodies, HL 1.0.1-TOI and H6-MG bound to their cognate fluorogens, thiazole orange and malachite green derivatives, respectively. Here we use fluorescencemore » correlation spectroscopy study the photophysics of these fluorescent complexes.« less

Fracture behavior of the Fe-8Al alloy FAP-Y

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alexander, D.J.

The tensile and impact properties of two heats of the reduced aluminum alloy FAP-Y have been measured and compared to the Fe{sub 3}Al alloy FA-129. The FAP-Y material has similar yield strengths up to 400{degrees}C, and much better ductility and impact properties, as compared to the FA-129. Despite excellent room-temperature ductility, the ductile-to-brittle transition temperature is still quite high, around 150{degrees}C. The material is found to be strain-rate sensitive, with a significant increase in the yield strength at strain rates of about 10{sup 3} s{sup {minus}1}. It is believed that this strain-rate sensitivity is responsible, at least in part, formore » the high ductile-to-brittle transition temperature.« less

14 CFR 1203.901 - Responsibilities.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program Committee § 1203.901 Responsibilities. (a) The Chairperson reports to the Administrator concerning the management and direction of the NASA Information Security Program as provided for...

14 CFR 1203.901 - Responsibilities.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program Committee § 1203.901 Responsibilities. (a) The Chairperson reports to the Administrator concerning the management and direction of the NASA Information Security Program as provided for...

The Effect of Contingent Reinforcement on Target Variables in Outpatient Psychotherapy for Depression: A Successful and Unsuccessful Case Using Functional Analytic Psychotherapy

ERIC Educational Resources Information Center

Kanter, Jonathan W.; Landes, Sara J.; Busch, Andrew M.; Rusch, Laura C.; Brown, Keri R.; Baruch, David E.; Holman, Gareth I.

2006-01-01

The current study investigated a behavior-analytic treatment, functional analytic psychotherapy (FAP), for outpatient depression utilizing two single-subject A/A+B designs. The baseline condition was cognitive behavioral therapy. Results demonstrated treatment success in 1 client after the addition of FAP and treatment failure in the 2nd. This…

Day Care in Vermont: An Evaluation of the Vermont Model FAP Child Care Service System.

ERIC Educational Resources Information Center

Siedman, Eileen

This book presents an extensive examination of the organization and operation of the Vermont model day care delivery system which was designed in the context of the proposed Family Assistance Plan (FAP). The model tested the ability of Federal and State employees to work together and share resources in designing a new approach to welfare reform.…

MiR-200c regulates ROS-induced apoptosis in murine BV-2 cells by targeting FAP-1.

PubMed

Yu, D S; Lv, G; Mei, X F; Cao, Y; Wang, Y F; Wang, Y S; Bi, Y L

2014-12-02

Objective:Reactive oxygen species (ROS) are significantly upregulated after spinal cord injury (SCI). MicroRNAs (miRNAs) are reported to be widely involved in regulating gene expression. This paper aims to explore the correlation between ROS-induced cell apoptosis and abnormal miRNA expression after SCI.Methods:To profile the expression of miRNAs after SCI, miRNA microarray was applied and the result was verified by reverse transcription quantitative PCR (RT-qPCR). ROS production following H 2 O 2 stimulation was examined using dihydroethidium staining and flow cytometry. The levels of miR-200c after H 2 O 2 treatment were determined using RT-qPCR. Cell viability and apoptosis were examined in murine BV-2 cells transfected with miR-200c mimics, inhibitor or negative control. Immunofluorescence and western blot were used to further explore the effects of miR-200c on Fas-associated phosphatase-1 (FAP-1) expression.Results:MiR-200c was showed to be significantly increased after SCI by miRNA microassay and RT-qPCR. ROS production enhanced miR-200c expression in a dose-dependent manner and induced significant apoptosis in BV-2 cells. The upregulation of miR-200c reduced cell viability and induced BV-2 cell apoptosis. MiR-200c negatively regulated the expression of FAP-1, thereby inducing FAS signaling-induced apoptosis. RT-qPCR analysis showed that the FAP-1-targeting small interfering RNA (siRNA) did not affect the level of miR-200c in murine BV-2 cells. In addition, suppression of FAP-1 by siRNA promoted apoptosis, even in cells that were co-transfected with the miR-200c inhibitor.Conclusions:The current data suggested that miR-200c contributes to apoptosis in murine BV-2 cells by regulating the expression of FAP-1. This proposes a therapeutic target for enhancing neural cell functional recovery after SCI.Spinal Cord advance online publication, 2 December 2014; doi:10.1038/sc.2014.185.

Child pain catastrophizing mediates the relationship between parent responses to pain and disability in youth with functional abdominal pain

PubMed Central

Cunningham, Natoshia Raishevich; Lynch-Jordan, Anne; Barnett, Kimberly; Peugh, James; Sil, Soumitri; Goldschneider, Kenneth; Kashikar-Zuck, Susmita

2014-01-01

Objectives Functional abdominal pain (FAP) in youth is associated with substantial impairment in functioning and prior research has shown that overprotective parent responses can heighten impairment. Little is known about how a range of parental behaviors in response to their child’s pain (overprotection, minimizing and/or encouragement) interact with child coping characteristics (e.g., catastrophizing) to influence functioning in youth with FAP. In this study, it was hypothesized that the relationship between parenting factors and child disability would be mediated by children’s level of maladaptive coping (i.e., pain catastrophizing). Methods Seventy-five patients with FAP presenting to a pediatric pain clinic and their caregivers participated. Youth completed measures of pain intensity (Numeric Rating Scale), pain catastrophizing (Pain Catastrophizing Scale), and disability (Functional Disability Inventory). Caregivers completed measures of parent pain catastrophizing (Pain Catastrophizing Scale), and parent responses to child pain behaviors (Adult Responses to Child Symptoms: protection, minimizing, and encouragement/monitoring subscales). Results Increased functional disability was significantly related to higher child pain intensity, increased child and parent pain catastrophizing, and higher levels of encouragement/monitoring and protection. Parent minimization was not related to disability. Child pain catastrophizing fully mediated the relationship between parent encouragement/monitoring and disability and partially mediated the relationship between parent protectiveness and disability. Conclusions The impact of parenting behaviors in response to FAP on child disability is determined in part by the child’s coping style. Findings highlight a more nuanced understanding of the parent-child interaction in determining pain-related disability levels, which should be taken into consideration in assessing and treating youth with FAP. PMID:25121521

Dosage analysis of cancer predisposition genes by multiplex ligation-dependent probe amplification

PubMed Central

Bunyan, D J; Eccles, D M; Sillibourne, J; Wilkins, E; Thomas, N Simon; Shea-Simonds, J; Duncan, P J; Curtis, C E; Robinson, D O; Harvey, J F; Cross, N C P

2004-01-01

Multiplex ligation-dependent probe amplification (MLPA) is a recently described method for detecting gross deletions or duplications of DNA sequences, aberrations which are commonly overlooked by standard diagnostic analysis. To determine the incidence of copy number variants in cancer predisposition genes from families in the Wessex region, we have analysed the hMLH1 and hMSH2 genes in patients with hereditary nonpolyposis colorectal cancer (HNPCC), BRCA1 and BRCA2 in families with hereditary breast/ovarian cancer (BRCA) and APC in patients with familial adenomatous polyposis coli (FAP). Hereditary nonpolyposis colorectal cancer (n=162) and FAP (n=74) probands were fully screened for small mutations, and cases for which no causative abnormality were found (HNPCC, n=122; FAP, n=24) were screened by MLPA. Complete or partial gene deletions were identified in seven cases for hMSH2 (5.7% of mutation-negative HNPCC; 4.3% of all HNPCC), no cases for hMLH1 and six cases for APC (25% of mutation negative FAP; 8% of all FAP). For BRCA1 and BRCA2, a partial mutation screen was performed and 136 mutation-negative cases were selected for MLPA. Five deletions and one duplication were found for BRCA1 (4.4% of mutation-negative BRCA cases) and one deletion for BRCA2 (0.7% of mutation-negative BRCA cases). Cost analysis indicates it is marginally more cost effective to perform MLPA prior to point mutation screening, but the main advantage gained by prescreening is a greatly reduced reporting time for the patients who are positive. These data demonstrate that dosage analysis is an essential component of genetic screening for cancer predisposition genes. PMID:15475941

Oestrogen receptor beta isoform expression in sporadic colorectal cancer, familial adenomatous polyposis and progressive stages of colorectal cancer.

PubMed

Stevanato Filho, Paulo Roberto; Aguiar Júnior, Samuel; Begnami, Maria Dirlei; Kuasne, Hellen; Spencer, Ranyell Matheus; Nakagawa, Wilson Toshihiko; Bezerra, Tiago Santoro; Kupper, Bruna Catin; Takahashi, Renata Maymi; Barros Filho, Mateus; Rogatto, Silvia Regina; Lopes, Ademar

2017-11-13

Among the sex hormones, oestrogen may play a role in colorectal cancer, particularly in conjunction with oestrogen receptor-β (ERβ). The expression of ERβ isoform variants and their correlations with familial adenomatous polyposis (FAP) syndrome and sporadic colorectal carcinomas are poorly described. This study aimed to investigate the expression levels of the ERβ1, ERβ2, ERβ4 and ERβ5 isoform variants using quantitative RT-PCR (921 analyses) in FAP, normal mucosa, adenomatous polyps and sporadic colorectal carcinomas. Decreased expression of ERβ isoforms was identified in sporadic polyps and in sporadic colorectal cancer as well as in polyps from FAP syndrome patients compared with normal tissues (p < 0.001). In FAP patients, ERβ1 and ERβ5 isoforms showed significant down-expression in polyps (p < 0.001) compared with matched normal tissues. However, no differences were observed when sporadic colorectal carcinomas were compared to normal mucosa tissues. These findings suggest an association of the ERβ isoform variants in individuals affected by germline mutations of the APC gene. Progressively decreased expression of ERβ was found in polyps at early stages of low-grade dysplasia, followed by T1-T2 and T3-T4 tumours (p < 0.05). In sporadic colorectal cancer, the loss of expression was an independent predictor of recurrence, and ERβ1 and ERβ5 expression levels were associated with better disease-free survival (p = 0.002). These findings may provide a better understanding of oestrogens and their potential preventive and therapeutic effects on sporadic colorectal cancer and cancers associated with FAP syndrome.

WNT Inhibitory Activity of Malus Pumila miller cv Annurca and Malus domestica cv Limoncella Apple Extracts on Human Colon-Rectal Cells Carrying Familial Adenomatous Polyposis Mutations.

PubMed

Riccio, Gennaro; Maisto, Maria; Bottone, Sara; Badolati, Nadia; Rossi, Giovanni Battista; Tenore, Gian Carlo; Stornaiuolo, Mariano; Novellino, Ettore

2017-11-18

Inhibitors of the Wingless-related Integration site (WNT)/β-catenin pathway have recently been under consideration as potential chemopreventive agents against Familial Adenomatous Polyposis (FAP). This autosomal-dominant syndrome is caused by germline mutations in the gene coding for the protein APC and leads to hyperactivation of the WNT/β-catenin signaling pathway, uncontrolled intestinal cell proliferation and formation of adenocarcinomas. The aim of the present work was to: (i) test, on in vitro cultures of cells carrying FAP mutations and on ex vivo biopsies of FAP patients, the WNT inhibitory activity of extracts from two common southern Italian apples, Malus pumila Miller cv. 'Annurca' and Malus domestica cv 'Limoncella'; (ii) identify the mechanisms underpinning their activities and; (iii) evaluate their potency upon gastrointestinal digestion. We here show that both Annurca and Limoncella apple extracts act as WNT inhibitors, mostly thanks to their polyphenolic contents. They inhibit the pathway in colon cells carrying FAP mutations with active dilutions falling in ranges close to consumer-relevant concentrations. Food-grade manufacturing of apple extracts increases their WNT inhibitory activity as result of the conversion of quercetin glycosides into the aglycone quercetin, a potent WNT inhibitor absent in the fresh fruit extract. However, in vitro simulated gastrointestinal digestion severely affected WNT inhibitory activity of apple extracts, as result of a loss of polyphenols. In conclusion, our results show that apple extracts inhibit the WNT pathway in colon cells carrying FAP mutations and represent a potential nutraceutical alternative for the treatment of this pathology. Enteric coating is advisable to preserve the activity of the extracts in the colon-rectal section of the digestive tract.

