493 research outputs found
Lowâvolume, highâthroughput sandwich immunoassays for profiling plasma proteins in mice: Identification of earlyâstage systemic inflammation in a mouse model of intestinal cancer
Mouse models of human cancers may provide a valuable resource for the discovery of cancer biomarkers. We have developed a practical strategy for profiling specific proteins in mouse plasma using lowâvolume sandwichâimmunoassays. We used this method to profile the levels of 14 different cytokines, acuteâphase reactants, and other cancer markers in plasma from mouse models of intestinal tumors and their wildâtype littermates, using as little as 1.5ÎŒl of diluted plasma per assay. Many of the proteins were significantly and consistently upâregulated in the mutant mice. The mutant mice could be distinguished nearly perfectly from the wildâtype mice based on the combined levels of as few as three markers. Many of the proteins were upâregulated even in the mutant mice with few or no tumors, suggesting the presence of a systemic host response at an early stage of cancer development. These results have implications for the study of host responses in mouse models of cancers and demonstrate the value of a new lowâvolume, highâthroughput sandwichâimmunoassay method for sensitively profiling protein levels in cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135703/1/mol2200712216-sup-mmc1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135703/2/mol2200712216.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135703/3/mol2200712216-sup-mmc2.pd
Darifenacin hydroÂbromide
In the title compound {systematic name: (S)-3-[(aminocarÂbonyl)diphenylmethyl]-1-[2-(2,3-diÂhyÂdroÂbenzofuran-5-yl)ethyl]pyrrolidinium bromide}, C28H31N2O2
+·Brâ, the pyrrolidine rings adopts an envelope conformation. The two phenyl rings make a dihedral angle of 72.5â
(1)°. The four coplanar atoms of the pyrrolidine ring makes dihedral angles of 33.1â
(2) and 82.8â
(2)° with the two phenyl rings. The molÂecular conformation is influenced by a CâHâŻO interÂaction. In the crystal packing, there are two NâHâŻBr hydrogen bonds running in opposite directions. They appear to form C(10) and C(9) chain motifs in the unit cell. In addition, the molÂecular packing is further stabilized by CâHâŻBr and CâHâŻO hydrogen bonds. The C atom bonded to the benzofuran ring system is disordered in a 0.66:0.34 ratio
Glycogene Expression Alterations Associated with Pancreatic Cancer Epithelial-Mesenchymal Transition in Complementary Model Systems
The ability to selectively detect and target cancer cells that have undergone an epithelial-mesenchymal transition (EMT) may lead to improved methods to treat cancers such as pancreatic cancer. The remodeling of cellular glycosylation previously has been associated with cell differentiation and may represent a valuable class of molecular targets for EMT.As a first step toward investigating the nature of glycosylation alterations in EMT, we characterized the expression of glycan-related genes in three in-vitro model systems that each represented a complementary aspect of pancreatic cancer EMT. These models included: 1) TGFÎČ-induced EMT, which provided a look at the active transition between states; 2) a panel of 22 pancreatic cancer cell lines, which represented terminal differentiation states of either epithelial-like or mesenchymal-like; and 3) actively-migrating and stationary cells, which provided a look at the mechanism of migration. We analyzed expression data from a list of 587 genes involved in glycosylation (biosynthesis, sugar transport, glycan-binding, etc.) or EMT. Glycogenes were altered at a higher prevalence than all other genes in the first two models (p<0.05 and <0.005, respectively) but not in the migration model. Several functional themes were shared between the induced-EMT model and the cell line panel, including alterations to matrix components and proteoglycans, the sulfation of glycosaminoglycans; mannose receptor family members; initiation of O-glycosylation; and certain forms of sialylation. Protein-level changes were confirmed by Western blot for the mannose receptor MRC2 and the O-glycosylation enzyme GALNT3, and cell-surface sulfation changes were confirmed using Alcian Blue staining.Alterations to glycogenes are a major component of cancer EMT and are characterized by changes to matrix components, the sulfation of GAGs, mannose receptors, O-glycosylation, and specific sialylated structures. These results provide leads for targeting aggressive and drug resistant forms of pancreatic cancer cells
