CA19-9 as a Potential Target for Radiolabeled Antibody-Based Positron Emission Tomography of Pancreas Cancer.

Introduction. Sensitive and specific imaging of pancreas cancer are necessary for accurate diagnosis, staging, and treatment. The vast majority of pancreas cancers express the carbohydrate tumor antigen CA19-9. The goal of this study was to determine the potential to target CA19-9 with a radiolabeled anti-CA19-9 antibody for imaging pancreas cancer. Methods. CA19-9 was quantified using flow cytometry on human pancreas cancer cell lines. An intact murine anti-CA19-9 monoclonal antibody was labeled with a positron emitting radionuclide (Iodine-124) and injected into mice harboring antigen positive and negative xenografts. MicroPET/CT were performed at successive time intervals (72 hours, 96 hours, 120 hours) after injection. Radioactivity was measured in blood and tumor to provide objective confirmation of the images. Results. Antigen expression by flow cytometry revealed approximately 1.3 × 10(6) CA19-9 antigens for the positive cell line and no expression in the negative cell line. Pancreas xenograft imaging with Iodine-124-labeled anti-CA19-9 mAb demonstrated an average tumor to blood ratio of 5 and positive to negative tumor ratio of 20. Conclusion. We show in vivo targeting of our antigen positive xenograft with a radiolabeled anti-CA19-9 antibody. These data demonstrate the potential to achieve anti-CA19-9 antibody based positron emission tomography of pancreas cancer

Automatic Software Test Data Generation for Spanning Sets Coverage Using Genetic Algorithms

Software testing takes a considerable amount of time and resources spent on producing software. Therefore, it would be useful to have ways to reduce the cost of software testing. The new concepts of spanning sets of entities suggested by Marré and Bertolino are useful for reducing the cost of testing. In fact, to reduce the testing effort, the generation of test data can be targeted to cover the entities in the spanning set, rather than all the entities in the tested program. Marré and Bertolino presented an algorithm based on the subsumption relation between entities to find spanning sets for a family of control flow and data flow-based test coverage criteria. This paper presents a new general technique for the automatic test data generation for spanning sets coverage. The proposed technique applies to the algorithm proposed recently by Marré and Bertolino to automatically generate the spanning sets of program entities that satisfy a wide range of control flow and data flow-based test coverage criteria. Then, it uses a genetic algorithm to automatically generate sets of test data to cover these spanning sets. The proposed technique employed the concepts of spanning sets to limit the number of test cases, guide the test case selection, overcome the problem of the redundant test cases and automate the test path generation

A Comprehensive Genetic Characterization of Bacterial Motility

We have developed a powerful experimental framework that combines competitive selection and microarray-based genetic footprinting to comprehensively reveal the genetic basis of bacterial behaviors. Application of this method to Escherichia coli motility identifies 95% of the known flagellar and chemotaxis genes, and reveals three dozen novel loci that, to varying degrees and through diverse mechanisms, affect motility. To probe the network context in which these genes function, we developed a method that uncovers genome-wide epistatic interactions through comprehensive analyses of double-mutant phenotypes. This allows us to place the novel genes within the context of signaling and regulatory networks, including the Rcs phosphorelay pathway and the cyclic di-GMP second-messenger system. This unifying framework enables sensitive and comprehensive genetic characterization of complex behaviors across the microbial biosphere

Genetic Architecture of Intrinsic Antibiotic Susceptibility

BACKGROUND:Antibiotic exposure rapidly selects for more resistant bacterial strains, and both a drug's chemical structure and a bacterium's cellular network affect the types of mutations acquired. METHODOLOGY/PRINCIPAL FINDINGS:To better characterize the genetic determinants of antibiotic susceptibility, we exposed a transposon-mutagenized library of Escherichia coli to each of 17 antibiotics that encompass a wide range of drug classes and mechanisms of action. Propagating the library for multiple generations with drug concentrations that moderately inhibited the growth of the isogenic parental strain caused the abundance of strains with even minor fitness advantages or disadvantages to change measurably and reproducibly. Using a microarray-based genetic footprinting strategy, we then determined the quantitative contribution of each gene to E. coli's intrinsic antibiotic susceptibility. We found both loci whose removal increased general antibiotic tolerance as well as pathways whose down-regulation increased tolerance to specific drugs and drug classes. The beneficial mutations identified span multiple pathways, and we identified pairs of mutations that individually provide only minor decreases in antibiotic susceptibility but that combine to provide higher tolerance. CONCLUSIONS/SIGNIFICANCE:Our results illustrate that a wide-range of mutations can modulate the activity of many cellular resistance processes and demonstrate that E. coli has a large mutational target size for increasing antibiotic tolerance. Furthermore, the work suggests that clinical levels of antibiotic resistance might develop through the sequential accumulation of chromosomal mutations of small individual effect

Physical, psychosocial, relationship, and economic burden of caring for people with cancer: A review

The aim of this article is to provide an overview of the issues faced by caregivers of people diagnosed with cancer, with a particular emphasis on the physical, psychosocial, and economic impact of caring. A review of the literature identified cancer as one of the most common health conditions in receipt of informal caregiving, with the majority of caregivers reporting taking on the role of caring because of family responsibility and there being little choice or no one else to provide the care. For some, caregiving can extend for several years and become equivalent to a full-time job, with significant consequent health, psychosocial, and financial burdens. Having a better understanding of the critical and broad roles that caregivers play in the oncology setting and the impact of these on their health and well-being may assist health care professionals in supporting caregivers with these tasks and targeting services and interventions toward those most in need. Copyright © 2012 by American Society of Clinical Oncology