WNT Inhibitory Activity of Malus Pumila miller cv Annurca and Malus domestica cv Limoncella Apple Extracts on Human Colon-Rectal Cells Carrying Familial Adenomatous Polyposis Mutations

PubMed Central

Maisto, Maria; Bottone, Sara; Badolati, Nadia; Rossi, Giovanni Battista; Novellino, Ettore

2017-01-01

Inhibitors of the Wingless-related Integration site (WNT)/β-catenin pathway have recently been under consideration as potential chemopreventive agents against Familial Adenomatous Polyposis (FAP). This autosomal-dominant syndrome is caused by germline mutations in the gene coding for the protein APC and leads to hyperactivation of the WNT/β-catenin signaling pathway, uncontrolled intestinal cell proliferation and formation of adenocarcinomas. The aim of the present work was to: (i) test, on in vitro cultures of cells carrying FAP mutations and on ex vivo biopsies of FAP patients, the WNT inhibitory activity of extracts from two common southern Italian apples, Malus pumila Miller cv. ‘Annurca’ and Malus domestica cv ‘Limoncella’; (ii) identify the mechanisms underpinning their activities and; (iii) evaluate their potency upon gastrointestinal digestion. We here show that both Annurca and Limoncella apple extracts act as WNT inhibitors, mostly thanks to their polyphenolic contents. They inhibit the pathway in colon cells carrying FAP mutations with active dilutions falling in ranges close to consumer-relevant concentrations. Food-grade manufacturing of apple extracts increases their WNT inhibitory activity as result of the conversion of quercetin glycosides into the aglycone quercetin, a potent WNT inhibitor absent in the fresh fruit extract. However, in vitro simulated gastrointestinal digestion severely affected WNT inhibitory activity of apple extracts, as result of a loss of polyphenols. In conclusion, our results show that apple extracts inhibit the WNT pathway in colon cells carrying FAP mutations and represent a potential nutraceutical alternative for the treatment of this pathology. Enteric coating is advisable to preserve the activity of the extracts in the colon-rectal section of the digestive tract. PMID:29156563

Eosinophilic Esophagitis in Children and Adolescents with Abdominal Pain: Comparison with EoE-Dysphagia and Functional Abdominal Pain.

PubMed

Gunasekaran, Thirumazhisai; Prabhakar, Gautham; Schwartz, Alan; Gorla, Kiranmai; Gupta, Sandeep; Berman, James

2016-01-01

Aim. Compare EoE-AP with EoE-D for clinical, endoscopy (EGD), histology and outcomes and also with FAP-N. Method. Symptoms, physical findings, EGD, histology, symptom scores, and treatments were recorded for the three groups. Cluster analysis was done. Results. Dysphagia and abdominal pain were different in numbers but not statistically significant between EoE-AP and EoE-D. EGD, linear furrows, white exudates were more in the EoE-D and both combined were significant (p < 0.05). EoE-D, peak and mean eosinophils (p  0.06) and eosinophilic micro abscesses (p  0.001) were higher. Follow-Up. Based on single symptom, EoE-AP had 30% (p  0.25) improvement, EoE-D 86% (p < 0.001) and similar with composite score (p  0.57 and <0.001, resp.). Patients who had follow-up, EGD: 42.8% with EoE-AP and 77.8% with EoE-D, showed single symptom improvement and the eosinophil count fell from 38.5/34.6 (peak and mean) to 31.2/30.4 (p  0.70) and from 43.6/40.8 to 25.2/22.8 (p < 0.001), respectively. FAP-N patients had similar symptom improvement like EoE-D. Cluster Analysis. EoE-AP and FAP-N were similar in clinical features and response to treatment, but EoE-D was distinctly different from EoE-AP and FAP-N. Conclusion. Our study demonstrates that EoE-AP and EoE-D have different histology and outcomes. In addition, EoE-AP has clinical features similar to the FAP-N group.

Eosinophilic Esophagitis in Children and Adolescents with Abdominal Pain: Comparison with EoE-Dysphagia and Functional Abdominal Pain

PubMed Central

Gorla, Kiranmai; Gupta, Sandeep

2016-01-01

Aim. Compare EoE-AP with EoE-D for clinical, endoscopy (EGD), histology and outcomes and also with FAP-N. Method. Symptoms, physical findings, EGD, histology, symptom scores, and treatments were recorded for the three groups. Cluster analysis was done. Results. Dysphagia and abdominal pain were different in numbers but not statistically significant between EoE-AP and EoE-D. EGD, linear furrows, white exudates were more in the EoE-D and both combined were significant (p < 0.05). EoE-D, peak and mean eosinophils (p  0.06) and eosinophilic micro abscesses (p  0.001) were higher. Follow-Up. Based on single symptom, EoE-AP had 30% (p  0.25) improvement, EoE-D 86% (p < 0.001) and similar with composite score (p  0.57 and <0.001, resp.). Patients who had follow-up, EGD: 42.8% with EoE-AP and 77.8% with EoE-D, showed single symptom improvement and the eosinophil count fell from 38.5/34.6 (peak and mean) to 31.2/30.4 (p  0.70) and from 43.6/40.8 to 25.2/22.8 (p < 0.001), respectively. FAP-N patients had similar symptom improvement like EoE-D. Cluster Analysis. EoE-AP and FAP-N were similar in clinical features and response to treatment, but EoE-D was distinctly different from EoE-AP and FAP-N. Conclusion. Our study demonstrates that EoE-AP and EoE-D have different histology and outcomes. In addition, EoE-AP has clinical features similar to the FAP-N group. PMID:27610357

Early postoperative and long-term oncological outcomes of laparoscopic treatment for patients with familial adenomatous polyposis

PubMed Central

Kim, Hye Jin; Park, Jun Seok; Park, Soo Yeun; Choi, Wohn Ho; Ryuk, Jong Pil

2012-01-01

Purpose We evaluated the short- and long-term outcomes of laparoscopic total proctocolectomy with ileal pouch-anal anastomosis (TPC/IPAA) for treatment of familial adenomatous polyposis (FAP). Also, we assessed the oncologic outcomes in FAP patients with coexisting malignancy. Methods From August 1999 to September 2010, 43 FAP patients with or without coexisting malignancy underwent TPC/IPAA by a laparoscopic-assisted or hand-assisted laparoscopic surgery. Results The median age was 33 years (range, 18 to 58 years) at the time of operation. IPAA was performed by a hand-sewn method in 21 patients (48.8%). The median operative time was 300 minutes (range, 135 to 610 minutes), which reached a plateau after 22 operations. Early postoperative complications within 30 days occurred in 7 patients (16.3%) and long-term morbidity occurred in 15 patients (34.9%) including 6 (14.0%) with desmoid tumors and 3 (7.0%) who required operative treatment. Twenty-two patients (51.2%) were diagnosed with coexisting colorectal malignancy. The median follow-up was 58.5 months (range, 7.9 to 97.8 months). There was only 1 case of local recurrence in the pelvic cavity. No cases of adenocarcinoma at the residual rectal mucosa developed. 5-year disease-free survival rate for 22 patients who had coexisting malignancy was 86.5% and 5-year overall survival rate was 92.6%. Three patients died from pulmonary or hepatic metastasis. Conclusion Laparoscopic TPC/IPAA in patients with FAP is feasible and offers favorable postoperative outcomes. It also delivered acceptable oncological outcomes in patients with coexisting malignancy. Therefore, laparoscopic TPC/IPAA may be a favorable treatment option for FAP. PMID:23166888

A Clinical Observation of Functional Abdominal Pain Syndrome in Patients Treated by Traditional Chinese Spinal Orthopedic Manipulation.

PubMed

Qu, Liu-Xin; Xing, Li-Yang; Wanda, Norman; Chen, Hong; Li, Ming-Ju; Gao, Song; Li, Ping

2018-02-01

To evaluate the clinical effect of traditional Chinese spinal orthopedic manipulation (TCSOM) in treating patients with functional abdominal pain syndrome (FAPS) in comparison with Pinaverium Bromide (Dicetel, PBD), and to assess a possible cause for FAPS. Eighty patients with FAPS were randomly and equally assigned to the TCSOM group and PBD group according to the random number table. All patients in the TCSOM group were treated with a maximum of 5 times of spinal manipulations. Patients in the PBD group were instructed to take 50 mg 3 times a day, consistently for 2 weeks. The symptoms of pre- and post-treatment were assessed on a visual analog scale (VAS) pain score. A symptom improvement rating (SIR) was implemented to evaluate the effects of the treatments. The symptoms of 27 cases of the TCSOM group were relieved soon after the first TCSOM treatment and 9 cases were significantly improved. The VAS pain scores in the TCSOM group were significantly lower than those in the PBD group after 2 weeks treatment. According to the SIR based on VAS, the TCSOM group included 30 cases with excellent results, 7 cases with good, and 3 cases with poor. Adverse events to the treatment were not reported. Based on VAS, the PBD group reported 8 cases with excellent results, 10 cases with good and 22 cases with poor. There was a significant difference between the two groups (P<0.01). The displacement of intervertebral discs and/or vertebra in the thoracic or lumbar region seems to be a contributing factor in the symptoms of FAPS. TCSOM is an effective treatment for FAPS.

Functional Abdominal Pain Patient Subtypes in Childhood Predict Functional Gastrointestinal Disorders with Chronic Pain and Psychiatric Comorbidities in Adolescence and Adulthood

PubMed Central

Walker, Lynn S.; Sherman, Amanda L.; Bruehl, Stephen; Garber, Judy; Smith, Craig A.

2012-01-01

Although pediatric functional abdominal pain (FAP) has been linked to abdominal pain later in life, childhood predictors of long-term outcomes have not been identified. This study evaluated whether distinct FAP profiles based on patterns of pain and adaptation in childhood could be identified and whether these profiles predicted differences in clinical outcomes and central sensitization (wind-up) on average 9 years later. In 843 pediatric FAP patients, cluster analysis was used to identify subgroups at initial FAP evaluation based on profiles of pain severity, gastrointestinal (GI) and non-GI symptoms, pain threat appraisal, pain coping efficacy, catastrophizing, negative affect, and activity impairment. Three profiles were identified: High Pain Dysfunctional, High Pain Adaptive, and Low Pain Adaptive. Logistic regression analyses controlling for age and sex showed that, compared to pediatric patients with the Low Pain Adaptive profile, those with the High Pain Dysfunctional profile were significantly more likely at long-term follow-up to meet criteria for pain-related functional gastrointestinal disorder (FGID) (OR: 3.45; CI: 1.95–6.11), FGID with comorbid non-abdominal chronic pain (OR: 2.6; CI:1.45–4.66), and FGID with comorbid anxiety or depressive psychiatric disorder (OR: 2.84; CI: 1.35–6.00). Pediatric patients with the High Pain Adaptive profile had baseline pain severity comparable to the High Pain Dysfunctional profile, but had outcomes as favorable as the Low Pain Adaptive profile. In laboratory pain testing at follow-up, High Pain Dysfunctional patients exhibited significantly greater thermal wind-up than Low Pain Adaptive patients, suggesting that a subgroup of FAP patients has outcomes consistent with widespread effects of heightened central sensitization. PMID:22721910

Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.

PubMed

Cheng, Timothy H T; Gorman, Maggie; Martin, Lynn; Barclay, Ella; Casey, Graham; Saunders, Brian; Thomas, Huw; Clark, Sue; Tomlinson, Ian

2015-02-01

The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10(-7)). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

Analysis of Sr{sub 5{minus}x}Ba{sub x}(PO{sub 4}){sub 3}F:Yb{sup 3+} crystals for improved laser performance with diode-pumping

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schaffers, K.I.; Bayramian, A.J.; Marshall, C.D.