Heterogeneity of glycan biomarker clusters as an indicator of recurrence in pancreatic cancer
IntroductionOutcomes following tumor resection vary dramatically among patients with pancreatic ductal adenocarcinoma (PDAC). A challenge in defining predictive biomarkers is to discern within the complex tumor tissue the specific subpopulations and relationships that drive recurrence. Multiplexed immunofluorescence is valuable for such studies when supplied with markers of relevant subpopulations and analysis methods to sort out the intra-tumor relationships that are informative of tumor behavior. We hypothesized that the glycan biomarkers CA19-9 and STRA, which detect separate subpopulations of cancer cells, define intra-tumoral features associated with recurrence.MethodsWe probed this question using automated signal thresholding and spatial cluster analysis applied to the immunofluorescence images of the STRA and CA19-9 glycan biomarkers in whole-block sections of PDAC tumors collected from curative resections.ResultsThe tumors (N = 22) displayed extreme diversity between them in the amounts of the glycans and in the levels of spatial clustering, but neither the amounts nor the clusters of the individual and combined glycans associated with recurrence. The combined glycans, however, marked divergent types of spatial clusters, alternatively only STRA, only CA19-9, or both. The co-occurrence of more than one cluster type within a tumor associated significantly with disease recurrence, in contrast to the independent occurrence of each type of cluster. In addition, intra-tumoral regions with heterogeneity in biomarker clusters spatially aligned with pathology-confirmed cancer cells, whereas regions with homogeneous biomarker clusters aligned with various non-cancer cells.ConclusionThus, the STRA and CA19-9 glycans are markers of distinct and co-occurring subpopulations of cancer cells that in combination are associated with recurrence. Furthermore, automated signal thresholding and spatial clustering provides a tool for quantifying intra-tumoral subpopulations that are informative of outcome
Directive 02-14: Tax Obligations of Persons Purchasing Cigarettes in Interstate Commerce for which the Massachusetts Cigarette Excise Has Not Been Paid
The development of accurate clinical biomarkers has been challenging in part due to the diversity between patients and diseases. One approach to account for the diversity is to use multiple markers to classify patients, based on the concept that each individual marker contributes information from its respective subclass of patients. Here we present a new strategy for developing biomarker panels that accounts for completely distinct patient subclasses. Marker State Space (MSS) defines "marker states" based on all possible patterns of high and low values among a panel of markers. Each marker state is defined as either a case state or a control state, and a sample is classified as case or control based on the state it occupies. MSS was used to define multi-marker panels that were robust in cross validation and training-set/test-set analyses and that yielded similar classification accuracy to several other classification algorithms. A three-marker panel for discriminating pancreatic cancer patients from control subjects revealed subclasses of patients based on distinct marker states. MSS provides a straightforward approach for modeling highly divergent subclasses of patients, which may be adaptable for diverse applications.</p
Recommandations pour lâutilisation de la toxine botulinique de type A (BotoxÂź) dans lâhyperactivitĂ© vĂ©sicale rĂ©fractaire idiopathique
