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Acinar cell cystadenocarcinoma is a rare malignant epithelial neoplasm of the pancreas with a diffusely cystic, gross architecture in which the cysts are lined with neoplastic epithelial cells that demonstrate evidence of pancreatic exocrine enzyme production. This is the 10th case that has been reported in the literature. A 77-year-old male complaining of left hypochondrial pain was referred to our hospital for treatment of a pancreatic tumor. A huge, honeycomb-structured tumor was detected in the pancreatic tail. Distal pancreatectomy with total resection of the residual stomach and partial resection of the transverse colon were performed. Microscopically, there were variably sized cystic lesions in the tumor. Immunohistochemical examinations revealed that tumor cells were positive for alpha 1-antichymotrypsin and alpha 1-trypsin, showing that tumor cells had features of pancreatic acinar cells. Thus, the tumor was diagnosed as acinar cell cystadenocarcinoma. Herein, we report a rare case with acinar cell cystadenocarcinoma, which is the 10th case reported in the literature based on a PubMed search. We managed to resect the tumor completely by distal pancreatectomy with total resection of the residual stomach and partial resection of the transverse colon. The patient is still alive 26 months after surgery without any recurrence after 1 year of adjuvant chemotherapy with S-1.

Alzheimer’s disease (AD) is the most common form of dementia and has no cure. Therapeutic strategies focusing on the reduction of oxidative stress, modulation of amyloid-beta (Aβ) toxicity and inhibition of tau protein hyperphosphorylation are warranted to avoid the development and progression of AD. The aim of this study was to screen the crude extracts (CEs) and ethyl-acetate fractions (EAFs) of Guazuma ulmifolia, Limonium brasiliense, Paullinia cupana, Poincianella pluviosa, Stryphnodendron adstringens and Trichilia catigua using preliminary in vitro bioassays (acetylcholinesterase inhibition, antioxidant activity and total polyphenol content) to select extracts/fractions and assess their protective effects against Aβ25–35 toxicity in SH-SY5Y cells. The effect of the EAF of S. adstringens on mitochondrial membrane potential, lipid peroxidation, superoxide production and mRNA expression of 10 genes related to AD was also evaluated and the electropherogram fingerprints of EAFs were established by capillary electrophoresis. Chemometric tools were used to correlate the in vitro activities of the samples with their potential to be evaluated against AD and to divide extracts/fractions into four clusters. Pretreatment with the EAFs grouped in cluster 1 (S. adstringens, P. pluviosa and L. brasiliense) protected SH-SY5Y cells from Aβ25-35-induced toxicity. The EAF of S. adstringens at 15.62 μg/mL was able completely to inhibit the mitochondrial depolarization (69%), superoxide production (49%) and Aβ25-35-induced lipid peroxidation (35%). With respect to mRNA expression, the EAF of S. adstringens also prevented the MAPT mRNA overexpression (expression ratio of 2.387x) induced by Aβ25–35, which may be related to tau protein hyperphosphorylation. This is the first time that the neuroprotective effects of these fractions have been demonstrated and that the electropherogram fingerprints for the EAFs of G. ulmifolia, L. brasiliense, P. cupana, P. pluviosa and S. adstringens have been established. The study expands knowledge of the in vitro protective effects and quality control of the evaluated fractions. [ABSTRACT FROM AUTHOR]

P-glycoprotein (Pgp) is an efflux pump important in multidrug resistance of cancer cells and in determining drug pharmacokinetics. Pgp is a prototype ATP-binding cassette transporter with two nucleotide-binding domains (NBDs) that bind and hydrolyze ATP. Conformational changes at the NBDs (the Pgp engines) lead to changes across Pgp transmembrane domains that result in substrate translocation. According to current alternating access models (substrate-binding pocket accessible only to one side of the membrane at a time), binding of ATP promotes NBD dimerization, resulting in external accessibility of the drug-binding site (outward-facing, closed NBD conformation), and ATP hydrolysis leads to dissociation of the NBDs with the subsequent return of the accessibility of the binding site to the cytoplasmic side (inward-facing, open NBD conformation). However, previous work has not investigated these events under near-physiological conditions in a lipid bilayer and in the presence of transport substrate. Here, we used luminescence resonance energy transfer (LRET) to measure the distances between the two Pgp NBDs. Pgp was labeled with LRET probes, reconstituted in lipid nanodiscs, and the distance between the NBDs was measured at 37 °C. In the presence of verapamil, a substrate that activates ATP hydrolysis, the NBDs of Pgp reconstituted in nanodiscs were never far apart during the hydrolysis cycle, and we never observed the NBD–NBD distances of tens of Å that have previously been reported. However, we found two main conformations that coexist in a dynamic equilibrium under all conditions studied. Our observations highlight the importance of performing studies of efflux pumps under near-physiological conditions, in a lipid bilayer, at 37 °C, and during substrate-stimulated hydrolysis. [ABSTRACT FROM AUTHOR]