Crystals of Yb{sup 3+}:Sr{sub 1-x}Ba{sub x}(PO{sub 4}){sub 3}F (0 < x < 5) have been investigated as a means to obtain broader absorption bands than are currently available with Yb{sup 3+}:S-FAP [Yb{sup 3+}: Sr{sub 5}(PO{sub 4}){sub 3}F], thereby improving diode-pumping efficiency for high peak power applications. Large diode-arrays have a FWHM pump band of >5 nm while the FWHM of the 900 nm absorption band for Yb:S-FAP is 5.5 nm; therefore, a significant amount of pump power can be wasted due to the nonideal overlap. Spectroscopic analysis of Yb:Sr{sub 5-x}Ba{sub x}-FAP crystals indicates that adding barium to the lattice increasesmore » the pump band to 13-16 run which more than compensates for the diode-array pump source without a detrimental reduction in absorption cross section. However, the emission cross section decreases by approximately half with relatively no effect on the emission lifetime. The small signal gain has also been measured and compared to the parent material Yb:S-FAP and emission cross sections have been determined by the method of reciprocity, the Filchtbauer-Ladenburg method, and small signal gain. Overall, Yb{sup 3+}:Sr{sub 5-x}Ba{sub x}(PO{sub 4}){sub 3}F crystals appear to achieve the goal of nearly matching the favorable thermal and laser performance properties of Yb:S-FAP while having a broader absorption band to better accommodate diode pumping.« less

PTT analysis of polyps from FAP patients reveals a great majority of APC truncating mutations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luijt, R.B. van der; Khan, P.M.; Tops, C.M.J.

The adenomatous polyposis coli (APC) gene plays an important role in colorectal carcinogenesis. Germline APC mutations are associated with familial adenomatous polyposis (FAP), an autosomal dominantly inherited predisposition to colorectal cancer, characterized by the development of numerous adenomatous polyps in the large intestine. In order to investigate whether somatic inactivation of the remaining APC allele is necessary for adenoma formation, we collected multiple adenomatous polyps from individual FAP patients and investigated the presence of somatic mutations in the APC gene. The analysis of somatic APC mutations in these tumor samples was performed using a rapid and sensitive assay, called themore » protein truncation test (PTT). Chain-terminating somatic APC mutations were detected in the great majority of the tumor samples investigated. As expected, these mutations were mainly located in the mutation cluster region (MCR) in exon 15. Our results confirm that somatic mutation of the second APC allele is required for adenoma formation in FAP. Interestingly, in the polyps investigated in our study, the second APC allele is somatically inactivated through point mutation leading to a stop codon rather than by loss of heterozygosity. The observation that somatic second hits in APC are required for tumor development in FAP is in apparent accordance with the Knudson hypothesis for classical tumor suppressor genes. However, it is yet unknown whether chain-terminating APC mutations lead to a truncated protein exerting a dominant-negative effect or whether these mutations result in a null allele. Further investigation of this important issue will hopefully provide a better understanding of the mechanism of action of the mutated APC alleles in colorectal carcinogenesis.« less

Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davies, D.R.; Armstrong, J.G.; Thakker, N.

Familial adenomatous polyposis (FAP) is associated with a number of extraintestinal manifestations, which include osteomas, epidermoid cysts, and desmoid tumors, often referred to as {open_quotes}Gardner syndrome.{close_quotes} Recent studies have suggested that some of the phenotypic features of FAP are dependent on the position of the mutation within the APC gene. In particular, the correlation between congenital hypertrophy of the retinal pigment epithelium (CHRPE) and APC genotype indicates that affected families may be divided into distinct groups. We have investigated the association between the dento-osseous features of GS on dental panoramic radiographs (DPRs) and APC genotype in a regional cohort ofmore » FAP families. DPRs were performed on 84 affected individuals from 36 families, and the dento-osseous features of FAP were quantified by a weighted scoring system. Significant DPR abnormalities were present in 69% of affected individuals. The APC gene mutation was identified in 27 of these families, and for statistical analysis these were subdivided into three groups. Group 1 comprised 18 affected individuals from seven families with mutations 5{prime} of exon 9; these families (except one) did not express CHRPE. Groups 2 comprised 38 individuals from 16 families with mutations between exon 9 and codon 1444, all of whom expressed CHRPE. Group 3 comprised 11 individuals from four families with mutations 3{prime} of codon 1444, none of whom expressed CHRPE. Families with mutations 3{prime} of codon 1444 had significantly more lesions on DPRs (P < .001) and appeared to have a higher incidence of desmoid tumors. These results suggest that severity of some of the features of Gardner syndrome may correlate with genotype in FAP. 32 refs., 2 figs., 2 tabs.« less

Polyphyllin I inhibits gastric cancer cell proliferation by downregulating the expression of fibroblast activation protein alpha (FAP) and hepatocyte growth factor (HGF) in cancer-associated fibroblasts.

PubMed

Dong, Ruizeng; Guo, Jianmin; Zhang, Zewei; Zhou, Yimin; Hua, Yonghong

2018-03-18

The aim of this study was to identify the anti-cancer mechanism of Polyphyllin I (PPI) on gastric cancer cells via its activity on cancer-associated fibroblasts (CAFs). We cultured purified gastric CAFs obtained from fresh human gastric cancer tissue and examined the effect of Polyphyllin I on CAF proliferation using a colorimetric viability assay. In addition, we established a nude mouse xenograft model to examine the effect of Polyphyllin I administration on tumorigenesis. Using Western analysis, we quantified protein expression of the CAF-derived cytokines fibroblast activation protein alpha (FAP), secreted protein acidic and cysteine rich (SPARC), stromal cell-derived factor 1 (SDF-1), hepatocyte growth factor tenascin-C (TNC), and hepatocyte growth factor (HGF) in both in vitro and in vivo models. We found that Polyphyllin I inhibits the proliferation of CAFs in a concentration-dependent manner. Following treatment with 2 μg/ml PPI for 24 h in vitro, the expression of FAP, SDF-1 and HGF protein in CAFs was significantly lower than that in the control group, but there was no significant difference in SPARC and TNC protein expression between the two groups. In the nude mouse xenograft model, the tumor inhibition rate was 45.5% when PPI was administered early and 29.4% with administration in the third week. The expression of FAP and HGF in the xenografts was significantly decreased, while the expression of SPARC, SDF-1, and TNC was largely unaltered. Altogether, these data suggest that Polyphyllin I can inhibit the proliferation of gastric cancer cells by downregulating the expression of FAP and HGF in CAFs in vivo. Copyright © 2018 Elsevier Inc. All rights reserved.

Tagging of Endogenous BK Channels with a Fluorogen-Activating Peptide Reveals β4-Mediated Control of Channel Clustering in Cerebellum

PubMed Central

Pratt, Christopher P.; Kuljis, Dika A.; Homanics, Gregg E.; He, Jianjun; Kolodieznyi, Dmytro; Dudem, Srikanth; Hollywood, Mark A.; Barth, Alison L.; Bruchez, Marcel P.

2017-01-01

BK channels are critical regulators of neuronal activity, controlling firing, neurotransmitter release, cerebellar function, and BK channel mutations have been linked to seizure disorders. Modulation of BK channel gating is well characterized, regulated by accessory subunit interactions, intracellular signaling pathways, and membrane potential. In contrast, the role of intracellular trafficking mechanisms in controlling BK channel function, especially in live cells, has been less studied. Fluorogen-activating peptides (FAPs) are well-suited for trafficking and physiological studies due to the binding of malachite green (MG)-based dyes with sub-nanomolar affinity to the FAP, resulting in bright, photostable, far-red fluorescence. Cell-excluded MG dyes enable the selective tagging of surface protein and tracking through endocytic pathways. We used CRISPR to insert the FAP at the extracellular N-terminus of BKα in the first exon of its native locus, enabling regulation by the native promoter elements and tag incorporation into multiple splice isoforms. Motor coordination was found to be normal; however, BK channel expression seems to be reduced in some locations. Alternate start site selection or post-translational proteolytic processing resulted in incomplete FAP tagging of the BKα proteins in brain tissues. In Purkinje cell somata, FAP revealed BK channel clustering previously only observed by electron microscopy. Measurement of these clusters in β4+/- and β4-/- mice showed that puncta number and cluster fluorescence intensity on the soma are reduced in β4-/- knockout animals. This novel mouse line provides a versatile fluorescent platform for studying endogenous BK channels in living and fixed tissues. Future studies could apply this line to ex vivo neuronal cultures to study live-cell channel trafficking. PMID:29163049

Long-term outcome of sporadic and FAP-associated desmoid tumors treated with high-dose selective estrogen receptor modulators and sulindac: a single-center long-term observational study in 134 patients.

PubMed

Quast, Daniel Robert; Schneider, Ralph; Burdzik, Emanuel; Hoppe, Steffen; Möslein, Gabriela

2016-01-01

Aim of this study is to evaluate the outcome of long-term conservative treatment with sulindac and high-dose selective estrogen receptor modulators (SERMs) for sporadic and FAP-associated desmoid tumors. Desmoids are very rare tumors in the general population but occur frequently in FAP patients, being encountered in 23-38 %. Treatment of desmoids is still most controversial since response cannot be predicted and they are prone to develop recurrence. This study included all desmoid patients that were treated and followed at our institution and had completed at least 1 year of treatment. Response was defined as stable size or regression of desmoid size between two CT or MRI scans. A total of 134 patients were included. 64 (47.8 %) patients had a confirmed diagnosis of FAP, 69 (51.5 %) patients were sporadic. Overall 114 (85.1 %) patients showed regressive or stable desmoid size. Patients with previous history of multiple desmoid-related surgeries showed less-favorable response. The mean time to reach at least stable size was 14.9 (±9.1) months. After regression or stabilization, medication was tapered in 69 (60.5 %) of the treated patients with only one long-term recurrence after >10 years. The results of this study fortify the role of sulindac and high-dose SERMs as an effective and safe treatment for both, sporadic and FAP-associated desmoid tumors. While invasive treatment frequently results in high recurrence rates, high morbidity and high mortality, this conservative treatment is successful in most patients. The recurrence rate is negligible with no desmoid-related mortality in this large series. Therefore surgical resection, especially for mesenteric desmoids, should be deferred favoring this convincingly effective, well tolerated regimen.

14 CFR 1203b.109 - Disclaimer.

Code of Federal Regulations, 2013 CFR

2013-01-01

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14 CFR 1203b.109 - Disclaimer.

Code of Federal Regulations, 2011 CFR

2011-01-01

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14 CFR 1203b.109 - Disclaimer.

Code of Federal Regulations, 2010 CFR

2010-01-01

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14 CFR 1203b.109 - Disclaimer.

Code of Federal Regulations, 2012 CFR

2012-01-01

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Gastrointestinal (GI) permeability correlates with trait anxiety and urinary norepinephrine/creatinine (CR)ratio in children with functional abdominal pain (FAP)and irritable bowel syndrome (IBS) but not in controls

USDA-ARS?s Scientific Manuscript database

FAP and IBS affect 10–15% of school age children and bear many similarities to irritable bowel syndrome (IBS) in adults (e.g., functional pain, visceral hyperalgesia). Animal models of IBS have suggested a relationship between neonatal stress/anxiety and increased GI permeability later in life. We h...

Glucose induces delocalization of a flagellar biosynthesis protein from the flagellated pole.

