Mucin pattern reflects the origin of the adenocarcinoma in Barrett's esophagus: a retrospective clinical and laboratorial study

Background: Mucin immunoexpression in adenocarcinoma arising in Barrett's esophagus (BE) may indicate the carcinogenesis pathway. The aim of this study was to evaluate resected specimens of adenocarcinoma in BE for the pattern of mucins and to correlate to the histologic classification. Methods: Specimens were retrospectively collected from thirteen patients who underwent esophageal resection due to adenocarcinoma in BE. Sections were scored for the grade of intestinal metaplasia. The tissues were examined by immunohistochemistry for MUC2 and MUC5AC antibodies. Results: Eleven patients were men. The mean age was 61 years old (varied from 40 to 75 years old). The tumor size had a mean of 4.7 +/- 2.3 cm, and the extension of BE had a mean of 7.7 +/- 1.5 cm. Specialized epithelium with intestinal metaplasia was present in all adjacent mucosas. Immunohistochemistry for MUC2 showed immunoreactivity in goblet cells, while MUC5AC was extensively expressed in the columnar gastric cells, localizing to the surface epithelium and extending to a variable degree into the glandular structures in BE. Tumors were classified according to the mucins in gastric type in 7/13 (MUC5AC positive) and intestinal type in 4/13 (MUC2 positive). Two tumors did not express MUC2 or MUC5AC proteins. The pattern of mucin predominantly expressed in the adjacent epithelium was associated to the mucin expression profile in the tumors, p = 0.047. Conclusion: Barrett's esophagus adenocarcinoma shows either gastric or intestinal type pattern of mucin expression. The two types of tumors developed in Barrett's esophagus may reflect the original cell type involved in the malignant transformation.

Expression of Monocarboxylate Transporters 1, 2, and 4 in Human Tumours and Their Association with CD147 and CD44

Monocarboxylate transporters (MCTs) are important cellular pH regulators in cancer cells; however, the value of MCT expression in cancer is still poorly understood. In the present study, we analysed MCT1, MCT2, and MCT4 protein expression in breast, colon, lung, and ovary neoplasms, as well as CD147 and CD44. MCT expression frequency was high and heterogeneous among the different tumours. Comparing with normal tissues, there was an increase in MCT1 and MCT4 expressions in breast carcinoma and a decrease in MCT4 plasma membrane expression in lung cancer. There were associations between CD147 and MCT1 expressions in ovarian cancer as well as between CD147 and MCT4 in both breast and lung cancers. CD44 was only associated with MCT1 plasma membrane expression in lung cancer. An important number of MCT1 positive cases are negative for both chaperones, suggesting that MCT plasma membrane expression in tumours may depend on a yet nonidentified regulatory protein.

Challenges and opportunities for primary, secondary, and tertiary prevention of Chagas' disease

A century after its discovery, Chagas' disease still represents a major public health challenge in Latin America. Moreover, because of growing population movements, an increasing number of cases of imported Chagas' disease have now been detected in non-endemic areas, such as North America and some European countries. This parasitic zoonosis, caused by Trypanosoma cruzi, is transmitted to humans by infected Triatominae insects, or occasionally by non-vectorial mechanisms, such as blood transfusion, mother to fetus, or oral ingestion of materials contaminated with parasites. Following the acute phase of the infection, untreated individuals enter a chronic phase that is initially asymptomatic or clinically unapparent. Usually, a few decades later, 40-50% of patients develop progressive cardiomyopathy and/or motility disturbances of the oesophagus and colon. In the last decades several interventions targeting primary, secondary and tertiary prevention of Chagas' disease have been attempted. While control of both vectorial and blood transfusion transmission of T cruzi (primary prevention) has been successful in many regions of Latin America, early detection and aetiological treatment of asymptomatic subjects with Chagas' disease (secondary prevention) have been largely underutilised. At the same time, in patients with established chronic disease, several pharmacological and non-pharmacological interventions are currently available and have been increasingly used with the intention of preventing or delaying complications of the disease (tertiary prevention). In this review we discuss in detail each of these issues.