The aim of this investigation was to determine whether circulating inflammatory biomarkers c-reactive protein (CRP), interleukin-6 (IL6), and alpha 1-antichymotrypsin (ACT) were related to structural brain measures assessed by magnetic resonance imaging (MRI). High-resolution structural MRI was collected on 680 non-demented elderly (mean age 80.1 years) participants of a community-based, multiethnic cohort. Approximately three quarters of these participants also had peripheral inflammatory biomarkers (CRP, IL6, and ACT) measured using ELISA. Structural measures including brain volumes and cortical thickness (with both global and regional measures) were derived from MRI scans, and repeated MRI measures were obtained after 4.5 years. Mean fractional anisotropy was used as the indicator of white matter integrity assessed with diffusion tensor imaging. We examined the association of inflammatory biomarkers with brain volume, cortical thickness, and white matter integrity using regression models adjusted for age, gender, ethnicity, education, APOE genotype, and intracranial volume. A doubling in CRP (b = −2.48, p = 0.002) was associated with a smaller total gray matter volume, equivalent to approximately 1.5 years of aging. A doubling in IL6 was associated with smaller total brain volume (b = −14.96, p < 0.0001), equivalent to approximately 9 years of aging. Higher IL6 was also associated with smaller gray matter (b = −6.52, p = 0.002) and white matter volumes (b = −7.47, p = 0.004). The volumes of most cortical regions including frontal, occipital, parietal, temporal, as well as subcortical regions including pallidum and thalamus were associated with IL6. In a model additionally adjusted for depression, vascular factors, BMI, and smoking status, the association between IL6 and brain volumes remained, and a doubling in ACT was marginally associated with 0.054 (p = 0.001) millimeter thinner mean cortical thickness, equivalent to that of approximately 2.7 years of aging. None of the biomarkers was associated with mean fractional anisotropy or longitudinal change of brain volumes and thickness. Among older adults, increased circulating inflammatory biomarkers were associated with smaller brain volume and cortical thickness but not the white matter tract integrity. Our preliminary findings suggest that peripheral inflammatory processes may be involved in the brain atrophy in the elderly. [ABSTRACT FROM AUTHOR]

Background: Calcific aortic stenosis (CAS) is the most common heart valve disease in the elderly, representing an important economic and social burden in developed countries. Currently, there is no way to predict either the onset or progression of CAS, emphasizing the need to identify useful biomarkers for this condition. Methods: We performed a multi-proteomic analysis on different kinds of samples from CAS patients and healthy donors: tissue, secretome and plasma. The results were validated in an independent cohort of subjects by immunohistochemistry, western blotting and selected reaction monitoring. Results: Alpha 1 antichymotrypsin (AACT) abundance was altered in the CAS samples, as confirmed in the validation phase. The significant changes observed in the amounts of this protein strongly suggest that it could be involved in the molecular mechanisms underlying CAS. In addition, our results suggest there is enhanced release of AACT into the extracellular fluids when the disease commences. Conclusions: The significant increase of AACT in CAS patients suggests it fulfils an important role in the physiopathology of this disease. These results permit us to propose that AACT may serve as a potential marker for the diagnosis of CAS, with considerable clinical value. [ABSTRACT FROM AUTHOR]

Understanding protein amyloidogenesis is an important topic in protein science, fueled by the role of amyloid aggregates, especially oligomers, in the etiology of a number of devastating human degenerative diseases. However, the mechanisms that determine the formation of amyloid oligomers remain elusive due to the high complexity of the amyloidogenesis process. For instance, gold nanoparticles promote or inhibit amyloid fibrillation. We have functionalized gold nanorods with a metal-chelating group to selectively immobilize soluble RepA-WH1, a model synthetic bacterial prionoid, using a hexa-histidine tag (H6). H6-RepA-WH1 undergoes stable amyloid oligomerization in the presence of catalytic concentrations of anisotropic nanoparticles. Then, in a physically separated event, such oligomers promote the growth of amyloid fibers of untagged RepA-WH1. SERS spectral changes of H6-RepA-WH1 on spherical citrate-AuNP substrates provide evidence for structural modifications in the protein, which are compatible with a gradual increase in β-sheet structure, as expected in amyloid oligomerization. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to evaluate the genetic variation of milk fat CLA, together with the variation of CLA precursors, including the individual PUFA that are potentially involved in the metabolic pathway of CLA. The allelic substitution effect, upon these FA, was estimated for a number of polymorphisms, that are located within 9 candidate genes known to influence milk FA partitioning. Sheep milk was chosen because it contains higher total fat percentage, and higher CLA levels per gram fat, than milk of other ruminants. Milk FAME analyses were performed on individual milk samples of sheep from three different breeds. Our results reflect the association of three genes (alpha-1-antichymotrypsin; diacylglycerol O-acyltransferase homolog-2; and zona pellucida glycoprotein-2) with the values of both linolenic FA and CLA; of three more genes (insulin-like growth factor I; lecithin-cholesterol acyltransferase and propionyl coenzyme A carboxylase, beta polypeptide) with the variability of linolenic FA; and of one gene, the fatty acid synthetase with the variability of CLA and stearic FA. The current study might contribute to the understanding of the metabolic pathway of PUFA in sheep milk, providing suggestions to modify milk fat composition through selection. [Copyright &y& Elsevier]