PubMed

Park, Soyoung; Park, Young-Ha; Lee, Chang-Ro; Kim, Yeon-Ran; Seok, Yeong-Jae

2016-09-01

To survive in a continuously changing environment, bacteria sense concentration gradients of attractants or repellents, and purposefully migrate until a more favourable habitat is encountered. While glucose is known as the most effective attractant, the flagellar biosynthesis and hence chemotactic motility has been known to be repressed by glucose in some bacteria. To date, the only known regulatory mechanism of the repression of flagellar synthesis by glucose is via downregulation of the cAMP level, as shown in a few members of the family Enterobacteriaceae. Here we show that, in Vibrio vulnificus, the glucose-mediated inhibition of flagellar motility operates by a completely different mechanism. In the presence of glucose, EIIA(Glc) is dephosphorylated and inhibits the polar localization of FapA (flagellar assembly protein A) by sequestering it from the flagellated pole. A loss or delocalization of FapA results in a complete failure of the flagellar biosynthesis and motility. However, when glucose is depleted, EIIA(Glc) is phosphorylated and releases FapA such that free FapA can be localized back to the pole and trigger flagellation. Together, these data provide new insight into a bacterial strategy to reach and stay in the glucose-rich area. © 2016 John Wiley & Sons Ltd.

A case of carcinoma of the papilla of Vater in a young man after subtotal colectomy for familial adenomatous polyposis.

PubMed

Komori, Shuji; Kawai, Masahiko; Nitta, Toyoo; Murase, Yusuke; Matsumoto, Keita; Shinoda, Chika; Kuno, Masashi; Sasaguri, Yuki; Fukada, Masahiro; Asano, Yoshimi; Kiyama, Shigeru; Tanaka, Chihiro; Nagao, Yasuko; Nagao, Narutoshi; Kunieda, Katsuyuki

2016-02-24

Carcinoma and adenoma of the duodenum, including the papilla of Vater, are problematic diseases in patients with familial adenomatous polyposis (FAP). A 36-year-old man underwent a periodic medical examination for early colon cancer originating from FAP for which laparoscopic-assisted subtotal colectomy with a J-shaped ileal pouch-rectal anastomosis was performed 3 years earlier. A tumor was detected at the papilla of Vater along with elevation of total bilirubin and hepatobiliary enzymes. Although cytology did not determine the tumor to be an adenocarcinoma, we suspected adenocarcinoma due to its hypervascularity shown by contrast-enhanced computed tomography. Pylorus-preserving pancreaticoduodenectomy with modified Imanaga reconstruction and regional lymph node dissection (D2) was performed. The pathological study showed that the tumor was a papillary and moderately differentiated tubular adenocarcinoma. The patient is currently in good health without recurrence, weight loss, or severe diarrhea at 12 months after surgery. Awareness of biliary-pancreatic symptoms and periodic gastroduodenoscopy might contribute both to the early detection of duodenal or periampullary polyps and cancer and to the radical treatment of FAP. Modified Imanaga reconstruction has the potential to become one of the more effective procedures for providing good quality of life to FAP patients with duodenal or periampullary cancer.

Preliminary data from a randomized pilot study of web-based functional analytic psychotherapy therapist training.

PubMed

Kanter, Jonathan W; Tsai, Mavis; Holman, Gareth; Koerner, Kelly

2013-06-01

Therapists of many persuasions emphasize the therapy relationship in their work, a priority backed by strong empirical evidence. Training in how to maximize the power and potential of the therapy relationship, however, has lagged behind. A novel approach to using the therapy relationship and to training therapists in its use is provided by Functional Analytic Psychotherapy (FAP). FAP training involves eight 2-hr weekly training sessions conducted online using web-conferencing technology. The training integrates behavioral principles with a focus on trainee-trainer and trainee-trainee relationships in a highly structured course that evokes the desirable FAP therapist-trainee behaviors and collectively shapes the behaviors through reinforcement by the trainer and other trainees. In a preliminary study, 16 therapist-trainees were randomly assigned to receive either immediate FAP training or training after a waitlist period. Significant and large effects of training were found on both self-reported and observer-assessed measures for the first training group, and the waitlist training group replicated the first training group with significant within-subject change over the course of training. Finally, qualitative feedback from therapists indicated high satisfaction with the primary elements of the training protocol. Several important limitations to this preliminary study are discussed.

Effects of elevated atmospheric CO2 on dissolution of geological fluorapatite in water and soil.

PubMed

Li, Zhen; Su, Mu; Tian, Da; Tang, Lingyi; Zhang, Lin; Zheng, Yangfan; Hu, Shuijin

2017-12-01

Most of phosphorus (P) is present as insoluble phosphorus-bearing minerals or organic forms in soil. Geological fluorapatite (FAp) is the dominant mineral-weathering source of P. In this study, FAp was added into water and soil under elevated CO 2 to investigate the pathway of P release. Two types of soils (an acidic soil from subtropical China and a saline-alkali soil from Tibet Plateau, China) with similar total P content were studied. In the solution, increased CO 2 in air enhanced the dissolution of FAp, i.e., from 0.04 to 1.18ppm for P and from 2.48 to 13.61ppm for Ca. In addition, release of Ca and P from FAp reached the maximum (2.14ppm for P and 13.84ppm for Ca) under the combination of elevated CO 2 and NaCl due to the increasing ion exchange. Consistent with the results from the solution, CO 2 elevation promoted P release more significantly (triple) in the saline-alkali soil than in the acidic soil. Therefore, saline-alkali soils in Tibet Plateau would be an important reservoir of available P under the global CO 2 rise. This study sheds the light on understanding the geological cycle of phosphorus. Copyright © 2017. Published by Elsevier B.V.

Genetic Counselor Practices Involving Pediatric Patients with FAP: an Investigation of their Self-Reported Strategies for Genetic Testing and Hepatoblastoma Screening.

PubMed

Lawson, Caitlin E; Attard, Thomas M; Dai, Hongying; Septer, Seth

2017-06-01

Familial adenomatous polyposis (FAP) is a cancer predisposition syndrome that causes early-onset polyposis and is associated with an increased risk for hepatoblastoma. There is currently a lack of consensus on when to order APC (adenomatous polyposis coli) gene testing or implement surveillance for hepatoblastoma. An online questionnaire was completed by 62 genetic counselors to capture their current practices regarding these questions. Extracolonic findings associated with FAP that were most likely to prompt APC testing in an otherwise asymptomatic 10 year-old child with a negative family history were multiple desmoid tumors, congenital hypertrophy of the retinal pigment epithelium (CHRPE), jaw osteomas, and hepatoblastoma. For hepatoblastoma screening, the majority did recommend this in children less than age five years with known APC mutations. An interval of every 3-6 months was most commonly suggested; however, responses extended to screening on a less than annual basis. These results highlight the need for further investigation into why some genetic counselors do not recommend APC testing in young at-risk children and what factors influence views about the ideal age and indication for APC testing. Studies of these issues would help to define the best clinical practice model for genetic testing and hepatoblastoma screening in pediatric patients with FAP.

Saying good goodbyes to your clients: A functional analytic psychotherapy (FAP) perspective.

PubMed

Tsai, Mavis; Gustafsson, Tore; Kanter, Jonathan; Plummer Loudon, Mary; Kohlenberg, Robert J

2017-03-01

Functional analytic psychotherapy (FAP) promotes client growth by shaping clients' daily life problems that also show up in session with their therapists. FAP therapists create evocative contexts within therapy that afford clients the opportunity to practice, refine, and be reinforced for new, more adaptive behaviors which then can be generalized into their outside lives. In FAP, the termination process will vary from client to client depending on the nature of the client's problems and targets. For many clients, the process can be a rich, multifaceted, final opportunity to evoke, reinforce, and promote generalization of clients' in-session improvements, particularly improvements related to vulnerable self-expression in the service of intimate and close relationships. By making explicit agreements at the outset of therapy to participate in an intentional termination process, and by later providing an evocative structure for ending therapy with vulnerable emotional expression, clients have the opportunity to develop more adaptive behaviors in the context of relationship endings which can be a painful part of the human experience. Equipped with the skills of open-hearted communication developed from an authentic relationship with their therapist, clients can leave therapy on a trajectory of further growth in interpersonal connection and living more boldly. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

14 CFR 91.25 - Aviation Safety Reporting Program: Prohibition against use of reports for enforcement purposes.

Code of Federal Regulations, 2010 CFR

2010-01-01

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Aeronautics and Space Report of the President: Fiscal Year 2005 Activities

NASA Technical Reports Server (NTRS)

2007-01-01

The National Aeronautics and Space Act of 1958 directed the annual Aeronautics and Space Report to include a "comprehensive description of the programmed activities and the accomplishments of all agencies of the United States in the field of aeronautics and space activities during the preceding calendar year." In recent years, the reports have been prepared on a fiscal-year basis, consistent with the budgetary period now used in programs of the Federal Government. This year's report covers activities that took place from October 1 , 2004, through September 30, 2005.

Aeronautics and Space Report of the President: Fiscal Year 2001 Activities

NASA Technical Reports Server (NTRS)

2001-01-01

The National Aeronautics and Space Act of 1958 directed the annual Aeronautics and Space Report to include a 'comprehensive description of the programmed activities and the accomplishments of all agencies of the United States in the field of aeronautics and space activities during the preceding calendar year.' In recent years the reports have been prepared on a fiscal-year basis consistent with the budgetary period now used in programs of the Federal Government. This year's report covers activities that took place from October 1, 2000, through September 30, 2001.

Aeronautics and Space Report of the President: Fiscal Year 1999 Activities

NASA Technical Reports Server (NTRS)

1999-01-01

The National Aeronautics and Space Act of 1958 directed the annual Aeronautics and Space Report to include a "comprehensive description of the programmed activities and the accomplishments of all agencies of the United States in the field of aeronautics and space activities during the preceding calendar year." In recent years, the reports have been prepared on a fiscal year basis, consistent with the budgetary period now used in programs of the Federal Government. This year's report covers activities that took place from October 1, 1998, through September 30, 1999.

Aeronautics and Space Report of the President: Fiscal Year 2003 Activities

NASA Technical Reports Server (NTRS)

2003-01-01

The National Aeronautics and Space Act of 1958 directed the annual Aeronautics and Space Report to include a comprehensive description of the programmed activities and the accomplishments of all agencies of the United States in the field of aeronautics and space activities during the preceding calendar year. In recent years, the reports have been prepared on a fiscal-year basis, consistent with the budgetary period now used in programs of the Federal Government. This year's report covers activities that took place from October 1, 2002, through September 30, 2003.

Aeronautics and Space Report of the President: Fiscal Year 2000 Activities

NASA Technical Reports Server (NTRS)

2000-01-01

The National Aeronautics and Space Act of 1958 directed the annual Aeronautics and Space Report to include a "comprehensive description of the programmed activities and the accomplishments of all agencies of the United States in the field of aeronautics and space activities during the preceding calendar year." In recent years, the reports have been prepared on a fiscal year basis, consistent with the budgetary period now used in programs of the Federal Government. This year's report covers activities that took place from October 1, 1999, through September 30, 2000.

Aeronautics and Space Report of the President: Fiscal Year 2007 Activities

NASA Technical Reports Server (NTRS)

2009-01-01

The National Aeronautics and Space Act of 1958 directed the annual Aeronautics and Space Report to include a "comprehensive description of the programmed activities and the accomplishments of all agencies of the United States in the field of aeronautics and space activities during the preceding calendar year." In recent years, the reports have been prepared on a fiscal-year basis, consistent with the budgetary period now used in programs of the Federal Government. This year's report covers activities that took place from October 1, 2006, through September 30, 2007.

Aeronautics and Space Report of the President - Fiscal Year 2008 Activities

NASA Technical Reports Server (NTRS)

2009-01-01

The National Aeronautics and Space Act of 1958 directed the annual Aeronautics and Space Report to include a "comprehensive description of the programmed activities and the accomplishments of all agencies of the United States in the field of aeronautics and space activities during the preceding calendar year." In recent years, the reports have been prepared on a fiscal-year basis, consistent with the budgetary period now used in programs of the Federal Government. This year's report covers activities that took place from October 1, 2007, through September 30, 2008.

Aeronautics and Space Report of the President - Fiscal Year 2010 Activities

NASA Technical Reports Server (NTRS)

2011-01-01

The National Aeronautics and Space Act of 1958 directed the annual Aeronautics and Space Report to include a "comprehensive description of the programmed activities and the accomplishments of all agencies of the United States in the field of aeronautics and space activities during the preceding calendar year." In recent years, the reports have been prepared on a fiscal-year basis, consistent with the budgetary period now used in programs of the Federal Government. This year's report covers activities that took place from October 1, 2009, through September 30, 2010.

