• Gina Kirchweger

On the Heels of NFκB

Bhattacharya et al., pp. 404–411

There is hardly any normal cellular or bodily function in which nuclear factor-kappa B, a family of structurally related proteins, is not involved: immune and inflammatory responses, developmental processes, cellular growth and apoptosis. But it is also frequently on the scene when things start to go wrong: cancer, arthritis, chronic inflammation, autoimmune diseases, asthma, neurodegenerative disorders and heart disease.

NFκB's central position within the network of intracellular signaling pathways has made factors of this network key targets for the development of novel drugs.

However, in order to uncover cause-and-effect correlation on a systems-wide level, to perform quantitative NFκB activity measurements in large patient cohorts and to assess drug efficacy, the availability of cheap, simple and reliable high-throughput assays is crucial.

On pages 404-411, Bhattacharya et al. describe the development of a fast, sensitive and cost-effective method that allows them to do just that. In contrast to earlier protocols, their chemiluminescent oligonucleotide-based ELISA (co-ELISA) allows researchers to quantify the activity of all DNA-binding NFκB subunits (i.e., RelA, p50, p52, RelB and c-Rel) without the need to separate nuclear and cytosolic fractions. The co-ELISA has a 3.5- to 43-fold higher signal-over-noise ratio than currently available assays, whereas the percent relative standard deviation is 3- to 6-fold lower. The only limitation—due to the intricate, differential molecular functions of the different NFκB components—is that DNA-binding activity does not necessarily correlate with transcriptional activation, which has to be addressed on a target gene-to-gene basis.

The Children of Chernobyl

Noshenko et al., pages 412–426

On April 26, 1986, the explosion at the Chernobyl power plant in Northern Ukraine sent 50 tons of radioactive dust over an area of nearly 140,000 square miles—covering parts of Ukraine, Belarus and Russia and exposing as many as 4.9 million people to significant doses of radiation. The health effects on the exposed population have been the focus of numerous epidemiological studies and it is now clear that the accident has resulted in a large increase in the incidence of childhood thyroid cancer. In contrast, several studies examining the incidence of leukemia in exposed populations came to contradictory conclusions.

In their retrospective case-control study, Noshenko et al. evaluated whether those who were under 6 years old at the time of the Chernobyl disaster and were permanent residents of the most radioactively contaminated territories (Rivne, Zhytomyr, Chernihiv, Cherkasy), and therefore exposed to radiation in excess of 10mGy, had an increased radiation-induced risk of acute leukemia during the first 11 years after the disaster. The risk of leukemia was significantly increased (−2.4 [95%CI: 1.4–4.0]) among those with radiation exposure doses higher than 10 mGy (p = 0.01). The initial diagnosis was most prevalent in children 5–9 years of age, particularly acute lymphoblast leukemia. Acute myeloid leukemia occurred more often in those who were 5–17 years of age. Although some confounding factors linked with leukemia tended to increase the strength of the association between leukemia risk and the dose of radiation exposure, these synergistic effects were not statistically significant. 1.

Illustration 1.

Geographic regions (oblasts) of Ukraine where the study was performed. Oblast (region) is an administratively geographically defined territorial unit with a population of 1-4 million people. Each oblast is divided into smaller unit or rayons (district). Typically, there are 15-20 rayons in an oblast with a population of approximately 70,000-100,000 people.

Turning Against the Self

McIntyre and Faulk, pp. 491–496

Since the first therapeutic monoclonal antibody (mAb) was approved by the FDA in 1986 as a transplant rejection drug (muronomab), the list of mAbs used in the clinic has grown exponentially, with hundreds more currently studied in pre-clinical and clinical trials. However, some mAb treatments generate severe side effects, presumably due to collateral damage from reactions with antigens from unintended targets. In an effort to diminish the often serious clinical complications resulting from mAb therapy in patients with organ transplants, cancer or autoimmune diseases, researchers have gone to great lengths to engineer mAbs via chimerization and humanization.

After showing previously that multiple autoantibodies are unmasked in human polyclonal antibody preparations when they are exposed to physiological oxidizing agents such as hemin—the normal degradation product of hemoglobin—McIntyre and Faulk extended their studies to 9 commonly used mAbs, including 4 chimeric, 4 humanized and 1 chemically modified chimeric Fab. They found that all 9 of them developed autoantibody activity to phospholipids and DNA after oxidation with hemin, while retaining their original specificity. Only 1, Rituxan, which has been found to have several dangerous side effects, including neutropenia and lung toxicity, demonstrated anti-phospholipid activity before exposure to hemin.

The results from the current study hint at the possibility that side effects resulting from the clinical use of mAbs may be caused by the unmasking of mAb autoantibody activity if such oxidation reactions also occur in vivo, which, however, has not been proven.