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The present work aims to study the influence of ammonium-quaternary monomers and chitosan, obtained from different sources, upon the effect of semi-interpenetrating polymer network (semi-IPN) hydrogels upon the removal of waterborne pathogens and bacteria from wastewater. To this end, the study was focused on using vinyl benzyl trimethylammonium chloride (VBTAC), a water-soluble monomer with known antibacterial properties, and mineral-enriched chitosan extracted from shrimp shells, to prepare the semi-IPNs. By using chitosan, which still contains the native minerals (mainly calcium carbonate), the study intends to justify that the stability and efficiency of the semi-IPN bactericidal devices can be modified and better improved. The new semi-IPNs were characterized for composition, thermal stability and morphology using well-known methods. Swelling degree (SD%) and the bactericidal effect assessed using molecular methods revealed that hydrogels made of chitosan derived from shrimp shell demonstrated the most competitive and promising potential for wastewater (WW) treatment.

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Wastewater (WW) has been widely recognized as the major sink of a variety of emerging pathogens (EPs), antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs), which may disseminate and impact wider environments. Improving and maximizing WW treatment efficiency to remove these microbial hazards is fundamentally imperative. Despite a variety of physical, biological and chemical treatment technologies, the efficiency of ARG removal is still far from satisfactory. Within our recently accomplished M-ERA.NET project, novel functionalized nanomaterials, i.e., molecularly imprinted polymer (MIP) films and quaternary ammonium salt (QAS) modified kaolin microparticles, were developed and demonstrated to have significant EP removal effectiveness on both Gram-positive bacteria (GPB) and Gram-negative bacteria (GNB) from WW. As a continuation of this project, we took the further step of exploring their ARG mitigation potential. Strikingly, by applying MIP and QAS functionalized kaolin microparticles in tandem, the ARGs prevalent in wastewater treatment plants (WWTPs), e.g., blaCTXM, ermB and qnrS, can be drastically reduced by 2.7, 3.9 and 4.9 log (copies/100 mL), respectively, whereas sul1, tetO and mecA can be eliminated below their detection limits. In terms of class I integron-integrase I (intI1), a mobile genetic element (MGE) for horizontal gene transfer (HGT), 4.3 log (copies/100 mL) reduction was achieved. Overall, the novel nanomaterials exhibit outstanding performance on attenuating ARGs in WW, being superior to their control references. This finding provides additional merit to the application of developed nanomaterials for WW purification towards ARG elimination, in addition to the proven bactericidal effect.

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Despite major efforts to combat pollution, the presence of pathogenic bacteria is still detected in surface water, soil and even crops due to poor purification of domestic and industrial wastewaters. Therefore, we have designed molecularly imprinted polymer films and quaternary ammonium-functionalized- kaolin microparticles to target specifically Gram-negative bacteria (GNB) and Gram-positive bacteria (GPB) in wastewaters and ensure a higher purification rate by working in tandem. According to the bacteriological indicators, a reduction by 90 % was registered for GNB (total coliforms and Escherichia coli O157) and by 77 % for GPB (Clostridium perfringens) in wastewaters. The reduction rates were confirmed when using pathogen genetic markers to quantify particular types of GNB and GPB, like Salmonella typhimurium (reduction up to 100 %),Campylobacter jejuni (reduction up to 70 %), Enterococcus faecalis (reduction up to 81 %), Clostridium perfringens (reduction up to 97 %) and Shiga toxin-producing Escherichia coli (reduction up to 64 %). In order to understand the bactericidal activity of prepared films and microparticles, we have performed several key analyses such as Cryo-TEM, to highlight the auto-assembly mechanism of components during the films formation, and 29 Si/13 C CP/MAS NMR, to reveal the way quaternary ammonium groups are grafted on the surface of kaolin microparticles.

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This review aims to highlight the applications of one of the most prominent optical biosensor technologies, surface plasmon resonance (SPR), in the drug discovery process and quality analysis of pharmaceutical compounds and their particularities. SPR assay formats and experimental issues are used for pharmacokinetic drug profiling, ADMET studies, high-throughput screening, and fragment-based drug screening, the last with an emphasis on the detection of small (drug) molecules. The classical method strengths and some applications of localized SPR and SPR imaging that are of high interest in the drug discovery process are presented, as well as possible challenges. While similar works treat separately the steps of drug discovery or focus only on the detection of drug residues in food or health safety, this review presents in a compact format the results and the progress obtained in both areas (drug discovery and quality analysis) based on the application of SPR biosensors.