Aeronautics and space report of the President: 1981 activities

NASA Technical Reports Server (NTRS)

1981-01-01

Achievements in the aeronautics and space program by function are summarized. Activities in communications, Earth's resources and environment, space science, space transportation, international activities, and aeronautics are included.

14 CFR 1203.409 - Exceptional cases.

Code of Federal Regulations, 2010 CFR

2010-01-01

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14 CFR 1203.300 - General.

Code of Federal Regulations, 2013 CFR

2013-01-01

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NASA LANGLEY RESEARCH CENTER AND THE TIDEWATER INTERAGENCY POLLUTION PREVENTION PROGRAM

EPA Science Inventory

National Aeronautics and Space Administration (NASA)'s Langley Research Center (LaRC) is an 807-acre research center devoted to aeronautics and space research. aRC has initiated a broad-based pollution prevention program guided by a Pollution Prevention Program Plan and implement...

FY 1978 aeronautics and space technology program summary

NASA Technical Reports Server (NTRS)

1977-01-01

Highlights of the aeronautics program include research on aircraft energy efficiency, supersonic cruise aircraft, vertical takeoff and landing aircraft, short haul/short takeoff and landing aircraft, and general aviation aircraft. The space technology program includes work on space structures, propulsion systems, power systems, materials, and electronics.

14 CFR § 1203b.109 - Disclaimer.

Code of Federal Regulations, 2014 CFR

2014-01-01

... otherwise lawful activities of security force personnel or the National Aeronautics and Space Administration... 14 Aeronautics and Space 5 2014-01-01 2014-01-01 false Disclaimer. § 1203b.109 Section § 1203b.109 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION SECURITY PROGRAMS; ARREST...

Project Mercury: Man-In-Space Program of the National Aeronautics and Space Administration. [Report of the Committee on Aeronautical and Space Sciences United States Senate

NASA Technical Reports Server (NTRS)

1959-01-01

The purpose of this staff study, made at the request of the chairman, is to serve members of the Committee on Aeronautical and Space Sciences as a source of basic information on Project Mercury, the man-in-space program of the National Aeronautics and Space Administration. The study is largely derived from unclassified information released by the National Aeronautics and Space Administration and testimony concerning Project Mercury given during hearings before this committee. The program descriptions are based upon current program planning. Since this is a highly advanced research and development program, the project is obviously subject to changes that may result from future developments and accomplishments characteristic of such research activities. Certain information with respect to revised schedules, obtained on a classified basis by the committee during inspection trips, is necessarily omitted. The appendixes to the study include information that may prove helpful on various aspects of space flight and exploration. Included are unofficial comments and observations relating to Russia's manned space flight activities and also a complete chronology of all satellites, lunar probes, and space probes up to the present.

National Aeronautics and Space Administration technology application team program

NASA Technical Reports Server (NTRS)

1972-01-01

Contracts are reported between the RTI TATeam and the National Aeronautics and Space Administration (NASA), the Environmental Protection Agency (EPA), and other governmental, educational, and industrial organizations participating in NASA's Technology Utilization Program.

14 CFR 1203.703 - Declassification.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM Foreign Government Information § 1203.703 Declassification. (a) Information classified in accordance with § 1203.400.... The Chairperson, NASA Information Security Program Committee, will initiate administrative functions...

14 CFR 1203.703 - Declassification.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM Foreign Government Information § 1203.703 Declassification. (a) Information classified in accordance with § 1203.400.... The Chairperson, NASA Information Security Program Committee, will initiate administrative functions...

Fibroblast Activation Protein-Alpha, a Serine protease that Facilitates Metastasis by Modification of Diverse Microenvironments

DTIC Science & Technology

2009-10-01

pyrrolidine (LAF-237, vildagliptin ). Both boroPro compounds are effective against FAP at nanomolar concentrations; however, micromolar LAF-237 is...dependent insulinotropic polypeptide (GIP) that are substrates for DPPIV. NVP LAF-237 or vildagliptin is one of the DPPIV inhibitors approved for type 2...peptide truncation by Tumor growth is promoted by catalytically-inactive FAP 24 Vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl

Illness representations, knowledge and motivation to perform presymptomatic testing for late-onset genetic diseases.

PubMed

Leite, Ângela; Dinis, Maria Alzira P; Sequeiros, Jorge; Paúl, Constança

2017-02-01

This study addresses the relation between illness representations, knowledge and motivation to perform the presymptomatic testing (PST) of subjects at-risk for Familial Amyloydotic Polyneuropathy (FAP), Huntington's disease (HD) and Machado-Joseph disease (MJD), compared with subjects at-risk for Hereditary Hemochromatosis (HH). The sample comprised a clinical group of 213 subjects at genetic risk for FAP, HD and MJD, and a comparison group of 31 subjects at genetic risk for HH, that answered three open-ended questions relating illness representations, knowledge about the disease, and motivation to perform PST. People at-risk for FAP, HD and MJD use more metaphors, make more references to the family, are more concerned with the future and feel more out of curiosity and to learn, than for HH. These subjects at-risk correspond to the profile of somatic individual or personhood, wherein the unsubjectivation of the disease can function as a coping mechanism.

Laser-induced atomic assembling of periodic layered nanostructures of silver nanoparticles in fluoro-polymer film matrix

NASA Astrophysics Data System (ADS)

Bagratashvili, V. N.; Rybaltovsky, A. O.; Minaev, N. V.; Timashev, P. S.; Firsov, V. V.; Yusupov, V. I.

2010-05-01

Fluorinated acrylic polymer (FAP) films have been impregnated with silver precursor (Ag(hfac)COD) by supercritical fluid technique and next irradiated with laser (λ = 532 nm). Laser-chemically reduced Ag atoms have been assembled into massifs of Ag nanoparticles (3 - 8 nm) in FAP/Ag(hfac)COD films matrix in the form of periodic layered nanostructures (horizontal to film surface) with unexpectedly short period (90 - 180 nm). The wavelet analysis of TEM images reveals the existence of even shorter-period structures in such films. Photolysis with non-coherent light or pyrolysis of FAP/Ag(hfac)COD film results in formation of Ag nanoparticles massifs but free of any periodic nanoparticle assemblies. Our interpretation of the observed effect of laser formation of short-period nano-sized Ag nanoparticle assemblies is based on self-enhanced interference process in the course of modification of optical properties of film.

Radioimmunoassay for detecting abnormal prealbumin in the serum for diagnosis of familial amyloidotic polyneuropathy (Japanese type)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakazato, M.; Kangawa, K.; Minamino, N.

In the serum of a Japanese patient with familial amyloidotic polyneuropathy (FAP), we demonstrated the presence of a prealbumin variant using a single amino acid substitution of a methionine residue for a valine at position 30. We have developed a highly sensitive and specific method for quantitative analysis of the prealbumin variant in the sera of FAP patients by using radioimmunoassay for a nonapeptide corresponding to subsequence (22-30) of the prealbumin variant. This peptide is produced from the prealbumin variant by cyanogen bromide cleavage followed by tryptic digestion. The serum administration of the prealbumin variant in five Japanese FAP patientsmore » ranges from 1.0 mg/dl to 7.8 mg/dl, which is 100 times or even higher than normal animals. This method should be helpful for an early diagnosis of this hereditary disease. 6 references, 4 figures, 1 table.« less

Funding and Strategic Alignment Guidance for Infusing Small Business Innovation Research Technology into NASA Programs Associated with the Aeronautics Research Mission Directorate

NASA Technical Reports Server (NTRS)

Nguyen, Hung D.; Steele, Gynelle C.

2015-01-01

This report is intended to help NASA program and project managers incorporate Small Business Innovation Research/Small Business Technology Transfer (SBIR/STTR) technologies that have gone through Phase II of the SBIR program into NASA Aeronautics and Mission Directorate (ARMD) programs. Other Government and commercial program managers can also find this information useful.

14 CFR 1203.202 - Responsibilities.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program § 1203.202 Responsibilities. (a) The Chairperson, NASA Information Security...) Ensuring effective compliance with and implementation of “the Order” and the Information Security Oversight...

14 CFR 1203.202 - Responsibilities.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program § 1203.202 Responsibilities. (a) The Chairperson, NASA Information Security...) Ensuring effective compliance with and implementation of “the Order” and the Information Security Oversight...

78 FR 34408 - Notice of Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-07

... United States Space Exploration programs. In evaluating an applicant for the Astronaut Candidate Program... NATIONAL AERONAUTICS AND SPACE ADMINISTRATION [Notice: (13-063)] Notice of Information Collection AGENCY: National Aeronautics and Space Administration (NASA). ACTION: Notice of information collection...

14 CFR § 1203.300 - General.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 5 2014-01-01 2014-01-01 false General. § 1203.300 Section § 1203.300 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM... research, technology or operations. ...

Development of trivalent ytterbium doped fluorapatites for diode-pumped laser applications

NASA Astrophysics Data System (ADS)

Bayramian, Andrew James

2000-11-01

A major motivator of this work is the Mercury Project, a one kilowatt diode-pumped solid-state laser system under development at Lawrence Livermore National Laboratory (LLNL), which incorporates ytterbium doped strontium fluorapatite, Sr5(PO4)3F (S-FAP), as the amplifier gain medium. The primary focus of this thesis is a full understanding of the properties of this material, which is necessary for proper design and modeling of the system. Ytterbium-doped fluorapatites were investigated at LLNL prior to this work and found to be ideal candidate materials for high-power amplifier systems providing high absorption and emission cross sections, long radiative lifetimes, and high efficiency. A family of barium substituted S-FAP crystals was grown in an effort to modify the pump and emission bandwidths for application to broadband diode pumping and short pulse generation. Crystals of Yb 3+:Srs5-xBax(PO4) 3F where x < 1 showed homogeneous lines offering 8.4 nm (1.8X enhancement) of absorption bandwidth and 6.9 nm (1.4X enhancement) of emission bandwidth. The gain saturation fluence of Yb:S-FAP was measured to be 3.2 J/cm 2 with homogeneous extraction using a pump-probe experiment where the probe laser was a high intensity Q-switched master oscillator power amplifier system. The crystal quality of Czochralski grown Yb:S-FAP boules, which is effected by defects such as cracking, cloudiness, bubble core, slip dislocations, and anomalous absorption, was investigated interferometrically and quantified by means of Power Spectral Density (PSD) plots. Stimulated Raman Scattering (SRS) losses were evaluated by first measuring the SRS gain coefficient to be 1.3 cm/GW, then modeling the losses in the Mercury amplifier system. Countermeasures including the addition of bandwidth to the extraction beam and wedging of amplifier surfaces are shown to reduce the SRS losses allowing efficient laser gain extraction at higher intensities. Finally, an efficient Q-switched Yb:S-FAP oscillator was developed which operates three-level at 985 nm with a 21% slope efficiency. Frequency conversion of the 985 nm light to the 2nd harmonic at 492.5 nm was achieved with a 31% conversion efficiency. A diode pumped, doubled Yb:S-FAP laser at 492.5 nm would make possible a compact, efficient, high-power blue laser source.