Abstract: There is increasing evidence from genetic, immunohistochemical, proteomic and epidemiological studies as well as in model systems that complement activation has an important role in the pathogenesis of Alzheimer''s disease (AD). The complement cascade is an essential element of the innate immune response. In the brain complement proteins are integral components of amyloid plaques and complement activation occurs at the earliest stage of the disease. The complement cascade has been implicated as a protective mechanism in the clearance of amyloid, and in a causal role through chronic activation of the inflammatory response. In this review we discuss the potential for complement activation to act as a biomarker for AD at several stages in the disease process. An accurate biomarker that has sufficient predictive, diagnostic and prognostic value would provide a significant opportunity to develop and test for effective novel therapies in the treatment of AD. [Copyright &y& Elsevier]

Background/Aims: Alpha-1 antichymotrypsin (ACT), a serine proteinase inhibitor, has been implicated in vascular pathology. The TT genotype of the ACT signal peptide A/T polymorphism has been reported to confer susceptibility to primary intracerebral hemorrhage (PICH). We conducted a prospective study to test possible association of ACT signal peptide A/T polymorphism with PICH in a Greek cohort with enough power (80%) to detect a twofold increase in the odds ratio. Methods: We prospectively recruited 147 patients with PICH. ACT signal peptide A/T genotypes were determined in patients and 206 healthy, age- and sex-matched control subjects from the neurology outpatient clinic using the polymerase chain reaction restriction fragment length polymorphism method. Results: Our study did not show an association between ACT signal peptide A/T polymorphism and PICH. We also failed to find any influence on age at onset, the location and volume of PICH as well as on clinical severity at admission or 6-month outcome. Conclusion: Our data failed to confirm an association between ACT signal peptide A/T polymorphism and PICH. However, we cannot exclude the possibility that the TT genotype confers susceptibility at less than a twofold increase. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Nur77 is one member of the nuclear receptor superfamily. As a transcription factor, Nur77 participates in a variety of biological processes, including T cell development, inflammatory responses, steroid hormone synthesis, and hepatic glucose metabolism. It typically acts via binding to the Nur77 responsive element (NBRE) in the promoter regions of its target genes. In the present study, we identified a novel Nur77-regulated gene, α1-antichymotrypsin/SerpinA3, via an approach combining computational prediction and wet-laboratory validations. First, we identified 483 candidate genes via a human genome-wide scan for NBREs in their proximal promoters. Three out of 14 function-associated genes were further identified to be transactivated by Nur77 in luciferase reporter gene assays in HEK 293T cells. The transactivation assay proved that the NBRE (−182 to −175) in the SerpinA3 promoter region is a novel Nur77-dependent functional motif in HEK 293T and HepG2 cells. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated that Nur77 physically associates with the SerpinA3 promoter region both in vitro and in vivo. Nur77 overexpression and RNA interference-mediated Nur77 gene knockdown analysis confirmed that SerpinA3 is indeed a novel Nur77-targeted gene. These data may throw light on the function of Nur77 in inflammatory responses and acute-phase reactions as well as the development of Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Background: Serine protease inhibitor member 3 of clade A (SERPINA3), also known as alpha-1-antichymotrypsin, inhibits the activity of cathepsin G. The release of neutrophil cathepsin G (proteolytic enzyme) can destroy the vascular matrix through degradation, platelet aggregation and coagulation disorders. In a previous report there was evidence that an alanine/threonine polymorphism was associated with the risk factor for aneurysmal subarachnoid hemorrhage (SAH) in a Polish population. We performed this study to determine whether this A15T polymorphism shows the same association in a Japanese population. Methods: A total of 437 patients with an aneurysmal SAH and 405 control cases of Japanese origin were genotyped for the A15T polymorphism and 2 further intronic single nucleotide polymorphisms by using polymerase chain reaction and direct sequencing. Results: In the patients with intracranial aneurysms the SERPINA3 A15T allele and genotype distribution did not differ significantly from the controls. Conclusion: In the Japanese population the A15T polymorphism of the SERPINA3 gene is not associated with aneurysmal SAH. