Cancer Screening by Systemic Administration of a Gene Delivery Vector Encoding Tumor-Selective Secretable Biomarker Expression

Cancer biomarkers facilitate screening and early detection but are known for only a few cancer types. We demonstrated the principle of inducing tumors to secrete a serum biomarker using a systemically administered gene delivery vector that targets tumors for selective expression of an engineered cassette. We exploited tumor-selective replication of a conditionally replicative Herpes simplex virus (HSV) combined with a replication-dependent late viral promoter to achieve tumor-selective biomarker expression as an example gene delivery vector. Virus replication, cytotoxicity and biomarker production were low in quiescent normal human foreskin keratinocytes and high in cancer cells in vitro. Following intravenous injection of virus >90% of tumor-bearing mice exhibited higher levels of biomarker than non-tumor-bearing mice and upon necropsy, we detected virus exclusively in tumors. Our strategy of forcing tumors to secrete a serum biomarker could be useful for cancer screening in high-risk patients, and possibly for monitoring response to therapy. In addition, because oncolytic vectors for tumor specific gene delivery are cytotoxic, they may supplement our screening strategy as a “theragnostic” agent. The cancer screening approach presented in this work introduces a paradigm shift in the utility of gene delivery which we foresee being improved by alternative vectors targeting gene delivery and expression to tumors. Refining this approach will usher a new era for clinical cancer screening that may be implemented in the developed and undeveloped world

Feeding fish oil and condensed corn distillers solubles increases conjugated linoleic acid in milk and modulates immune response in dairy cows.

Dairy cows are often subjected to dietary modifications so as to increase the healthful fatty acids in milk. The important fatty acids include conjugated linoleic acid and omega-3 / n-3 fatty acids. Conjugated linoleic acid, a naturally-occurring polyunsaturated fatty acid, is found preferentially in ruminant milk and meat. It has potential health benefits such as being anti-carcinogenic, anti-atherogenic, anti-obesity, and anti- diabetic as well as contributing to immune system enhancement in animal models and humans. Since the human body is unable to synthesize conjugated linoleic acid except from vaccenic acid which is also found in ruminant milk and meat, it is important to increase its production in milk. It has been observed that dietary polyunsaturated fatty acids influence the fatty acid composition of inflammatory and immune cells in humans; however, little information is available about the effects of conjugated linoleic acid on the immune system of dairy cattle. We conducted the following experiments, based on the hypothesis that feeding condensed com distiller solubles and fish oil would increase the conjugated linoleic acid content in milk and that conjugated linoleic acid improves the immune response. Twelve lactating Holstein cows were fed diets containing either fish oil or condensed com distiller solubles or both in a 4x 4 Latin square design. Feeding fish oil or condensed com distiller solubles resulted in decreased percentages and yield of fat in milk; however, greater concentrations of n-3 fatty acids, conjugated linoleic acid and vaccenic acid in milk were observed. Greater concentrations of vaccenic acid in milk and plasma indicated that endogenous synthesis from vaccenic acid also contributed to conjugated linoleic acid in milk. Immune tesponse was monitored by culturing peripheral blood mononuclear cells with mitogens to measure the proliferation response and cell surface phenotyping by flowcytometry for specific bovine leukocyte markers. Feeding the diet containing both fish oil and condensed corn distiller solubles resulted in decreased T cell mediated immunity and enhanced innate immune response. These results will help dairy producers to establish a nutritional practice for the production of milk rich in beneficial fatty acids resulting in increased net returns and also aid in the development of nutritionally-based therapeutic applications to augment host resistance

Distinct signatures for mutator sensitivity of lacZ reversions and for the spectrum of lacI/lacO forward mutations on the chromosome of nondividing Escherichia coli.