Tectonic control on sediment accretion and subduction off south central Chile: Implications for coseismic rupture processes of the 1960 and 2010 megathrust earthquakes

NASA Astrophysics Data System (ADS)

Contreras-Reyes, Eduardo; Flueh, Ernst R.; Grevemeyer, Ingo

2010-12-01

Based on a compilation of published and new seismic refraction and multichannel seismic reflection data along the south central Chile margin (33°-46°S), we study the processes of sediment accretion and subduction and their implications on megathrust seismicity. In terms of the frontal accretionary prism (FAP) size, the marine south central Chile fore arc can be divided in two main segments: (1) the Maule segment (south of the Juan Fernández Ridge and north of the Mocha block) characterized by a relative large FAP (20-40 km wide) and (2) the Chiloé segment (south of the Mocha block and north of the Nazca-Antarctic-South America plates junction) characterized by a small FAP (≤10 km wide). In addition, the Maule and Chiloé segments correlate with a thin (<1 km thick) and thick (˜1.5 km thick) subduction channel, respectively. The Mocha block lies between ˜37.5° and 40°S and is configured by the Chile trench, Mocha and Valdivia fracture zones. This region separates young (0-25 Ma) oceanic lithosphere in the south from old (30-35 Ma) oceanic lithosphere in the north, and it represents a fundamental tectonic boundary separating two different styles of sediment accretion and subduction, respectively. A process responsible for this segmentation could be related to differences in initial angles of subduction which in turn depend on the amplitude of the down-deflected oceanic lithosphere under trench sediment loading. On the other hand, a small FAP along the Chiloé segment is coincident with the rupture area of the trans-Pacific tsunamigenic 1960 earthquake (Mw = 9.5), while a relatively large FAP along the Maule segment is coincident with the rupture area of the 2010 earthquake (Mw = 8.8). Differences in earthquake and tsunami magnitudes between these events can be explained in terms of the FAP size along the Chiloé and Maule segments that control the location of the updip limit of the seismogenic zone. The rupture area of the 1960 event also correlates with a thick subduction channel (Chiloé segment) that may provide enough smoothness at the subduction interface allowing long lateral earthquake rupture propagation.

Model for the design of distributed data bases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ram, S.

This research focuses on developing a model to solve the File Allocation Problem (FAP). The model integrates two major design issues, namely Concurrently Control and Data Distribution. The central node locking mechanism is incorporated in developing a nonlinear integer programming model. Two solution algorithms are proposed, one of which was implemented in FORTRAN.V. The allocation of data bases and programs are examined using this heuristic. Several decision rules were also formulated based on the results of the heuristic. A second more comprehensive heuristic was proposed, based on the knapsack problem. The development and implementation of this algorithm has been leftmore » as a topic for future research.« less

Development of Trivalent Ytterbium Doped Fluorapatites for Diode-Pumped Laser Applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bayramian, Andrew J.

One of the major motivators of this work is the Mercury Project, which is a 1 kW scalable diode-pumped solid-state laser system under development at Lawrence Livermore National Laboratory (LLNL). Major goals include 100 J pulses, 10% wallplug efficiency, 10 Hz repetition rate, and a 5 times diffraction limited beam. To achieve these goals the Mercury laser incorporates ytterbium doped Sr 5(PO 4) 3F (S-FAP) as the amplifier gain medium. The primary focus of this thesis is a full understanding of the properties of this material which are necessary for proper design and modeling of the system. Ytterbium doped fluorapatites,more » which were previously investigated at LLNL, were found to be ideal candidate materials for a high power amplifier systems providing high absorption and emission cross sections, long radiative lifetimes, and high efficiency. A family of barium substituted S-FAP crystals were grown in an effort to modify the pump and emission bandwidths for application to broadband diode pumping and short pulse generation. Crystals of Yb 3+:Sr 5-xBa x(PO 4) 3F where x < 1 showed homogeneous lines offering 8.4 nm (1.8 times enhancement) of absorption bandwidth and 6.9 nm (1.4 times enhancement) of emission bandwidth. The gain saturation fluence of Yb:S-FAP was measured to be 3.2 J/cm 2 using a pump-probe experiment where the probe laser was a high intensity Q-switched master oscillator power amplifier system. The extraction data was successfully fit to a homogeneous extraction model. The crystal quality of Czochralski grown Yb:S-FAP crystals, which have been plagued by many defects such as cracking, cloudiness, bubble core, slip dislocations, and anomalous absorption, was investigated interferometrically and quantified by means of Power Spectral Density (PSD) plots. The very best crystals grown to date were found to have adequate crystal quality for use in the Mercury laser system. In addition to phase distortions which are fixed by material growth, thermal loading of the S-FAP media also leads to distortions due to thermal expansion, α, temperature dependent refractive index, ∂n/∂T, and stress optic effects. The stress optic coefficients necessary for modeling thermal distortions in Yb:S-FAP slab amplifiers were measured giving q 33 = 0.308 x 10 -12 Pa -1, and q 31 = 0.936 x 10 -12 Pa -1. Nonlinear optical losses due to high intensity laser interaction with S-FAP were evaluated including Stimulated Raman Scattering (SRS) and Stimulated Brillouin Scattering. The SRS gain coefficient was measured to be 1.3 cm/GW. The SRS losses in the Mercury amplifier system were successfully modeled and shown to be an issue for high-energy short pulse operation. Countermeasures including the addition of bandwidth to the extraction beam and wedging of amplifier surfaces would allow operation of the Mercury laser at 100 J and 2 ns output below SRS threshold. A simple model of SBS losses in the Mercury laser system shows SBS will also be a problem, however suppression is possible with the introduction of moderate bandwidth (relative to the SRS case). Finally, a Q-switched Yb:S-FAP oscillator was developed which operates three-level at 985 nm with a 21% slope efficiency. Frequency conversion of the 985 nm light to the 2nd harmonic at 492.5 nm was achieved with a 31% conversion efficiency. A diode pumped, doubled Yb:S-FAP laser at 492.5 nm would make a compact efficient blue laser source.« less

14 CFR 1203.602 - Authorization.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM Declassification and Downgrading § 1203.602 Authorization. Information shall be declassified or downgraded by the... writing by the Administrator or the Chairperson, NASA Information Security Program Committee. [48 FR 5891...

14 CFR 1203.602 - Authorization.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM Declassification and Downgrading § 1203.602 Authorization. Information shall be declassified or downgraded by the... writing by the Administrator or the Chairperson, NASA Information Security Program Committee. [48 FR 5891...

NASA aeronautics

NASA Technical Reports Server (NTRS)

Anderton, D. A.

1982-01-01

Aeronautical research programs are discussed in relation to research methods and the status of the programs. The energy efficient aircraft, STOL aircraft and general aviation aircraft are considered. Aerodynamic concepts, rotary wing aircraft, aircraft safety, noise reduction, and aircraft configurations are among the topics included.

Gene therapy approach to FAP: in vivo influence of T119M in TTR deposition in a transgenic V30M mouse model.

PubMed

Batista, A R; Gianni, D; Ventosa, M; Coelho, A V; Almeida, M R; Sena-Esteves, M; Saraiva, M J

2014-12-01

Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by extracellular deposition of amyloid fibrils composed by mutated transthyretin (TTR) mainly in the peripheral nervous system. At present, liver transplantation is still the standard treatment to halt the progression of clinical symptoms in FAP, but new therapeutic strategies are emerging, including the use of TTR stabilizers. Here we propose to establish a new gene therapy approach using adeno-associated virus (AAV) vectors to deliver the trans-suppressor TTR T119M variant to the liver of transgenic TTR V30M mice at different ages. This TTR variant is known for its ability to stabilize the tetrameric protein. Analysis of the gastrointestinal tract of AAV-treated animals revealed a significant reduction in deposition of TTR non-fibrillar aggregates in as much as 34% in stomach and 30% in colon, as well as decreased levels of biomarkers associated with TTR deposition, namely the endoplasmic reticulum stress marker BiP and the extracellular matrix protein MMP-9. Moreover, we showed with different studies that our approach leads to an increase in tetrameric and more stable forms of TTR, in favor of destabilized monomers. Altogether our data suggest the possibility to use this gene therapy approach in a prophylactic manner to prevent FAP pathology.

Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis.

PubMed

Yamaguchi, Kiyoshi; Nagayama, Satoshi; Shimizu, Eigo; Komura, Mitsuhiro; Yamaguchi, Rui; Shibuya, Tetsuo; Arai, Masami; Hatakeyama, Seira; Ikenoue, Tsuneo; Ueno, Masashi; Miyano, Satoru; Imoto, Seiya; Furukawa, Yoichi

2016-05-24

Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39-45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing.

Clinical and genetic characterization of classical forms of familial adenomatous polyposis: a Spanish population study.

PubMed

Rivera, B; González, S; Sánchez-Tomé, E; Blanco, I; Mercadillo, F; Letón, R; Benítez, J; Robledo, M; Capellá, G; Urioste, M

2011-04-01

Classical familial adenomatous polyposis (FAP) is characterized by the appearance of >100 colorectal adenomas. We screened the APC and MUTYH genes for mutations and evaluated the genotype-phenotype correlation in 136 Spanish classical FAP families. APC/MUTYH mutations were detected in 107 families. Sixty-four distinct APC point mutations were detected in 95 families of which all were truncating mutations. A significant proportion (39.6%) had not been previously reported. Mutations were spread over the entire coding region and great rearrangements were identified in six families. Another six families exhibited biallelic MUTYH mutations. No APC or MUTYH mutations were detected in 29 families. These APC/MUTYH-negative families showed clinical differences with the APC-positive families. A poor correlation between phenotype and mutation site was observed. Our results highlight that a broad approach in the genetic study must be considered for classical FAP due to involvement of both APC and MUTYH and the heterogeneous spectrum of APC mutations observed in this Spanish population. The scarcely consistent genotype-phenotype correlation does not allow making specific recommendations regarding screening and management. Differences observed in APC/MUTYH-negative families may reflect a genetic basis other than mutations in APC and MUTYH genes for FAP predisposition. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Gut-directed hypnotherapy for functional abdominal pain or irritable bowel syndrome in children: a systematic review.

PubMed

Rutten, Juliette M T M; Reitsma, Johannes B; Vlieger, Arine M; Benninga, Marc A

2013-04-01

Gut directed hypnotherapy (HT) is shown to be effective in adult functional abdominal pain (FAP) and irritable bowel syndrome (IBS) patients. We performed a systematic review to assess efficacy of HT in paediatric FAP/IBS patients. We searched Medline, Embase, PsychINFO, Cumulative Index to Nursing and Allied Health Literature databases and Cochrane Central Register of Controlled Trials for randomised controlled trials (RCT) in children with FAP or IBS, investigating efficacy of HT on the following outcomes: abdominal pain scores, quality of life, costs and school absenteeism. Three RCT comparing HT to a control treatment were included with sample sizes ranging from 22 to 52 children. We refrained from statistical pooling because of low number of studies and many differences in design and outcomes. Two studies examined HT performed by a therapist, one examined HT through self-exercises on audio CD. All trials showed statistically significantly greater improvement in abdominal pain scores among children receiving HT. One trial reported beneficial effects sustained after 1 year of follow-up. One trial reported statistically significant improvement in quality of life in the HT group. Two trials reported significant reductions in school absenteeism after HT. Therapeutic effects of HT seem superior to standard medical care in children with FAP or IBS. It remains difficult to quantify exact benefits. The need for more high quality research is evident.

NASA Aeronautics Research: An Assessment

NASA Technical Reports Server (NTRS)

2008-01-01

The U.S. air transportation system is vital to the economic well-being and security of the United States. To support continued U.S. leadership in aviation, Congress and NASA requested that the National Research Council undertake a decadal survey of civil aeronautics research and technology (R&T) priorities that would help NASA fulfill its responsibility to preserve U.S. leadership in aeronautics technology. In 2006, the National Research Council published the Decadal Survey of Civil Aeronautics. That report presented a set of six strategic objectives for the next decade of aeronautics R&T, and it described 51 high-priority R&T challenges--characterized by five common themes--for both NASA and non-NASA researchers. The National Research Council produced the present report, which assesses NASA's Aeronautics Research Program, in response to the National Aeronautics and Space Administration Authorization Act of 2005 (Public Law 109-155). This report focuses on three sets of questions: 1. How well does NASA's research portfolio implement appropriate recommendations and address relevant high-priority research and technology challenges identified in the Decadal Survey of Civil Aeronautics? If gaps are found, what steps should be taken by the federal government to eliminate them? 2. How well does NASA's aeronautics research portfolio address the aeronautics research requirements of NASA, particularly for robotic and human space exploration? How well does NASA's aeronautics research portfolio address other federal government department/agency non-civil aeronautics research needs? If gaps are found, what steps should be taken by NASA and/or other parts of the federal government to eliminate them? 3. Will the nation have a skilled research workforce and research facilities commensurate with the requirements in (1) and (2) above? What critical improvements in workforce expertise and research facilities, if any, should NASA and the nation make to achieve the goals of NASA's research program? This report continues the good work begun by the Decadal Survey of Civil Aeronautics, and it expands that work to consider in more depth NASA aeronautics research issues related to the space program, non-civil applications, workforce, and facilities.