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Sporadic inclusion body myositis (s-IBM) is a progressive muscle disease of unknown aetiology. Characteristically, intracellular amyloid deposits are detectable, including β-amyloid precursor protein, phosphorylated tau, α1-antichymotrypsin (α1-ACT) and apolipoprotein E (ApoE). Polymorphisms and mutations of the encoding genes have been identified in a variety of neurodegenerative diseases including Alzheimer’s disease (AD). Beside other factors, polymorphisms may lead to protein accumulation in both diseases. In particular, polymorphisms within the ApoE and α1-ACT gene have been implicated in the aetiology of AD and s-IBM. We analysed ApoE and α1-ACT gene polymorphisms in 35 s-IBM patients. We could not identify any statistical significant correlation between distinct ApoE and α1-ACT genotypes and the risk of developing s-IBM. Additionally, ApoE and α1-ACT genotypes seem not to influence the onset age of s-IBM. A combination of different α1-ACT and ApoE genotypes appears not to enhance the risk of developing s-IBM. Therefore, allelic variations of α1-ACT and ApoE are unlikely to be genetic key factors in the aetiology of s-IBM. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Increased levels of inflammatory proteins have been found in the brains and plasma samples of patients with dementia. Whether the levels of inflammatory proteins in plasma samples are elevated before clinical onset of dementia is unclear. To determine whether high levels of inflammatory proteins in plasma samples are associated with an increased risk of dementia.A case-cohort study within the Rotterdam Study, a population-based prospective cohort study in the Netherlands. Participants The source population comprises 6713 subjects who, at baseline (1990-1993), were free of dementia and underwent venipuncture. From these, we selected both a random subcohort of 727 subjects and 188 cases who had developed dementia at follow-up. Main Outcome Measures The associations between plasma levels of α1-antichymotrypsin, C-reactive protein, interleukin 6, the soluble forms of intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and the risk of dementia were examined using the Cox proportional hazards regression models. Results High levels of α1-antichymotrypsin, interleukin 6, and, to a lesser extent, C-reactive protein were associated with an increased risk of dementia; rate ratios per standard deviation increase were 1.49 (95% confidence interval, 1.23-1.81), 1.28 (95% confidence interval, 1.06-1.55), and 1.12 (95% confidence interval, 0.99-1.25), respectively. Similar associations were observed for Alzheimer disease, whereas rate ratios of vascular dementia were higher for α1-antichymotrypsin and C-reactive protein. Soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not associated with dementia. Plasma levels of inflammatory proteins are increased before clinical onset of dementia, Alzheimer disease, and vascular dementia. [ABSTRACT FROM AUTHOR]

Background -- Cystic fibrosis (CF) is characterized by an excess of free proteinases that destroy lung tissue. Despite this, previous studies have shown that patients with CF with a mild deficiency variant of the proteinase inhibitor α1-antitrypsin have less, rather than more, severe pulmonary disease. Alpha1-antichymotrypsin is another important serine proteinase inhibitor that protects the lung against proteolytic attack, and point mutations in the α1-antichymotrypsin gene that result in plasma deficiency are associated with chronic obstructive pulmonary disease. Methods-The effect of α1-antichymotrypsin deficiency and the -15 α1- antichymotrypsin signal peptide genotype on lung function was assessed in patients with CE Results-One hundred and fifty seven patients with CF were screened and 10 were identified with a plasma deficiency of α1-antichymotrypsin (plasma concentration < 0.2 g/l). In a multivariate analysis these individuals had significantly less severe lung disease than those who had normal or raised levels of α1-anti- chymotrypsin: forced expiratory volume in one second (FEV1) 69.9% predicted versus 53.2% predicted (p=0.04) and chest radiographic score of 7.2 versus 9.7 (p =0 .03) for those with and without α1-antichymotrypsin deficiency, respectively. The -15 signal peptide genotype did not affect plasma levels, but the -15 Ala/Ala signal peptide genotype was over-represented in individuals with CF compared with healthy blood donor controls. Conclusion-These data indicate that deficiency of α1-antichymotrypsin is associated with less severe pulmonary disease in patients with CF, and support our previous observations that mild genetic deficiency of a proteinase inhibitor is associated with an improved outcome. [ABSTRACT FROM AUTHOR]