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This study presents a multiparametric label-free analysis gathering surface plasmon resonance (SPR) and electrical impedance spectroscopy (EIS) for monitoring the progress of a model epithelial cell culture (Madin Darbey Canine Kidney - MDCK) exposed to a peptide with high bio-medical relevance, amyloid ß (Aß42). The approach surpasses the limitations in using the SPR angle for analyzing confluent cell monolayers and proposes a novel quantitative analysis of the SPR dip combined with advanced EIS as a tool for dynamic cell assessment. Long, up to 48h time series of EIS and SPR data reveal a biphasic cellular response upon Aß42 exposure corresponding to changes in cell-substrate adherence, cell-cell tightening or cytoskeletal remodeling. The equivalent circuit used for fitting the EIS spectra provided substantiation of SPR analysis on the progress of cell adhesion as well as insight on dynamics of cell-cell junction. Complementary endpoint assays: western blot analysis and atomic force microscopy experiments have been performed for validation. The proposed label free sensing of nonlethal effect of model amyloid protein at cellular level provides enhanced resolution on cell-surface and cell-cell interactions modulated by membrane related protein apparatus, applicable as well to other adherent cell types and amyloid compounds.

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Surface quality of the Surface Plasmon Resonance (SPR) chips is a major limiting issue in most SPR analyses, even more for supported lipid membranes experiments, where both the organization of the lipid matrix and the subsequent incorporation of the target molecule depend on the surface quality. A novel quantitative method to characterize the quality of SPR sensors chips is described for L1 chips subject to formation of lipid films, injection of membrane disrupting compounds, followed by appropriate regeneration procedures. The method consists in analysis of the SPR reflectivity curves for several standard solutions (e.g. PBS, HEPES or deionized water). This analysis reveals the decline of sensor surface as a function of the number of experimental cycles (consisting in biosensing assay and regeneration step) and enables active control of surface regeneration for enhanced reproducibility. We demonstrate that quantitative evaluation of the changes in reflectivity curves (shape of the SPR dip) and of the slope of the calibration curve provides a rapid and effective procedure for surface quality assessment. Whereas the method was tested on L1 SPR sensors chips, we stress on its amenability to assess the quality of other types of SPR chips, as well.

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Although modeling and experimental approaches to probe antimicrobial peptides-lipid membranes interaction have already been reported, quantitative evaluation of the whole process, including full dissolution of the lipid, is still missing. We report on the real-time assessment of the entire set of stages of melittin-membrane interaction, based on surface plasmon resonance (SPR) measurements, using supported lipid matrices on L1 sensors and long peptide injections. We advance a mathematical model which comprises a set of coupled kinetic equations and relates via the transfer matrix the evolution of lipid and peptide concentrations with the SPR sensorgram. Upon fitting the sensorgrams of melittin injections on POPC lipid matrices, in agreement with literature data, the model provides: association and dissociation rates, concentration thresholds, and evolution within each interacting layer of lipid and peptide concentrations as well as of peptide to lipid ratios. The proposed model combined with appropriate experimental protocols adds new depths to SPR investigation of peptide-lipid interaction offering a quantitative platform for research and controlled design of improved antimicrobial peptides. A wider applicability for quantitative assessment of other pore forming compounds on different lipid matrices is suggested.

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A new and exciting biosensing avenue based on assessment of the non-monotonous, concentration dependent effect of pore formation is discussed. A novel kinetic model is advanced to relate surface plasmon resonance (SPR) data with actual concentrations of interacting partners. Lipid modified L1 sensor chip provide the accessible platform for SPR exploration of peptide-membrane interaction, with POPC and melittin as model systems. We show that quantitative assessment of the interaction between an antimicrobial peptide and lipid modified sensors is capable to provide both sensing avenues and detailed mechanistic insights into effects of pore-forming compounds. The proposed model combined with appropriate design of the experimental protocol adds a new depth to the classic SPR investigation of peptide-lipid interaction offering a quantitative platform for detection, improved understanding of the manifold facets of the interaction and for supporting the controlled design of novel antimicrobial compounds. This biosensing approach can be applied to an entire set of pore-forming compounds including antimicrobial peptides and exo-toxins.