Trends in socioeconomic inequalities in cancer mortality in Barcelona: 1992-2003

Background: The objective of this study was to assess trends in cancer mortality by educational level in Barcelona from 1992 to 2003. Methods: The study population comprised Barcelona inhabitants aged 20 years or older. Data on cancer deaths were supplied by the system of information on mortality. Educational level was obtained from the municipal census. Age-standardized rates by educational level were calculated. We also fitted Poisson regression models to estimate the relative index of inequality (RII) and the Slope Index of Inequalities (SII). All were calculated for each sex and period (1992-1994, 1995-1997, 1998-2000, and 2001-2003). Results: Cancer mortality was higher in men and women with lower educational level throughout the study period. Less-schooled men had higher mortality by stomach, mouth and pharynx, oesophagus, larynx and lung cancer. In women, there were educational inequalities for cervix uteri, liver and colon cancer. Inequalities of overall and specific types of cancer mortality remained stable in Barcelona; although a slight reduction was observed for some cancers. Conclusion: This study has identified those cancer types presenting the greatest inequalities between men and women in recent years and shown that in Barcelona there is a stable trend in inequalities in the burden of cancer.

Effects of perinatal protein deprivation and recovery on esophageal myenteric plexus

AIM: To evaluate effects of pre- and postnatal protein deprivation and postnatal recovery on the myenteric plexus of the rat esophagus. METHODS: Three groups of young Wistar rats (aged 42 d) were studied: normal-fed (N42), protein-deprived (D42), and protein-recovered (R42). The myenteric neurons of their esophagi were evaluated by histochemical reactions for nicotinamide adenine dinucleotide (NADH), nitrergic neurons (NADPH)-diaphorase and acetylcholinesterase (AChE), immunohistochemical reaction for vasoactive intestinal polypeptide (VIP), and ultrastructural analysis by transmission electron microscopy. RESULTS: The cytoplasms of large and medium neurons from the N42 and R42 groups were intensely reactive for NADH. Only a few large neurons from the D42 group exhibited this aspect. NADPH detected in the D42 group exhibited low reactivity. The AChE reactivity was diffuse in neurons from the D42 and R42 groups. The density of large and small varicosities detected by immunohistochemical staining of VIP was low in ganglia from the D42 group. In many neurons from the D42 group, the double membrane of the nuclear envelope and the perinuclear cisterna were not detectable. NADH and NADPH histochemistry revealed no group differences in the profile of nerve cell perikarya (ranging from 200 to 400 mu m(2)). CONCLUSION: Protein deprivation causes a delay in neuronal maturation but postnatal recovery can almost completely restore the normal morphology of myenteric neurons. (C) 2010 Baishideng. All rights reserved.

Comparison of multispectral wide-field optical imaging modalities to maximize image contrast for objective discrimination of oral neoplasia

Multispectral widefield optical imaging has the potential to improve early detection of oral cancer. The appropriate selection of illumination and collection conditions is required to maximize diagnostic ability. The goals of this study were to (i) evaluate image contrast between oral cancer/precancer and non-neoplastic mucosa for a variety of imaging modalities and illumination/collection conditions, and (ii) use classification algorithms to evaluate and compare the diagnostic utility of these modalities to discriminate cancers and precancers from normal tissue. Narrowband reflectance, autofluorescence, and polarized reflectance images were obtained from 61 patients and 11 normal volunteers. Image contrast was compared to identify modalities and conditions yielding greatest contrast. Image features were extracted and used to train and evaluate classification algorithms to discriminate tissue as non-neoplastic, dysplastic, or cancer; results were compared to histologic diagnosis. Autofluorescence imaging at 405-nm excitation provided the greatest image contrast, and the ratio of red-to-green fluorescence intensity computed from these images provided the best classification of dysplasia/cancer versus non-neoplastic tissue. A sensitivity of 100% and a specificity of 85% were achieved in the validation set. Multispectral widefield images can accurately distinguish neoplastic and non-neoplastic tissue; however, the ability to separate precancerous lesions from cancers with this technique was limited. (C) 2010 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3516593]

