Effects of curative treatment emphasizing endurance training on the performance and blood pressure of hypertensive and normotensives

The problem of normal values of blood pressure after exercise taking into account the blood pressure at the end of the exercise test is discussed. Hypertensives showed a lower working capacity than normotensives. In normotensives, however, systolic blood pressure at the end of an exercise correlated well with the working capacity. After the endurance cure submaximal blood pressure was markedly lower in hypertensives with a striking dependence on the level of initial values. Systolic blood pressure at the end of an exercise test was not changed significantly. Most probably it is not possible to overcome this malregulation in hypertensives by endurance training alone

Suicide genes: Monitoring cells in patients with a safety switch

Clinical trials increasingly incorporate suicide genes either as direct lytic agents for tumors or as safety switches in therapies based on genetically modified cells. Suicide genes can also be used as non-invasive reporters to monitor the biological consequences of administering genetically modified cells to patients and gather information relevant to patient safety. These genes can monitor therapeutic outcomes addressable by early clinical intervention. As an example, our recent clinical trial used 18F-9-(4-fluoro-3-hydroxymethylbutyl)guanine (18FHBG) and PET/CT scans to follow T cells transduced with herpes simplex virus thymidine kinase (TK) after administration to patients. Guided by preclinical data we ultimately hope to discern whether a particular pattern of transduced T cell migration within patients reflects early development of Graft vs. Host Disease (GvHD). Current difficulties in terms of choice of suicide gene, biodistribution of radiolabeled tracers in humans versus animal models, and threshold levels of genetically modified cells needed for detection by PET/CT are discussed. As alternative suicide genes are developed, additional radiolabel probes suitable for imaging in patients should be considered

p53 deficiency linked to B cell translocation gene 2 (BTG2) loss enhances metastatic potential by promoting tumor growth in primary and metastatic sites in patient-derived xenograft (PDX) models of triple-negative breast cancer

Mini-signature of genes that interact with the p53 pathway and associated p values. (PDF 62 kb

Life's Joke: Bergson, Comedy, and the Meaning of Laughter

The present essay argues that Bergson’s account of the comic can only be fully appreciated when read in conjunction with his later metaphysical exposition of the élan vital in Creative Evolution and then by the account of fabulation that Bergson only elaborates fully three decades later in The Two Sources of Morality and Religion. The more substantive account of the élan vital ultimately shows that, in Laughter, Bergson misses his own point: laughter does not simply serve as a means for correcting human behavior but is rather the élan vital’s vital summons, the demand of life itself, that human beings challenge their obligations, question their societal forms, and thereby create new and, for Bergson, more ideal forms of life and community

Synthetic Lethality of Chk1 Inhibition Combined with p53 and/or p21 Loss During a DNA Damage Response in Normal and Tumor Cells

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction

Anticancer Gene Transfer for Cancer Gene Therapy

Gene therapy vectors are among the treatments currently used to treat malignant tumors. Gene therapy vectors use a specific therapeutic transgene that causes death in cancer cells. In early attempts at gene therapy, therapeutic transgenes were driven by non-specific vectors which induced toxicity to normal cells in addition to the cancer cells. Recently, novel cancer specific viral vectors have been developed that target cancer cells leaving normal cells unharmed. Here we review such cancer specific gene therapy systems currently used in the treatment of cancer and discuss the major challenges and future directions in this field

Heart and systemic effects of statin pretreatment in a rat model of abdominal sepsis. Assessment by Tc99m-sestamibi biodistribition

PURPOSE: To evaluate the heart and the Tc-99m-sestamibi biodistribution after statin pretreatment in a rat model of abdominal sepsis. METHODS: Twenty-four Wistar rats were randomly distributed into four groups (n=6 per group): 1) sepsis with simvastatin treatment, 2) sepsis with vehicle, 3) sham control with simvastatin and 4) sham control with vehicle. 24 hours after cecal ligation and puncture rats received 1.0MBq of Tc-99m-sestamibi i.v. 30min after, animals were euthanized for ex-vivo tissue counting and myocardium histological analysis. RESULTS: Myocardial histologic alterations were not detected 24 hours post-sepsis. There was significantly increased cardiac Tc-99m-sestamibi activity in the sepsis group with simvastatin treatment (1.9$\pm$0.3%ID/g, p<0.001) in comparison to the sepsis group+vehicle (1.0$\pm$0.2% ID/g), control sham group+ simvastatin (1.2$\pm$0.3% ID/g) and control sham group (1.3$\pm$0.2% ID/g). Significant Tc-99m-sestamibi activity in liver, kidney and lungs was also detected in the sepsis group treated with simvastatinin comparison to the other groups. CONCLUSIONS: Statin treatment altered the biodistribution of Tc-99m-sestamibi with increased cardiac and solid organ activity in rats with abdominal sepsis, while no impact on controls. Increased myocardial tracer activity may be a result of a possible protection effect due to increased tissue perfusion mediated by statins