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OBJECTIVE: Mortality due to esophageal adenocarcinoma has risen markedly, but the molecular mechanisms underlying this carcinogenesis are still incompletely understood. Findings from loss of heterozygosity (LOH) studies have suggested that the long arm of chromosome 4 might harbor tumor suppressor genes relevant to esophageal adenocarcinoma. METHODS: We performed LOH analysis of 4q in esophageal adenocarcinomas. Regions of LOH were further evaluated by studying two candidate tumor suppressor genes, hCDC4 and CARF, located within them. RESULTS: 54% of the adenocarcinomas examined showed allelic deletion. LOH was observed in 53, 40, 32, 38, and 27% of tumors at positions D4S1554 (the locus of CARF), D4S1572, D4S1548, D4S2934, and D4S3021, respectively. An area of allelic deletion (spanning 3 million bases) was identified at 4q31.1-3 in 37% of tumors. This region harbors a candidate tumor suppressor gene: hCDC4. However, sequencing of the coding regions of CARF and hCDC4 at 4q35 and 4q31, respectively, did not identify mutations. CONCLUSIONS: Our findings demonstrate frequent LOH in esophageal adenocarcinoma at several loci including a novel area of allelic deletion at 4q31.1-3. The results imply that mutational or other alterations at these loci may be involved in the pathogenesis of esophageal adenocarcinoma. Candidate tumor suppressor genes located within these regions merit further study.

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BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). We sought to determine the frequency of high-level microsatellite instability (MSI-H) and the mutational and methylation profile of MSI-H IBD-related neoplasms (IBDNs). METHODS: A total of 124 IBDNs (81 cancers, 43 dysplasias) from 78 patients were studied for the frequency of MSI-H and hypermethylation of 3 target genes: MLH1 , HPP1 , and RAB-32 . Fifteen MSI-H IBDNs were characterized according to their profile of frameshift mutations in 28 mononucleotide repeats and compared with 46 sporadic MSI-H CRCs. RESULTS: Nineteen of 124 IBDNs were MSI-H. The frequency of frameshift mutations in coding mononucleotide repeats was significantly lower in MSI-H IBDNs than in sporadic MSI-H CRCs for TGFBR2 (7 of 14 vs 34 of 43 samples; P = .047) and ACVR2 (3 of 14 vs 25 of 43 samples; P = .029). In contrast, ICA1 was mutated in 3 of 9 MSI-H IBDNs vs 2 of 54 sporadic MSI-H CRCs ( P = .028). HPP1 and RAB32 methylation was independent of MSI status and was observed in 4 of 59 and 0 of 64 nondysplastic mucosae, 20 of 38 and 1 of 25 dysplasias, and 28 of 61 and 20 of 60 carcinomas, respectively. CONCLUSIONS: The profiles of coding microsatellite mutations (instabilotypes) differ significantly between MSI-H IBDNs and MSI-H sporadic CRCs. Specifically, TGFBR2 and ACVR2 mutations are significantly rarer in MSI-H IBDNs than in MSI-H sporadic CRCs. Furthermore, HPP1 methylation occurs early, in 7% of nondysplastic and approximately half of dysplastic mucosae, whereas RAB32 methylation occurs at the transition to invasive growth, being rarer in dysplasias.