Identification of protein-coding and non-coding RNA expression profiles in CD34(+) and in stromal cells in refractory anemia with ringed sideroblasts

Background: Myelodysplastic syndromes (MDS) are a group of clonal hematological disorders characterized by ineffective hematopoiesis with morphological evidence of marrow cell dysplasia resulting in peripheral blood cytopenia. Microarray technology has permitted a refined high-throughput mapping of the transcriptional activity in the human genome. Non-coding RNAs (ncRNAs) transcribed from intronic regions of genes are involved in a number of processes related to post-transcriptional control of gene expression, and in the regulation of exon-skipping and intron retention. Characterization of ncRNAs in progenitor cells and stromal cells of MDS patients could be strategic for understanding gene expression regulation in this disease. Methods: In this study, gene expression profiles of CD34(+) cells of 4 patients with MDS of refractory anemia with ringed sideroblasts (RARS) subgroup and stromal cells of 3 patients with MDS-RARS were compared with healthy individuals using 44 k combined intron-exon oligoarrays, which included probes for exons of protein-coding genes, and for non-coding RNAs transcribed from intronic regions in either the sense or antisense strands. Real-time RT-PCR was performed to confirm the expression levels of selected transcripts. Results: In CD34(+) cells of MDS-RARS patients, 216 genes were significantly differentially expressed (q-value <= 0.01) in comparison to healthy individuals, of which 65 (30%) were non-coding transcripts. In stromal cells of MDS-RARS, 12 genes were significantly differentially expressed (q-value <= 0.05) in comparison to healthy individuals, of which 3 (25%) were non-coding transcripts. Conclusions: These results demonstrated, for the first time, the differential ncRNA expression profile between MDS-RARS and healthy individuals, in CD34(+) cells and stromal cells, suggesting that ncRNAs may play an important role during the development of myelodysplastic syndromes.

New antitumoral agents I: In vitro anticancer activity and in vivo acute toxicity of synthetic 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one and derivatives

This paper describes a new method for the preparation of 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one 1 and its derivatives 2-5. This set of synthetic compounds exhibited high antitumoral activities regarding in vitro screening against several human tumor cell lines as lung carcinoma NCI-460, melanoma UACC-62, breast MCF-7, colon HT-29, renal 786-O, ovarian OVCAR-03 and ovarian expressing the resistance phenotype for adriamycin NCI-ADR/ RES, prostate PC-3, and leukemia K-562. Compounds were also tested against murine tumor cell line B16F10 melanoma and lymphocytic leukemia L1210 as well as to their effect toward normal macrophages. Specific activity against colon cancer cells HT-29 was observed for all tested compounds and suggests further studies with models of colon cancer. Compounds 1, 2, and 4 showed significant cytotoxic activity with IC(50) values <= 2.3 mu M for all human cancer cell lines. Intraperitoneal acute administration of compound 1 and 2 showed very low toxicity rate. (C) 2010 Elsevier Ltd. All rights reserved.

Chemopreventive effects of beta-ionone and geraniol during rat hepatocarcinogenesis promotion: distinct actions on cell proliferation, apoptosis, HMGCoA reductase, and RhoA