14 CFR 1203.200 - Background and discussion.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 1203.200 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program § 1203.200 Background and discussion. (a) In establishing a... public inspection of that information that is classified to protect the national security. (b) In...

14 CFR 1203.200 - Background and discussion.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 1203.200 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM NASA Information Security Program § 1203.200 Background and discussion. (a) In establishing a... public inspection of that information that is classified to protect the national security. (b) In...

Preliminary Assessment of the Interior Noise Environment in the Large Civil Tiltrotor (LCTR2)

NASA Technical Reports Server (NTRS)

Grosveld, Ferdinand W.; Cabell, Randolph H.

2011-01-01

The second-generation Large Civil Tiltrotor (LCTR2) serves as a representative vehicle under the NASA Fundamental Aeronautics Program (FAP) Subsonic Rotary Wing (SRW) project with a design goal to transport 90 passengers over a distance of 1800 km at a speed of 550 km/hr. The tiltrotor combines the vertical lift capability of a helicopter with the speed, altitude, and range of a turboprop airplane. The blade-passage frequency of the four-bladed rotor is as low as 6.9 Hz during cruise conditions. The resulting low-frequency acoustic excitation and its harmonics, combined with the anticipated use of lightweight composite and sandwich materials for the fuselage sidewall, may pose a challenge to achieving acceptable interior noise levels. The objective of the present study is to perform a preliminary assessment of the expected interior noise environment in the LCTR2 cabin. The approach includes a combination of semi-empirical, analytical, and statistical energy analysis methods. Because the LCTR2 is a notional vehicle, the prediction approach was also applied to the XV-15 tiltrotor and Bombardier Q400 turobprop aircraft to compare predictions with publicly available experimental data. Guidance for the expected interior noise levels in the LCTR2 was obtained by considering both the predicted exterior noise levels and the transmission loss of a basic fuselage sidewall consisting of a skin, porous layer and a trim panel. Structural and acoustic resonances are expected to coincide with low order harmonics of the blade passage frequency. The estimated sound pressure levels in the LCTR2 may not be acceptable when evaluated against known characteristics of human response to low frequency sound.

Preliminary appraisal of the reliability and validity of the Colorado State University Feline Acute Pain Scale.

PubMed

Shipley, Hilary; Guedes, Alonso; Graham, Lynelle; Goudie-DeAngelis, Elizabeth; Wendt-Hornickle, Erin

2018-05-01

Objectives The objective of this study was to determine the inter-rater reliability and convergent validity of the Colorado State University Feline Acute Pain Scale (CSU-FAPS) in a preliminary appraisal of its performance in a clinical teaching setting. Methods Sixty-eight female cats were assessed for pain after ovariohysterectomy. A cohort of 21 cats was examined independently by four raters (two board-certified anesthesiologists and two anesthesia residents) with the CSU-FAPS, and intra-class correlation coefficient (ICC) was used to determine inter-rater reliability. Weighted Cohen's kappa was used to determine inter-rater reliability centered on the 'need to reassess analgesic plan' (dichotomous scale). A separate cohort of 47 cats was evaluated independently by two raters (one board-certified anesthesiologist and one veterinary small animal rotating intern) using the CSU-FAPS and the Glasgow Composite Measure Pain Scale (CMPS-Feline), and Spearman rank-order correlation was determined to assess convergent validity. Reliability was interpreted using Altman's classification as very good, good, moderate, fair and poor. Validity was considered adequate if correlation coefficients were between 0.4 and 0.8. Results The ICC was 0.61 for anesthesiologists and 0.67 for residents, indicating good reliability. Weighted Cohen's kappa was 0.79 for anesthesiologists and 0.44 for residents, indicating moderate to good reliability. The Spearman rank correlation indicated a statistically significant ( P = 0.0003) positive correlation (0.31; 95% confidence interval 0.14-0.46) between the CSU-FAPS and the CMPS-Feline. Conclusions and relevance The CSU-FAPS showed moderate-to-good inter-rater reliability when used by veterinarians to assess pain level or need to reassess analgesic plan after ovariohysterectomy in cats. The validity fell short of current guidelines for correlation coefficients and further refinement and testing are warranted to improve its performance.

A different view on the Necker cube-Differences in multistable perception dynamics between Asperger and non-Asperger observers.

PubMed

Kornmeier, Jürgen; Wörner, Rike; Riedel, Andreas; Tebartz van Elst, Ludger

2017-01-01

During observation of the Necker cube perception becomes unstable and alternates repeatedly between a from-above-perspective ("fap") and a from-below-perspective ("fbp") interpretation. Both interpretations are physically equally plausible, however, observers usually show an a priori top-down bias in favor of the fap interpretation. Patients with Autism spectrum disorder are known to show an altered pattern of perception with a focus on sensory details. In the present study we tested whether this altered perceptual processing affects their reversal dynamics and reduces the perceptual bias during Necker cube observation. 19 participants with Asperger syndrome and 16 healthy controls observed a Necker cube stimulus continuously for 5 minutes and indicated perceptual reversals by key press. We compared reversal rates (number of reversals per minute) and the distributions of dwell times for the two interpretations between observer groups. Asperger participants showed less perceptual reversal than controls. Six Asperger participants did not perceive any reversal at all, whereas all observers from the control group perceived at least five reversals within the five minutes observation time. Further, control participants showed the typical perceptual bias with significant longer median dwell times for the fap compared to the fbp interpretation. No such perceptual bias was found in the Asperger group. The perceptual system weights the incomplete and ambiguous sensory input with memorized concepts in order to construct stable and reliable percepts. In the case of the Necker cube stimulus, two perceptual interpretations are equally compatible with the sensory information and internal fluctuations may cause perceptual alternations between them-with a slightly larger probability value for the fap interpretation (perceptual bias). Smaller reversal rates in Asperger observers may result from the dominance of bottom-up sensory input over endogenous top-down factors. The latter may also explain the absence of a fap bias.

Analysis of transthyretin in human serum by capillary zone electrophoresis electrospray ionization time-of-flight mass spectrometry. Application to familial amyloidotic polyneuropathy type I.

PubMed

Pont, Laura; Benavente, Fernando; Barbosa, José; Sanz-Nebot, Victoria

2015-06-01

Transthyretin (TTR) is known to misfold and aggregate, causing different types of amyloidosis. Familial amyloidotic polyneuropathy type I (FAP-I), which is the most common hereditary systemic amyloidosis, is associated with a TTR variant that presents a single amino acid substitution of valine for methionine at position 30 (Met 30). To screen for TTR-related amyloidosis rapidly and reliably, we have developed a novel procedure based on the analysis of monomers from the homotetrameric protein (∼56 kDa). First, we established a CZE-ESI-TOF-MS method to detect wild-type (normal) TTR with or without several PTMs, as well as an extra minor isoform in TTR standard solutions. Later, a sample pretreatment based on immunoprecipitation (IP) and centrifugal filtration was optimized to analyze serum samples from healthy controls and FAP-I patients (including an asymptomatic patient, a symptomatic patient, a liver-transplanted patient with the specific mutation, and a patient originally without the mutation who received a liver transplant from an FAP-I patient (iatrogenic FAP-I)). The mutant TTR (Met 30) variant with a relative molecular mass 32.07 higher than the wild-type TTR was found in the asymptomatic, the symptomatic and the iatrogenic FAP-I patients, who interestingly also presented the same concentration ratio between both variants of TTR (abnormal and normal). In contrast, as in the healthy controls, the abnormal TTR variant was not detected in the liver-transplanted patient with the specific mutation, which confirms the effectiveness of the treatment. The proposed procedure could be regarded as a suitable screening system for individuals with suspected TTR amyloidosis, and to gain insight into TTR structure, to understand the mechanism underlying the disease. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Kinetics and mechanism of natural fluorapatite dissolution at 25 °C and pH from 3 to 12

NASA Astrophysics Data System (ADS)

Chaïrat, Claire; Schott, Jacques; Oelkers, Eric H.; Lartigue, Jean-Eric; Harouiya, Najatte

2007-12-01

The dissolution rates of natural fluorapatite (FAP), Ca 10(PO 4) 6F 2, were measured at 25 °C in mixed-flow reactors as a function of pH from 3.0 to 11.7, and aqueous calcium, phosphorus, and fluoride concentration. After an initial preferential Ca and/or F release, stoichiometric Ca, P, and F release was observed. Measured FAP dissolution rates decrease with increasing pH at 3 ⩽ pH ⩽ 7, FAP dissolution rates are pH independent at 7 ⩽ pH ⩽ 10, and FAP dissolution rates again decrease with increasing pH at pH ⩾ 10. Measured FAP dissolution rates are independent of aqueous Ca, P, and F concentration at pH ≈ 3 and pH ≈ 10. Apatite dissolution appears to be initiated by the relatively rapid removal from the near surface of F and the Ca located in the M1 sites, via proton for Ca exchange reactions. Dissolution rates are controlled by the destruction of this F and Ca depleted surface layer. The destruction of this layer is facilitated by the adsorption/penetration of protons into the surface at acidic conditions, and by surface hydration at neutral and basic conditions. Taking into account these two parallel mechanisms, measured fluorapatite forward dissolution rates can be accurately described using r+(molms)=6.61×10-6{aK}/{1+aK+aCa4aF1.4aOH0.6aH6K}+3.69×10-8[tbnd CaOH2+] where ai refers to the activity of the ith aqueous species, [tbnd CaOH2+] denotes the concentration of hydrated calcium sites at the surface of the leached layer (mol m -2), and Kex and Kads stand for the apparent stability constants of the Ca 2+/H + exchange and adsorption/penetration reactions, respectively.

Arterial Pressure Gradients during Upright Posture and 30 deg Head Down Tilt

NASA Technical Reports Server (NTRS)

Sanchez, E. R; William, J. M.; Ueno, T.; Ballard, R. E.; Hargens, A. R.; Holton, Emily M. (Technical Monitor)

1997-01-01

Gravity alters local blood pressure within the body so that arterial pressures in the head and foot are lower and higher, respectively, than that at heart level. Furthermore, vascular responses to local alterations of arterial pressure are probably important to maintain orthostatic tolerance upon return to the Earth after space flight. However, it has been difficult to evaluate the body's arterial pressure gradient due to the lack of noninvasive technology. This study was therefore designed to investigate whether finger arterial pressure (FAP), measured noninvasively, follows a normal hydrostatic pressure gradient above and below heart level during upright posture and 30 deg head down tilt (HDT). Seven healthy subjects gave informed consent and were 19 to 52 years old with a height range of 158 to 181 cm. A Finapres device measured arterial pressure at different levels of the body by moving the hand from 36 cm below heart level (BH) to 72 cm above heart level (AH) in upright posture and from 36 cm BH to 48 cm AH during HDT in increments of 12 cm. Mean FAP creased by 85 mmHg transitioning from BH to AH in upright posture, and the pressure gradient calculated from hydrostatic pressure difference (rho(gh)) was 84 mmHg. In HDT, mean FAP decreased by 65 mmHg from BH to AH, and the calculated pressure gradient was also 65 mmHg. There was no significant difference between the measured FAP gradient and the calculated pressure gradient, although a significant (p = 0.023) offset was seen for absolute arterial pressure in upright posture. These results indicate that arterial pressure at various levels can be obtained from the blood pressure at heart level by calculating rho(gh) + an offset. The offset equals the difference between heart level and the site of measurement. In summary, we conclude that local blood pressure gradients can be measured by noninvasive studies of FAP.

Ensuring US National Aeronautics Test Capabilities

NASA Technical Reports Server (NTRS)

Marshall, Timothy J.