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Patients with Barrett's esophagus (BE) are at increased risk of developing esophageal adenocarcinoma (EAC). Clinical neoplastic progression risk factors, such as age and the length of the esophageal BE segment, have been identified. However, improved molecular biomarkers predicting increased progression risk are needed for improved risk assessment and stratification. Using real-time quantitative methylation-specific PCR, we screened 10 genes (HPP1, RUNX3, RIZ1, CRBP1, 3-OST-2, APC, TIMP3, p16, MGMT, p14) for promoter hypermethylation in 77 EAC, 93 BE, and 64 normal esophagus (NE) specimens. A subset of genes manifesting significant differences in methylation frequencies between BE and EAC was then analysed in 20 dysplastic specimens. All 10 genes except p14 were frequently methylated in EACs, with RUNX3, HPP1, CRBP1, RIZ1, and OST-2 representing novel methylation targets in EAC and/or BE. p16, RUNX3, and HPP1 displayed increasing methylation frequencies in BE vs EAC. Furthermore, these increases in methylation occurred early, at the interface between BE and low-grade dysplasia (LGD). To demonstrate the silencing effect of hypermethylation, we selected the EAC cells BIC1, in which the HPP1 promoter is natively methylated, and subjected them to 5-aza-2'-deoxycytidine (Aza-C) treatment. Real-time RT-PCR indicated increased HPP1 mRNA levels after 3 days of Aza-C treatment, as well as decreased levels of methylated HPP1 DNA. Hypermethylation of a subset of six genes (APC, TIMP3, CRBP1, p16, RUNX3, and HPP1) was then tested in a retrospective longitudinal study of 99 BE and nine LGD specimens obtained from 53 BE patients undergoing surveillance endoscopy. Only high-grade dysplasia (HGD) or EAC were defined as progression end points. Two patient groups were compared: eight progressors (P) and 45 nonprogressors (NP), using Cox proportional hazards models to determine the relative progression risks of age, BE segment length, and methylation events. Multivariate analyses revealed that only hypermethylation of p16 (odds ratio (OR) 1.74, 95% confidence interval (CI) 1.33-2.20), RUNX3 (OR 1.80, 95% CI 1.08-2.81), and HPP1 (OR 1.77, 95% CI 1.06-2.81) were independently associated with an increased risk of progression, whereas age, BE segment length, and hypermethylation of TIMP3, APC, or CRBP1 were not independent risk factors. In combined analyses, risk was detectable up to, but not earlier than, 2 years preceding neoplastic progression. Hypermethylation of p16, RUNX3, and HPP1 in BE or LGD may represent independent risk factors for the progression of BE to HGD or EAC. These findings have implications regarding risk stratification, early EAC detection, and the appropriate endoscopic surveillance interval for patients with BE.

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The activin type II receptor (ACVR2) gene is a putative tumor suppressor gene that is frequently mutated in microsatellite-unstable colon cancers (MSI-H colon cancers). ACVR2 is a member of the transforming growth factor (TGF)-beta type II receptor (TGFBR2) family and controls cell growth and differentiation. SMAD proteins are major intracellular effectors shared by ACVR2 and TGFBR2 signaling; however, additional shared effector mechanisms remain to be explored. To discover novel mechanisms transmitting the ACVR2 signal, we restored ACVR2 function by transfecting wild-type ACVR2 (wt-ACVR2) into a MSI-H colon cancer cell line carrying an ACVR2 frameshift mutation. The effect of ACVR2 restoration on cell growth, SMAD phosphorylation, and global molecular phenotype was then evaluated. Decreased cell growth was observed in wt-ACVR2 transfectants relative to ACVR2-deficient vector-transfected controls. Western blotting revealed higher expression of phosphorylated SMAD2 in wt-ACVR2 transfectants versus controls, suggesting cells deficient in ACVR2 had impaired SMAD signaling. Microarray-based differential expression analysis revealed substantial ACVR2-induced overexpression of genes implicated in the control of cell growth and tumorigenesis, including the activator protein (AP)-1 complex genes JUND, JUN, and FOSB, as well as the small GTPase signal transduction family members, RHOB, ARHE, and ARHGDIA. Overexpression of these genes is shared with TGFBR2 activation. This observed similarity between the activin and TGF-beta signaling systems suggests that activin may serve as an alternative activator of TGF-beta effectors, including SMADs, and that frameshift mutation of ACVR2 may contribute to MSI-H colon tumorigenesis via disruption of alternate TGF-beta effector pathways.