A conditional lethal galE(Ts)-based strategy was employed in Escherichia coli, first to eliminate all growth-associated chromosomal reversions in lacZ or forward mutations in lacI/lacO by incubation at the restrictive temperature and subsequently to recover (as papillae) spontaneous mutations that had arisen in the population of nondividing cells after shift to the permissive temperature. Data from lacZ reversion studies in mutator strains indicated that the products of all genes for mismatch repair (mutHLS, dam, uvrD), of some for oxidative damage repair (mutMT), and of that for polymerase proofreading (dnaQ) are required in dividing cells; some others for oxidative damage repair (mutY, nth nei) are required in both dividing and nondividing cells; and those for alkylation damage repair (ada ogt) are required in nondividing cells. The spectrum of lacI/lacO mutations in nondividing cells was distinguished both by lower frequencies of deletions and IS1 insertions and by the unique occurrence of GC-to-AT transitions at lacO +5. In the second approach to study mutations that had occurred in nondividing cells, lacI/lacO mutants were selected as late-arising papillae from the lawn of a galE+ strain; once again, transitions at lacO +5 were detected among the mutants that had been obtained from populations initially grown on poor carbon sources such as acetate, palmitate, or succinate. Our results indicate that the lacO +5 site is mutable only in nondividing cells, one possible mechanism for which might be that random endogenous alkylation (or oxidative) damage to DNA in these cells is efficiently corrected by the Ada Ogt (or Nth Nei) repair enzymes at most sites but not at lacO +5. Furthermore, the late-arising papillae from the second approach were composed almost exclusively of dominant lacI/lacO mutants. This finding lends support to "instantaneous gratification" models in which a spontaneous lesion, occurring at a random site in DNA of a nondividing cell, is most likely to be fixed as a mutation if it allows the cell to immediately exit the nondividing state

Values alignment in sustaining healthcare innovation processes

Innovating has always been an integral aspect of health and care as it impacts the ability to deliver and improve services for increasingly complex needs. Yet, health and care innovations often fail to spread or are slow in uptake. In this chapter, we focus on the role of values in implementing and sustaining innovation in healthcare settings. We argue that the alignment or mismatch of values has significant implications for the uptake and diffusion of innovations. Using data from two case studies of social care innovations we show that the mechanisms that underpin values alignment as well as the actors involved change as innovations evolve

Drink, drugs and gambling

In this collection are included Gandhiji's writings (often only in extract form), and reports of his talks on drink, drugs, smoking and gambling. He himself said that for him intoxicants meant all these habit-forming indulgences, even tea

Conjugated linoleic acid (CLA) in milk increases in cows fed condensed corn distillers solubles and fish oil.

Twelve lactating Holstein cows were randomly assigned to 1 of 4 experimental diets in a replicated 4 x 4 Latin square design with 4-wk periods to ascertain the lactational response to feeding fish oil (FO), condensed corn distillers solubles (CDS) as a source of extra linoleic acid, or both. Diets contained either no FO or 0.5% FO and either no CDS or 10% CDS in a 2 x 2 factorial arrangement of treatments. Diets were fed as total mixed rations for ad libitum consumption. The forage to concentrate ratio was 55:45 on a dry matter basis for all diets and the diets contained 16.2% crude protein. The ether extract concentrations were 2.86, 3.22, 4.77, and 5.02% for control, FO, CDS, and FOCDS diets, respectively. Inclusion of FO or CDS or both had no effect on dry matter intake, feed efficiency, body weight, and body condition scores compared with diets without FO and CDS, respectively. Yields of milk (33.3 kg/d), energy-corrected milk, protein, lactose, and milk urea N were similar for all diets. Feeding FO and CDS decreased milk fat percentages (3.85, 3.39, 3.33, and 3.12%) and yields compared with diets without FO and CDS. Proportions of trans-11 C18:1 (vaccenic acid), cis-9 trans-11 conjugated linoleic acid (CLA; 0.52, 0.90, 1.11, and 1.52 g/100 g of fatty acids), and trans-10 cis-12 CLA (0.07, 0.14, 0.13, and 0.16 g/100 g of fatty acids) in milk fat were increased by FO and CDS. No interactions were observed between FO and CDS on cis-9 trans-11 CLA although vaccenic acid tended to be higher with the interaction. The addition of CDS to diets increased trans-10 C18:1. Greater ratios of vaccenic acid to cis-9 trans-11 CLA in plasma than in milk fat indicate tissue synthesis of cis-9 trans-11 CLA in the mammary gland from vaccenic acid in cows fed FO or CDS. Feeding fish oil at 0.5% of diet dry matter with a C18:2 n-6 rich source such as CDS increased the milk CLA content but decreased milk fat percentages

From evidence use to evidencing work : towards a processual view of the role of evidence in commissioning policy-making

Evidence cannot directly lead decision-makers as evidence is not found, rather, it is assembled (“constituted”) locally through an observable negotiated social process. Evidence is thus an outcome; it is always the result of the collective work entailed in its production and use, work that we refer to as ‘evidencing work’. Adopting a processual view, in the chapter we start to unpack and make visible the evidencing work that goes into turning evidential information into evidence using illustrative data from Clinical Commissioning Groups in the UK. In doing so we argue that much can be gained if shift from treating evidence as an entity toward evidencing as the giving of evidential value to information in the clinical decision-making process. This has implications evidence-based health care policy and management in terms of the role that evidencing plays in the decision-making process