Chemopreventive activities of the dietary isoprenoids beta-ionone (beta I) and geraniol (GOH) were evaluated during the promotion phase of hepatocarcinogenesis. Over 5 consecutive weeks, rats received daily 16 mg/100 g body weight (b.w.) of beta I (beta I group), 25 mg/100 g b.w. of GOH (GOH group), or only corn oil (CO group, controls). Compared to the CO group, the following was observed: only the beta I group showed a decrease in the mean number of visible hepatocyte nodules (P<.05); beta I and GOH groups had reduced mean number of persistent preneoplastic lesions (pPNLs) (P<.05), but no differences regarding number of remodeling PNL (rPNLs) were observed; only the beta I group exhibited smaller rPNL size and percentage of liver sections occupied by pPNLs (P<.05), whereas the GOH group displayed a smaller percentage of liver sections occupied by rPNLs (P<.05); a trend was observed in the beta I group, which showed reduced cell proliferation of pPNLs (P<.10), and the GOH group had increased apoptosis in pPNLs and rPNLs (P<.05); only the beta I group displayed reduced total plasma cholesterol concentrations (P<.05) and increased hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase mRNA levels (P<.05): only the GOH group had lower hepatic membrane RhoA protein levels (P<.05); both the beta I- and GOH-treated groups had higher hepatic concentrations of beta I and GOH, respectively (P<.05). Given these data, beta I and GOH show promising chemopreventive effects during promotion of hepatocarcinogenesis by acting through distinct mechanism of actions: beta I may inhibit cell proliferation and modulate HMGCoA reductase, and GOH can induce apoptosis and inhibit RhoA activation. (C) 2011 Elsevier Inc. All rights reserved.

Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug

Hepatocellular carcinoma (HCC) ranks in prevalence and mortality among top 10 cancers worldwide. Butyric acid (BA), a member of histone deacetylase inhibitors (HDACi) has been proposed as an anticareinogenic agent. However, its short half-life is a therapeutical limitation. This problem could be circumvented with tributyrin (TB), a proposed BA prodrug. To investigate TB effectiveness for chemoprevention, rats were treated with the compound during initial phases of ""resistant hepatocyte"" model of hepatocarcinogenesis, and cellular and molecular parameters were evaluated. TB inhibited (p < 0.05) development of hepatic preneoplastic lesions (PNL) including persistent ones considered HCC progression sites. TB increased (p < 0.05) PNL remodeling, a process whereby they tend to disappear. TB did not inhibit cell proliferation in PNL, but induced (p < 0.05) apoptosis in remodeling ones. Compared to controls, rats treated with TB presented increased (P < 0.05) hepatic levels of BA indicating its effectiveness as a prodrug. Molecular mechanisms of TB-induced hepatocarcinogenesis chemoprevention were investigated. TB increased (p < 0.05) hepatic nuclear histone H3K9 hyperacetylation specifically in PNL and p21 protein expression, which could be associated with inhibitory HDAC effects. Moreover, it reduced (p < 0.05) the frequency of persistent PNL with aberrant cytoplasmic p53 accumulation, an alteration associated with increased malignancy. Original data observed in our study support the effectiveness of TB as a prodrug of BA and as an HDACi in hepatocarcinogenesis chemoprevention. Besides histone acetylation and p21 restored expression, molecular mechanisms involved with TB anticarcinogenic actions could also be related to modulation of p53 pathways. (C) 2008 Wiley-Liss, Inc.

Chemical Constituents of Papulaspora immersa, an Endophyte from Smallanthus sonchifolius (Asteraceae), and Their Cytotoxic Activity