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PCNA and esophagin have been implicated in the multistep process of carcinogenesis, but simultaneous characterization of these proteins in the early stages of esophageal neoplastic progression has yet to be undertaken. In morphologically normal esophageal epithelium, esophagin stains the granular layer cells, principally in their cell membrane portions. PCNA, in contrast, stains the nuclei of cells in the parabasal and basal layers. We examined 201 regions from 47 patients that represented different stages of esophageal neoplasia, comprising 34 areas of normal mucosa, 18 of dysplasia in squamous epithelium (DYS/SC), 39 squamous cell carcinoma (SCCA), 29 areas of Barrett's esophagus, 48 of Barrett's dysplasia (DYS/BAR) and 33 areas of adenocarcinoma (AC). The immunostaining patterns of esophagin and PCNA were evaluated and graded for level of expression. There was loss of esophagin expression in the high- and low-grade dysplasias compared to normal epithelia. In the squamous dysplasias, there was more intense staining (of esophagin) in the atypical nuclei and superficial squamous epithelial cells than in the basal cells. PCNA staining was increased in intensity in the high-grade dysplasias relative to normal basal layer cells. Combined analysis of esophagin and PCNA appears to reveal an inverse relationship between proliferation and differentiation during esophageal neoplastic progression. Moreover, this combined staining approach also offers promise for detecting esophageal cancer in early, precancerous stages.

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Gene silencing through CpG island hypermethylation has been associated with genesis or progression of frequent microsatellite instability (MSI-H) cancers. To identify novel methylation sites unique to MSI-H colon cancers in an unbiased fashion, we conducted a global expression profiling-based methylation target search. We identified 81 genes selectively down-regulated in MSI-H cancers using cDNA microarray analysis of 41 primary colon cancers. Forty six of these 81 genes contained CpG islands overlapping their 5'untranslated regions. Initial screening of six genes in 57 primary colon cancers detected the following gene with MSI-H cancer-specific hypermethylation: RAB32, a ras family member and A-kinase-anchoring protein, was methylated in 14 of 25 (56%) MSI-H cancers but in none of 32 non-MSI-H cancers or 23 normal colonic specimens. RAB32 hypermethylation correlated with RAB32 mRNA down-regulation and with hMLH1 hypermethylation. In addition, the protein-tyrosine phosphatase receptor type O gene, PTPRO, was frequently methylated in right-sided tumors. This methylation screening strategy should identify additional genes inactivated by epigenetic silencing in colorectal and other cancers.

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The rising incidence and poor prognosis of esophageal adenocarcinoma in the Western world have intensified research efforts into earlier methods of detection of this disease and its relationship to Barrett's esophagus. The progression of Barrett's esophagus to adenocarcinoma has been the focus of particular scrutiny, and a number of potential tissue and serum-based disease biomarkers have emerged. The epidemiology and pathogenesis of esophageal adenocarcinoma are outlined. Tissue biomarkers allowing risk stratification of Barrett's are reviewed as well as strategies currently being used to discover novel biomarkers that will facilitate the early detection of esophageal adenocarcinoma. Finally, the uses of biomarkers as predictive tests for targeted treatments and as surrogate endpoints in chemoprevention trials are considered.

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To discover a biological basis for clinical subgroupings within breast cancers, we applied principal components (PCs) analysis to cDNA microarray data from 36 breast cancers. We correlated the resulting PCs with clinical features. The 35 PCs discovered were ranked in order of their impact on gene expression patterns. Interestingly, PC 7 identified a unique subgroup consisting of estrogen receptor (ER); (+) African-American patients. This group exhibited global molecular phenotypes significantly different from both ER (-) African-American women and ER (+) or ER (-) Caucasian women (P < 0.001). Additional significant PCs included PC 4, correlating with lymph node metastasis (P = 0.04), and PC 10, with tumor stage (stage 2 versus stage 3; P = 0.007). These results provide a molecular phenotypic basis for the existence of a biologically unique subgroup comprising ER (+) breast cancers from African-American patients. Moreover, these findings illustrate the potential of PCs analysis to detect molecular phenotypic bases for relevant clinical or biological features of human tumors in general.