Novologues Containing a Benzamide Side Chain Manifest Anti-proliferative Activity Against Two Breast Cancer Cell Lines

The heat shock protein 90 (Hsp90) folding machinery is essential for the maturation of nascent polypeptides into their biologically active three-dimensional-structures and for the rematuration/clearance of misfolded proteins that form under cellular stress.1–3 As a prosurvival chaperone, Hsp90 overexpression is commonly observed in transformed cells, which is required to sustain the hostile tumor micro-environment associated with nutrient deprivation and hypoxia. Pharmacological inhibition of Hsp90 has been shown to induce the degradation of oncogenic proteins associated with all six hallmarks of cancer that rely upon Hsp90.4–8 Consequently, Hsp90 represents a highly sought after target for the treatment of cancer. In fact, 17 small molecules that bind competitively to the N-terminal ATP-binding pocket are under clinical evaluation against various cancers.9,10 However, heat shock factor 1 (HSF-1), the master regulator of the pro-survival heat shock response also binds Hsp90. Ultimately, Hsp90 N-terminal inhibition results in HSF-1 release, and upon phosphorylation, trimerizes and translocates to the nucleus wherein it binds the heat shock elements to activate the pro-survival, heat shock response (HSR). The HSR serves to expand the cellular buffering capacity and to assist in the maturation of mutated and oncogenic substrates.11 This concomitant heat shock response is detrimental to the treatment of cancer and may lead to drug resistance and tumor metastasis.12 Recent studies have demonstrated that allosteric modulation of the Hsp90 C-terminus can separate the pro-survival heat shock response from pro-apoptotic, client protein degradation.13–20 Two classes of small molecules derived from novobiocin 1, (Figure 1) the first identified Hsp90 C-terminal inhibitor, were discovered via the structure-activity relationship studies. KU-32 (2), which lacks a 4-hydroxyl, the 3’-carbamate, and contains an acetamide in lieu of a prenylated benzamide, represents a lead compound that induces the heat shock response at concentrations much lower than that needed for client protein degradation.2,21 Consequently, this class of analogues has been evaluated as neuroprotective agents to refold protein aggregates.22–24 In contrast, KU-174 (3) contains a biarylamide side chain in lieu of the acetamide, and induces Hsp90 client protein degradation without induction of the heat shock response.25–26 Therefore, this class of novobiocin analogues manifests optimal properties for the treatment of cancer, as no HSR is observed with such compounds

Response of maize inbred lines to two European corn borer (Ostrinia nubilalis) strains in Canada

Six lignées de maïs-grain (CM47, A619, F2, CM107, CM7 et A654) ont été évaluées en 1986 et 1987 dans quatre localités de l'Ontario et du Québec pour leur résistance à des infestations artificielles de la pyrale du maïs, Ostrinia nubilalis, de la race univoltine et de la première génération de la race bivoltine. Trois critères ont été utilisés: la criblure du feuillage, les dégâts totaux des plantes à la récolte, et le rapport longueur des galeries creusées par les chenilles dans les tiges sur la hauteur des plantes. Des interactions importantes ont été observées pour les critères utilisés entre les années et localités, mais la réaction des lignées de maïs a été plutôt constante. Pour tous les critères, la race univoltine a souvent causé, d'une façon significative, plus de dégâts aux plantes que la race bivoltine. En général, la lignée A619 a démontré le plus de résistance-tolérance tout en conservant une bonne tenue des tiges jusqu'à la récolte. On aurait avantage à utiliser la race univoltine dans les programmes d'amélioration génétique du maïs pour sa résistance à la pyrale.In 1986 and 1987, six maize inbred lines (CM47, A619, F2, CM107, CM7, and A654) were evaluated at four locations across Ontario and Quebec for their resistance to artificially infested univoltine and lst generation bivoltine strains of the European corn borer, Ostrinia nubilalis. Three criteria were used: leaf feeding, total plant damage at harvest and length of tunnels/plant height ratio. Substantial interactions in borer damage measurements were observed between locations and years, but inbred reaction was relatively consistent. For all criteria, the univoltine strain often caused significantly more damage than the bivoltine borer. In general, A619 had the greatest resistance-tolerance with good standability until harvest. Wherever possible, evaluation of genetic resistance in maize germplasm should be conducted using the univoltine borer strain

A mitochondrial cytopathy presenting with persistent troponin elevation: case report

Background Mitochondrial diseases represent an important potential cause of cardiomyopathy and should be considered in patients presenting with multisystem manifestations. Timely diagnosis of a mitochondrial disorder is needed as it can have reproductive implications for the offspring of the proband.Case Summary We describe a case of undifferentiated rising and persistent troponin elevation in a 70-year-old female with only mild heart failure symptoms and signs. An eventual diagnosis of a mitochondrial cytopathy was made after genetic testing, striated muscle, and endomyocardial biopsy. Multidisciplinary involvement was vital in securing the ultimate diagnosis and is a key lesson from this case. On follow up, with institution of heart failure therapy including cardiac resynchronisation device therapy there was improvement in exercise tolerance and symptoms. Discussion For discussion is the investigation of undifferentiated cardiomyopathies and consideration of mitochondrial disorders as an important diagnosis to exclude prior to diagnosis as an idiopathic cardiomyopathy