Papulaspora immersa H. H. HOTS ON was isolated from roots and leaves of Smallanthus sonchifolius (POEPP. and ENDL.) H. ROB. (Asteraceae), traditionally known as Yacon. The fungus was cultured in rice, and, from the AcOEt fraction, 14 compounds were isolated. Among them, (22E,24R)-8,14-epoxyergosta-4,22-diene-3,6-dione (4), 2,3-epoxy-1,2,3,4-tetrahydronaphthalene-c-1,c-4,8-triol (10), and the chromone papulasporin (13) were new secondary metabolites. The spectral data of the known natural products were compared with the literature data, and their structures were established as the (24R)stigmast 4 en 3 one (1), 24-methylenecycloartan-3 beta-ol (2), (22E,24R)-ergosta-4,6,8(14),22-tetraen-3-one (3), (-)-(3R,4R)-4-hydroxymellein (5), (-)-(3R)-5-hydroxymellein (6), 6,8-dihydroxy-3-methylisocoumarin (7), (-)-(4S)-4,8-dihydroxy-alpha-tetralone (8), naphthalene-1,8-diol (9), 6,7,8-trihydroxy-3-methylisocoumarin (11), 7-hydroxy-2,5-dimethylchromone (12), and tyrosol (14). Compound 4 showed the highest cytotoxic activity against the human tumor cell lines MDA-MB435 (melanoma), HCT-8 (colon), SF295 (glioblastoma), and HL-60 (promyelocytic leukemia), with IC(50) values of 3.3, 14.7, 5.0 and 1.6 mu m, respectively. Strong synergistic effects were also observed with compound 5 and some of the isolated steroidal compounds.

Does Cyclophosphamide Play a Protective Role Against Neuronal Loss in Chronic T. cruzi Infection?

In this study, we verified the possible role of cyclophosphamide (CY) in protecting or not against neuronal losses in young and aged male Calomys callosus chronically infected with the MORC-1 strain of Trypanosoma cruzi through numerical quantification of neurons from the myenteric plexus of the colon and quantification of nitric-oxide concentration (NO) during the acute and chronic phase of infection. For this purpose, groups of young C. callosus were infected with the MORC-1 strain of T. cruzi. A group of infected animals received i.p. 0.2 mg/ml genuxal dissolved in distilled water treatment with CY. NO concentration in aged animals displayed reduced levels when compared to those found in young animals. No significant alterations in the number of neurons were observed in young animals, but for aged ones, a protective role of CY in reducing neuron loss was noted, in addition to enhancing the neuronal volume, area, and perimeter. These results suggest that CY administration, depending on the dose and time span, can act as a protective agent against neuronal losses.

Innate immune lectins kill bacteria expressing blood group antigen

The expression of ABO(H) blood group antigens causes deletion of cells that generate self-specific antibodies to these antigens but this deletion limits adaptive immunity toward pathogens bearing cognate blood group antigens. To explore potential defense mechanisms against such pathogens, given these limitations in adaptive immunity, we screened for innate proteins that could recognize human blood group antigens. Here we report that two innate immune lectins, galectin-4 (Gal-4) and Gal-8, which are expressed in the intestinal tract, recognize and kill human blood group antigen-expressing Escherichia coli while failing to alter the viability of other E. coli strains or other Gram-negative or Gram-positive organisms both in vitro and in vivo. The killing activity of both Gal-4 and Gal-8 is mediated by their C-terminal domains, occurs rapidly and independently of complement and is accompanied by disruption of membrane integrity. These results demonstrate that innate defense lectins can provide immunity against pathogens that express blood group-like antigens on their surface.

Alkyl halides, super hydrogen production and the pathogenesis of pneumatosis cystoides coli