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The activin type II receptorgene (ACTRII) is mutated in 58.1% of microsatellite-unstable (MSI-H) colorectal cancers and is a close relative of the TGFbeta-1 type II receptor, which is known to be involved in both MSI-H and non-MSI-H colorectal carcinogenesis. We therefore sought to determine whether ACTRII was involved in non-MSI-H colorectal cancers. We evaluated ACTRII inactivation by allelic deletion, loss of mRNA expression, or somatic mutation in 51 non-MSI-H colon cancers. Loss of heterozygosity (LOH) at the ACTRII locus (2q23.1) was found in 9 (17.6%) of 51 primary tumors. Loss of ACTRII mRNA expression was seen in one (14.3%) of the seven LOH-positive primary tumors from which total RNA was available. We also performed DNA sequencing analysis of tumors showing LOH. One LOH-positive primary tumor exhibited a novel germline missense sequence alteration (amino acid substitution, 117 Ile to Phe) that was not found in 23 additional normal individuals, implying that this alteration is not a frequent polymorphism. We conclude that ACTRII is probably involved in both non-MSI-H and MSI-H colorectal carcinogenesis, but more frequently in the latter subgroup.

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Frequent microsatellite instability MSI (MSI-H) occurring in human tumors is characterized by defective DNA mismatch repair and unique clinical features. However, infrequent MSI (MSI-L) has not been attributable to any other defined molecular pathway, and its existence as a biologically distinct category has been challenged. Moreover, the global molecular phenotypes (GMPs) underlying MSI-H, MSI-L, or microsatellite-stable (MSS) tumors have never been evaluated. To evaluate the impact of MSI status on GMP and to determine the importance of MSI relative to other molecular and clinical features, cDNA microarray-derived data from 41 colon cancers were interpreted using principal components analysis. The clinically relevant principal component with the greatest impact on GMP was component 3, which distinguished MSI-H from non-MSI-H (i.e., MSI-L and microsatellite stable) tumors and was designated the MSI-H separator. Notably, MSI-L cancers were also clearly distinguished from non-MSI-L tumors by another principle component, component 10 (the "MSI-L separator"). This second finding validates the existence of MSI-L tumors as a distinct molecular phenotypic category. Thus, both components 3 and 10 reflected different aspects of MSI and helped to establish principal components analysis as a useful tool to identify and characterize distinct biological features of human malignancy.

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Frequent loss of heterozygosity (LOH) on human chromosome 7q31 has been reported in numerous malignancies. Suppressor of tumorigenicity 7 (ST7) has been identified as a candidate tumor suppressor gene in this region. To identify whether 7q31 and genetic alterations of ST7 were involved in human esophageal carcinogenesis, we performed LOH mapping of a 5.4 cM region at 7q31-q35 in 43 primary esophageal carcinomas, as well as mutational analyses of the ST7 gene in tumors with LOH in this region. Of 43 tumors, 12 (28%) showed LOH at 7q31-q35. These included four (22%) of 18 squamous cell carcinomas and eight (32%) of 25 adenocarcinomas. The peak LOH locus was D7S480, lying 4.2 Mb telomeric to ST7 and showing LOH in eight of 37 informative tumors, or 22%. No mutations were found in the entire coding or flanking intronic regions of the ST7 gene among 12 tumors with 7q-LOH. In addition, quantitative RT-PCR analyses of ST7 mRNA expression levels in 11/13 normal-tumor pairs failed to show more than a 50% decrease in tumor ST7 mRNA relative to matched normal tissues. These data suggest that LOH at 7q31-q35 is involved in the origin or progression of at least a subset of esophageal carcinomas, but that ST7 is not the target gene of this somatic event.

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The HPP1 gene was cloned as a frequently methylated gene in hyperplastic polyps of the colon. It has been shown that HPP1 expression is silenced by HPP1 gene hypermethylation in sporadic colorectal cancers. To determine the role of HPP1 in ulcerative colitis (UC)-associated carcinogenesis, the prevalence of HPP1 methylation was investigated in three different histological stages of UC-associated carcinogenesis (non-neoplastic UC colon, dysplasia, and carcinoma). Quantitative methylation-specific PCR and quantitative reverse transcription-PCR were used to determine HPP1 gene methylation and expression levels, respectively. HPP1 methylation was observed in 24 of 48 (50%) adenocarcinomas and in 4 of 10 (40%) dysplasias. In contrast, no non-neoplastic UC mucosa showed HPP1 methylation. HPP1 expression in the HCT116 colon cancer cell line was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine. In conclusion, our data suggest that methylation of HPP1 is a relatively common early event in UC-associated carcinogenesis. HPP1 offers potential as a biomarker for the early detection of cancer or dysplasia in UC.

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