RĂ©sumĂ©ObjectifsDĂ©finir des recommandations pour lâutilisation pratique de la toxine botulinique de type A (BoNTA) dans lâhyperactivitĂ© vĂ©sicale rĂ©fractaire idiopathique (HAVRI).MĂ©thodeĂlaboration de recommandations de bonne pratique par consensus formalisĂ©, validĂ©es par un groupe de 13 experts puis par un groupe de lecture indĂ©pendant.RĂ©sultatsEn cas dâinfection urinaire celle-ci doit ĂȘtre traitĂ©e et lâinjection reportĂ©e. Avant lâinjection, il est recommandĂ© de sâassurer de la faisabilitĂ© et de lâacceptabilitĂ© de lâauto-sondage. Lâinjection peut ĂȘtre rĂ©alisĂ©e aprĂšs une anesthĂ©sie locale urĂ©tro-vĂ©sicale (lidocaĂŻne), Ă©ventuellement complĂ©tĂ©e par lâinhalation de protoxyde dâazote et parfois sous anesthĂ©sie gĂ©nĂ©rale. Lâinjection sera rĂ©alisĂ©e au bloc opĂ©ratoire ou en salle dâendoscopie. La vessie ne doit pas ĂȘtre trop remplie (risque de perforation). Le traitement doit ĂȘtre appliquĂ© en 10 à 20 injections de 0,5 à 1mL rĂ©parties de maniĂšre homogĂšne dans la vessie en restant Ă distance des mĂ©ats urĂ©tĂ©raux. Il nâest pas recommandĂ© de laisser en place une sonde vĂ©sicale sauf en cas dâhĂ©maturie importante. Le patient doit ĂȘtre surveillĂ© jusquâĂ la reprise mictionnelle. Une note dâinformation sur les effets indĂ©sirables Ă©ventuels doit lui ĂȘtre remise Ă sa sortie. Une consultation doit ĂȘtre prĂ©vue 3 mois aprĂšs la premiĂšre injection (calendrier mictionnel, dĂ©bitmĂ©trie, rĂ©sidu post-mictionnel et examen cytobactĂ©riologique des urines). Un rĂ©sidu >200mL et/ou symptomatique doit faire discuter des auto-sondages. Une nouvelle injection pourra ĂȘtre envisagĂ©e lorsque le bĂ©nĂ©fice clinique de la prĂ©cĂ©dente sâestompe (entre 6 et 9 mois).ConclusionsLe respect de ces recommandations devrait permettre une utilisation optimale de la BoNTA.Niveau de preuve3.SummaryObjectivesProvide guidelines for practical usage of botulinum toxin type A (BoNTA) for refractory idiopathic Overactive Bladder management.Patients and methodsGuidelines using formalized consensus guidelines method. These guidelines have been validated by a group of 13 experts quoting proposals, subsequently reviewed by an independent group of experts.ResultsIn the case of patients with urinary tract infection, it must be treated and injection postponed. Before proposing an injection, it is recommended to ensure the feasibility and acceptability of self-catheterisation by patient. The injection can be performed after local anesthesia of the bladder and urethra (lidocaine), supplemented where necessary by nitrous oxide inhalation and sometimes under general anesthesia. Injection is performed in the operating room or endoscopy suite. The bladder should not be too filled (increased risk of perforation). Treatment should be applied in 10 to 20 injections of 0.5 to 1mL homogeneously distributed in the bladder at a distance from the urethral orifices. It is not recommended to leave a urinary catheter in place except in cases of severe hematuria. The patient should be monitored until resumption of micturition. After the first injection, an appointment must be scheduled within 3 months (micturition diary, uroflowmetry, measurement of residual urine and urine culture). Performance of self-catheterisation should be questioned in the case of a symptomatic post-void residual and/or a residue>200mL. A new injection may be considered when the clinical benefit of the previous injection diminishes (between 6 and 9 months). A period of three months must elapse between each injection.ConclusionsImplementation of these guidelines may promote best practice usage of BoNTA with optimal risk/benefit ratio
The Marker State Space (MSS) Method for Classifying Clinical Samples
The development of accurate clinical biomarkers has been challenging in part due to the diversity between patients and diseases. One approach to account for the diversity is to use multiple markers to classify patients, based on the concept that each individual marker contributes information from its respective subclass of patients. Here we present a new strategy for developing biomarker panels that accounts for completely distinct patient subclasses. Marker State Space (MSS) defines "marker states" based on all possible patterns of high and low values among a panel of markers. Each marker state is defined as either a case state or a control state, and a sample is classified as case or control based on the state it occupies. MSS was used to define multi-marker panels that were robust in cross validation and training-set/test-set analyses and that yielded similar classification accuracy to several other classification algorithms. A three-marker panel for discriminating pancreatic cancer patients from control subjects revealed subclasses of patients based on distinct marker states. MSS provides a straightforward approach for modeling highly divergent subclasses of patients, which may be adaptable for diverse applications. © 2013 Fallon et al
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