Background and aims-The colons of patients with pneumatosis cystoides coli produce excessive H-2. Exposure to alkyl halides could explain this. Six consecutive patients who had pneumatosis cystoides coli while taking chloral hydrate (1-5+ g/day) are reported. Patients 2 and 3 were investigated after they had ceased chloral hydrate treatment. One produced methane, the other did not. (Pneumatosis cystoides coli patients are non-methanogenic according to the literature.) Both had overnight fasting breath H-2 of less than 10 ppm. A literature review disclosed just one patient who was using chloral at the time of diagnosed pneumatosis cystoides coli, but an epidemic of the disease in workers exposed to trichloroethylene. Methods-(i) In vitro experiments with human faeces: chloral or closely related alkyl halides were added to anaerobic faecal cultures derived from four methane-producing and three non-methanogenic human subjects. H-2 and CH4 gases were measured. (ii) In vivo animal experiment: chloral hydrate was added to drinking water of four Wistar rats, and faecal HI compared with control rats. Results-Alkyl halides increased H-2 up to 900 times in methanogenic and 10 times in non-methanogenic faecal cultures. The K-i of chloral was 0.2 mM. Methanogenesis was inhibited in concert with the increase in net H-2. In the rat experiment, chloral hydrate increased H-2 10 times, but did not cause pneumatosis. Conclusions-Chloral and trichloroethylene are alkyl halides chemically similar to chloroform, a potent inhibitor of H-2 consumption by methanogens and acetogens. These bacteria are the most important H-2-consuming species in the colon. It is postulated that exposure to these alkyl halides increases net H-2 production, which sets the scene for counterperfusion supersaturation and the formation of gas cysts. In recent times, very low prescribing rates for chloral have caused primary pneumatosis cystoides to become extremely rare. As with primary pneumatosis, secondary pneumatosis cystoides, which occurs if there is small bowel bacterial overgrowth distal to a proximally located gut obstruction, is predicted by counterperfusion supersaturation. Inherent unsaturation due to metabolism of O-2 is a safety factor, which could explain why gas bubbles do not form more often in tissue with high H-2 tension.

Derivatives of 1,3,5-triamino-1,3,5-trideoxy-cis-inositas versatile pentadentate ligands for protein labeling with Re-186/188. Prelabeling, biodistribution, and X-ray structural studies

The pentadentate H(3)bhci [1,3,5-trideoxy-1,3-bis((2-hydroxybenzyl)amino)-cis-inistol] and its bifunctionalized analogue H(3)bhci-glu-H [1,3,5-trideoxy-1,3-bis((2-hydroxybenzyl)amino)-5-glutaramido-cis-inositol] were synthesized, and their coordination chemistry was investigated with inactive rhenium, with no carrier added Re-188 and with carrier added Re-186. The neutral Re(V) complexes [ReO-(bhci)] and [ReO(bhci-glu-H)] are formed in good yields starting from [ReOCl3(P(C6H5)(3))(2)] or in quantitative yield directly from [(ReO4)-Re-186/188](-) in aqueous solution by reduction with Sn(II) or Sn(0). The X-ray structures of [ReO(bhci)] and [ReO(bhci-glu-H)] were elucidated revealing pentadentate side on coordination of the ligands to the Re=O core. The basic cyclohexane frame adopts a chair form in the case of [ReO(bhci)] and a twisted boat form in the case of [ReO(bhci-glu-H)]. [ReO(bhci)] crystallizes in the monoclinic space group C2/c with a = 27.425(3), b = 14.185(1), c = 19.047(2) Angstrom, and beta = 103.64(2)degrees and [ReO(bhci-glu-H)] in the monoclinic space group P2(1)/c with a = 13.056(3), b = 10.180(1), c = 22.378(5) Angstrom and beta = 98.205(9)degrees Both Re-188 complexes are stable in human serum for at least 3 days without decomposition. After injection into mice, [ReO(bhci-glu)](-) is readily excreted through the intestines, while [ReO(bhci)] is excreted by intestines, liver, and the kidneys. TLC investigations of the urine showed exclusively the complexes [ReO(bhci-glu-H)] and [ReO(bhci)], respectively, and no decomposition products. For derivatization of antibodies, the carboxylic group of [ReO(bhci-glu-H)] was activated with N-hydroxysuccinimide, which required unusually vigorous reaction conditions (heating). The anti colon cancer antibody mAb-35 [IgG and F(ab')(2) fragment] was labeled with [(ReO)-Re-186/188(bhci-glu)] to a specific activity of up to 1.5 mCi/mg (55 MBq/mg) with full retention of immunoreactivity. Labeling yields followed pseudo-first-order kinetics in antibody concentration with the ratio of rates between aminolysis and hydrolysis being about 2. Biodistributions of Re-186-labeled intact mAb-35 as well as of its F(ab')(2) fragment in tumor-bearing nude mice revealed good uptake by the tumor with only low accumulation of radioactivity in normal tissue.