2010-01-01

U.S. leadership in aeronautics depends on ready access to technologically advanced, efficient, and affordable aeronautics test capabilities. These systems include major wind tunnels and propulsion test facilities and flight test capabilities. The federal government owns the majority of the major aeronautics test capabilities in the United States, primarily through the National Aeronautics and Space Administration (NASA) and the Department of Defense (DoD). However, changes in the Aerospace landscape, primarily the decrease in demand for testing over the last 20 years required an overarching strategy for management of these national assets. Therefore, NASA established the Aeronautics Test Program (ATP) as a two-pronged strategic initiative to: (1) retain and invest in NASA aeronautics test capabilities considered strategically important to the agency and the nation, and (2) establish a strong, high level partnership with the DoD. Test facility utilization is a critical factor for ATP because it relies on user occupancy fees to recover a substantial part of the operations costs for its facilities. Decreasing utilization is an indicator of excess capacity and in some cases low-risk redundancy (i.e., several facilities with basically the same capability and overall low utilization). However, low utilization does not necessarily translate to lack of strategic importance. Some facilities with relatively low utilization are nonetheless vitally important because of the unique nature of the capability and the foreseeable aeronautics testing needs. Unfortunately, since its inception, the customer base for ATP has continued to shrink. Utilization of ATP wind tunnels has declined by more than 50% from the FY 2006 levels. This significant decrease in customer usage is attributable to several factors, including the overall decline in new programs and projects in the aerospace sector; the impact of computational fluid dynamics (CFD) on the design, development, and research process; and the reductions in wind tunnel testing requirements within the largest consumer of ATP wind tunnel test time, the Aeronautics Research Mission Directorate (ARMD). Retirement of the Space Shuttle Program and recent perturbations of NASA's Constellation Program will exacerbate this downward trend. Therefore it is crucial that ATP periodically revisit and determine which of its test capabilities are strategically important, which qualify as low-risk redundancies that could be put in an inactive status or closed, and address the challenges associated with both sustainment and improvements to the test capabilities that must remain active. This presentation will provide an overview of the ATP vision, mission, and goals as well as the challenges and opportunities the program is facing both today and in the future. We will discuss the strategy ATP is taking over the next five years to address the National aeronautics test capability challenges and what the program will do to capitalize on its opportunities to ensure a ready, robust and relevant portfolio of National aeronautics test capabilities.

14 CFR 399.91 - Air carrier participation in programs of technical assistance to airlines of less developed...

Code of Federal Regulations, 2011 CFR

2011-01-01

... § 399.91 Air carrier participation in programs of technical assistance to airlines of less developed... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Air carrier participation in programs of technical assistance to airlines of less developed countries. 399.91 Section 399.91 Aeronautics and Space...

14 CFR 399.91 - Air carrier participation in programs of technical assistance to airlines of less developed...

Code of Federal Regulations, 2010 CFR

2010-01-01

... § 399.91 Air carrier participation in programs of technical assistance to airlines of less developed... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Air carrier participation in programs of technical assistance to airlines of less developed countries. 399.91 Section 399.91 Aeronautics and Space...

Tumor Microenvironment Gene Signature as a Prognostic Classifier and Therapeutic Target

DTIC Science & Technology

2016-06-01

smooth muscle actin (αSMA, encoded by gene ACTA2), fibroblast activation protein ( FAP ), podoplanin (PDPN), palladin (PALLD), tenascin-C (TNC...0.73 0.75 0.752 4 COL3A1 0.85 0.7 0.88 0.64 0.85 0.68 0.63 0.83 0.86 0.85 0.54 0.66 0.79 0.751 5 FAP 0.77 0.72 0.83 0.55 0.69 0.75 0.63 0.77 0.77 0.85

Budget estimates, fiscal year 1995. Volume 1: Agency summary, human space flight, and science, aeronautics and technology

NASA Technical Reports Server (NTRS)

1994-01-01

The NASA budget request has been restructured in FY 1995 into four appropriations: human space flight; science, aeronautics, and technology; mission support; and inspector general. The human space flight appropriations provides funding for NASA's human space flight activities. This includes the on-orbit infrastructure (space station and Spacelab), transportation capability (space shuttle program, including operations, program support, and performance and safety upgrades), and the Russian cooperation program, which includes the flight activities associated with the cooperative research flights to the Russian Mir space station. These activities are funded in the following budget line items: space station, Russian cooperation, space shuttle, and payload utilization and operations. The science, aeronautics, and technology appropriations provides funding for the research and development activities of NASA. This includes funds to extend our knowledge of the earth, its space environment, and the universe and to invest in new technologies, particularly in aeronautics, to ensure the future competitiveness of the nation. These objectives are achieved through the following elements: space science, life and microgravity sciences and applications, mission to planet earth, aeronautical research and technology, advanced concepts and technology, launch services, mission communication services, and academic programs.

14 CFR 1259.401 - Responsibilities.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Responsibilities. 1259.401 Section 1259.401 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NATIONAL SPACE GRANT COLLEGE AND FELLOWSHIP PROGRAM Space Grant College and Consortium Designation § 1259.401 Responsibilities. Each...

14 CFR 1259.401 - Responsibilities.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Responsibilities. 1259.401 Section 1259.401 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NATIONAL SPACE GRANT COLLEGE AND FELLOWSHIP PROGRAM Space Grant College and Consortium Designation § 1259.401 Responsibilities. Each...

14 CFR 1259.401 - Responsibilities.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Responsibilities. 1259.401 Section 1259.401 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NATIONAL SPACE GRANT COLLEGE AND FELLOWSHIP PROGRAM Space Grant College and Consortium Designation § 1259.401 Responsibilities. Each...

14 CFR 1203.601 - Responsibilities.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Responsibilities. 1203.601 Section 1203.601 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM... authority may declassify or downgrade information that is subject to the final classification jurisdiction...

14 CFR 1251.540 - Employment.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National Aeronautics and Space Administration § 1251.540 Employment. No qualified individual with handicaps shall, on...

14 CFR 1251.540 - Employment.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National Aeronautics and Space Administration § 1251.540 Employment. No qualified individual with handicaps shall, on...

14 CFR 1251.540 - Employment.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National Aeronautics and Space Administration § 1251.540 Employment. No qualified individual with handicaps shall, on...

14 CFR 1251.540 - Employment.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National Aeronautics and Space Administration § 1251.540 Employment. No qualified individual with handicaps shall, on...

14 CFR 1203.601 - Responsibilities.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Responsibilities. 1203.601 Section 1203.601 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM... authority may declassify or downgrade information that is subject to the final classification jurisdiction...

14 CFR 1203.300 - General.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false General. 1203.300 Section 1203.300 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM Classification Principles and Considerations § 1203.300 General. In general, the types of NASA-generated...

14 CFR 1203.801 - Redelegation.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Redelegation. 1203.801 Section 1203.801 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM Delegation of... TOP SECRET, SECRET, or CONFIDENTIAL original classification authority or declassification authority is...

14 CFR 1273.40 - Monitoring and reporting program performance.

Code of Federal Regulations, 2010 CFR

2010-01-01

... performance. 1273.40 Section 1273.40 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION... program performance. (a) Monitoring by grantees. Grantees are responsible for managing the day-to-day... assure compliance with applicable Federal requirements and that performance goals are being achieved...

14 CFR 1251.501 - Purpose.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National... basis of handicap in programs or activities conducted by Executive agencies or the United States Postal...

14 CFR 1251.501 - Purpose.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National... basis of handicap in programs or activities conducted by Executive agencies or the United States Postal...

14 CFR 1251.501 - Purpose.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National... basis of handicap in programs or activities conducted by Executive agencies or the United States Postal...

14 CFR § 1251.501 - Purpose.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National... basis of handicap in programs or activities conducted by Executive agencies or the United States Postal...

14 CFR 1251.501 - Purpose.

Code of Federal Regulations, 2011 CFR

2011-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National... basis of handicap in programs or activities conducted by Executive agencies or the United States Postal...

14 CFR 151.89 - Roads.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false Roads. 151.89 Section 151.89 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS FEDERAL AID TO AIRPORTS Project Programming Standards § 151.89 Roads. (a) Federal-aid Airport Program funds...

14 CFR 151.89 - Roads.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false Roads. 151.89 Section 151.89 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS FEDERAL AID TO AIRPORTS Project Programming Standards § 151.89 Roads. (a) Federal-aid Airport Program funds...

14 CFR 152.417 - Monitoring employment.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Monitoring employment. 152.417 Section 152.417 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS AIRPORT AID PROGRAM Nondiscrimination in Airport Aid Program § 152.417 Monitoring employment. (a...

Aeronautics research and technology program and specific objectives

NASA Technical Reports Server (NTRS)

1981-01-01

Aeronautics research and technology program objectives in fluid and thermal physics, materials and structures, controls and guidance, human factors, multidisciplinary activities, computer science and applications, propulsion, rotorcraft, high speed aircraft, subsonic aircraft, and rotorcraft and high speed aircraft systems technology are addressed.

14 CFR 91.1085 - Hazardous materials recognition training.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false Hazardous materials recognition training. 91.1085 Section 91.1085 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF... Ownership Operations Program Management § 91.1085 Hazardous materials recognition training. No program...

14 CFR 91.1085 - Hazardous materials recognition training.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false Hazardous materials recognition training. 91.1085 Section 91.1085 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF... Ownership Operations Program Management § 91.1085 Hazardous materials recognition training. No program...

14 CFR 91.1085 - Hazardous materials recognition training.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Hazardous materials recognition training. 91.1085 Section 91.1085 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF... Ownership Operations Program Management § 91.1085 Hazardous materials recognition training. No program...

14 CFR 91.1085 - Hazardous materials recognition training.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false Hazardous materials recognition training. 91.1085 Section 91.1085 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF... Ownership Operations Program Management § 91.1085 Hazardous materials recognition training. No program...

14 CFR 91.1085 - Hazardous materials recognition training.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false Hazardous materials recognition training. 91.1085 Section 91.1085 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF... Ownership Operations Program Management § 91.1085 Hazardous materials recognition training. No program...

14 CFR 151.89 - Roads.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Roads. 151.89 Section 151.89 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRPORTS FEDERAL AID TO AIRPORTS Project Programming Standards § 151.89 Roads. (a) Federal-aid Airport Program funds...

Western Aeronautical Test Range

NASA Technical Reports Server (NTRS)

Sakahara, Robert D.

2008-01-01

This viewgraph presentation reviews the work of the Western Aeronautical Test Range (WATR). NASA's Western Aeronautical Test Range is a network of facilities used to support aeronautical research, science missions, exploration system concepts, and space operations. The WATR resides at NASA's Dryden Flight Research Center located at Edwards Air Force Base, California. The WATR is a part of NASA's Corporate Management of Aeronautical Facilities and funded by the Strategic Capability Asset Program (SCAP). Maps show the general location of the WATR area that is used for aeronautical testing and evaluation. The products, services and facilities of WATR are discussed,

14 CFR 1203.300 - General.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true General. 1203.300 Section 1203.300 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM... information and material requiring protection in the interest of national security lie in the areas of applied...

14 CFR § 1251.540 - Employment.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON BASIS OF HANDICAP Enforcement of Nondiscrimination on the Basis of Handicap in Programs or Activities Conducted by the National Aeronautics and Space Administration § 1251.540 Employment. No qualified individual with handicaps shall, on...

14 CFR 1203.300 - General.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false General. 1203.300 Section 1203.300 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION INFORMATION SECURITY PROGRAM... information and material requiring protection in the interest of national security lie in the areas of applied...

14 CFR 1253.510 - Recruitment.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Recruitment. 1253.510 Section 1253.510 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON THE BASIS OF SEX IN... in Employment in Education Programs or Activities Prohibited § 1253.510 Recruitment. (a...

14 CFR 1253.510 - Recruitment.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Recruitment. 1253.510 Section 1253.510 Aeronautics and Space NATIONAL AERONAUTICS AND SPACE ADMINISTRATION NONDISCRIMINATION ON THE BASIS OF SEX IN... in Employment in Education Programs or Activities Prohibited § 1253.510 Recruitment. (a...