Aim Papillary thyroid carcinoma (PTC) is the most common malignant tumour of the thyroid gland. The immunohistochemical profile of PTC is characterized by immunoreactivity of tumour cells for cytokeratins, thyroglobulin, vimentin, EMA and S100 protein. Recently, the presence of a serum protease inhibitor, alpha-1-antitrypsin (A1AT), has been demonstrated in tumour cells of PTC. The aim of our study was to test immunoreactivity of PTC for another inhibitor of proteases, alpha-1-antichymotrypsin (A1ACT). Methods and results Serial paraffin sections of nine consecutive cases of PTC were tested with anti-A1AT and anti-A1ACT antibodies. No immunoreactivity for A1AT and A1ACT was found in the normal thyroid tissue surrounding each tumour. In seven out of nine cases, tumour cells of PTC showed cytoplasmic immunoreactivity for A1ACT. In two cases, A1ACT was detected even in the nuclei. Immunoreactivity for A1AT was found only in three cases. Two cases of PTC showed no staining for both A1ACT and A1AT. No significant correlation of A1ACT staining was found with various prognostic indices (age of patients, histological pattern, tumour size, presence of regional lymph node metastases). The two cases showing a lack of staining for both A1ACT and A1AT showed a more aggressive clinical behaviour. Conclusions Our preliminary study shows that A1ACT is expressed by tumour cells in a large proportion of papillary carcinomas of the thyroid gland. Its significance remains, to the best of our knowledge, still unknown. The observation of a more aggressive behaviour in the two cases characterized by the absence of immunoreactivity for both A1ACT and A1AT suggests that the presence or absence of protease inhibitors could play a role in controlling tumour progression in PTC. [ABSTRACT FROM AUTHOR]

An increasing number of proteins are being shown to assemble into amyloid structures, self-seeding fibrillar aggregates that may lead to pathological states or play essential biological functions in organisms. Bacterial cell factories have raised as privileged model systems to understand the mechanisms behind amyloid assembly and the cellular fitness cost associated to the formation of these aggregates. In the near future, these bacterial systems will allow implementing high-throughput screening approaches to identify effective modulators of amyloid aggregation. [ABSTRACT FROM AUTHOR]

A total of seven routinely processed biopsy specimens of facial skin lesions with infestation of Demodex folliculorum or D. brevis were immunostained for plasma proteins and secretory proteins. The cuticular layer of the mites located within the pilosebaceous unit was selectively immunoreactive for IgD (delta chain), alpha-1-antitrypsin and alpha-1-antichymotrypsin. Negative results were obtained for IgG, IgA, IgM, IgE, albumin, fibrinogen, C3, amyloid P component, prealbumin, lysozyme and lactoferrin. These findings suggest a novel function of IgD and serum protease inhibitors as a protective host response to the mite. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether thrombomodulin dysregulation is involved in the development of preeclampsia after oocyte donation (OD). Women who become pregnant after OD are prone to develop preeclampsia, a syndrome characterized by an aberrant immunologic response, hypercoagulability, and endothelial dysfunction. A mediator of inflammation and coagulation is thrombomodulin, which has a possible role to play in this syndrome.Design: Case-control study.Setting: Not applicable.Patient(s): Placentas from 82 women with an uncomplicated pregnancy (48 naturally conceived, 21 IVF, and 33 OD pregnancies) and 9 women with an OD pregnancy complicated by preeclampsia have been studied.Intervention(s): None.Main Outcome Measure(s): Abundances of thrombomodulin protein and vitamin D receptor (VDR) were determined using immunohistochemistry; mRNA expression was determined using quantitative polymerase chain reaction.Result(s): Placental thrombomodulin protein abundance was lower in OD pregnancies (diffuse pattern in 45%) than in controls (diffuse pattern in 96%). Placental thrombomodulin mRNA expression was lower in OD pregnancies complicated by preeclampsia (0.72 ± 0.47) compared with in uncomplicated OD pregnancies (0.43 ± 0.18). Thrombomodulin expression correlated with inflammation and coagulation. VDR expression was decreased in OD pregnancies complicated by preeclampsia and was correlated with thrombomodulin mRNA.Conclusion(s): Pregnancies conceived through OD lose placental thrombomodulin expression. This loss is associated with an increased coagulation and inflammation and indicates that endothelial protection is diminished in OD pregnancies, which might be an explanation for the increased risk for preeclampsia. Vitamin D metabolism is dysregulated in OD pregnancies and might be a target for therapy. [ABSTRACT FROM AUTHOR]