Faculty Bibliography

PURPOSE:This review summarizes the conclusions and recommendations of the new National Council on Radiation Protection and Measurements (NCRP) Commentary No. 26 guidance on radiation dose limits for the lens of the eye. The NCRP addressed radiation protection principles in respect to the lens of the eye, discussed the current understanding of eye biology and lens effects, reviewed and evaluated epidemiology, and assessed exposed populations with the potential for significant radiation exposures to the lens while suggesting monitoring and protection practices. CONCLUSIONS:Radiation-induced damage to the lens of the eye can include the loss of clarity resulting in opacification or clouding several years after exposure. The impact is highly dependent on the type of radiation, how the exposure of the lens was delivered, the genetic susceptibilities of the individual exposed, and the location of the opacity relative to the visual axis of the individual. The preponderance of epidemiological evidence suggests that lens damage could occur at lower doses than previously considered and the NCRP has determined that it is prudent to reduce the recommended annual lens of the eye occupational dose limit from an equivalent dose of 150 mSv to an absorbed dose of 50 mGy. Significant additional research is still needed in the following areas: comprehensive evaluation of the overall effects of ionizing radiation on the eye, dosimetry methodology and dose-sparing optimization techniques, additional high quality epidemiology studies, and a basic understanding of the mechanisms of cataract development.

Purpose The European Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC) staging classifications are two widely used systems in managing pancreatic neuroendocrine tumors. However, there is no universally accepted system. Methods An analysis was performed to evaluate the application of the ENETS and AJCC staging classifications using the SEER registry (N = 2,529 patients) and a multicentric series (N = 1,143 patients). A modified system was proposed based on analysis of the two existing classifications. The modified system was then validated. Results The proportion of patients with AJCC stage III disease was extremely low for both the SEER series (2.2%) and the multicentric series (2.1%). For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage IIA disease, and patients with stage IIIB disease had a lower hazard ratio for death than did patients with stage IIIA disease. We modified the ENETS staging classification by maintaining the ENETS T, N, and M definitions and adopting the AJCC staging definitions. The proportion of patients with stage III disease using the modified ENETS (mENETS) system was higher than that of the AJCC system in both the SEER series (8.9% v 2.2%) and the multicentric series (11.6% v 2.1%). In addition, the hazard ratio of death for patients with stage III disease was higher than that for patients with stage IIB disease. Moreover, statistical significance and proportional distribution were observed in the mENETS staging classification. Conclusion An mENETS staging classification is more suitable for pancreatic neuroendocrine tumors than either the AJCC or ENETS systems and can be adopted in clinical practice.

Discrimination discovery from data is an important data mining task, whose goal is to identify patterns of illegal and unethical discriminatory activities against protected-by-law groups, e.g., ethnic minorities. While any legally valid proof of discrimination requires evidence of causality, the state-of-the-art methods are essentially correlation based, albeit, as it is well known, correlation does not imply causation. In this paper, we take a principled causal approach to discrimination detection following Suppes"™ probabilistic causation theory. In particular, we define a method to extract, from a dataset of historical decision records, the causal structures existing among the attributes in the data. The result is a type of constrained Bayesian network, which we dub Suppes-Bayes causal network (SBCN). Next, we develop a toolkit of methods based on random walks on top of the SBCN, addressing different anti-discrimination legal concepts, such as direct and indirect discrimination, group and individual discrimination, genuine requirement, and favoritism. Our experiments on real-world datasets confirm the inferential power of our approach in all these different tasks.

As an important regulator of macrophage cholesterol efflux and HDL biogenesis, miR-33 is a promising target for treatment of atherosclerosis, and numerous studies demonstrate that inhibition of miR-33 increases HDL levels and reduces plaque burden. However, important questions remain about how miR-33 impacts atherogenesis, including whether this protection is primarily due to direct effects on plaque macrophages or regulation of lipid metabolism in the liver. We demonstrate that miR-33 deficiency in Ldlr^-/- mice promotes obesity, insulin resistance, and hyperlipidemia but does not impact plaque development. We further assess how loss of miR-33 or addition of miR-33b in macrophages and other hematopoietic cells impact atherogenesis. Macrophage-specific loss of miR-33 decreases lipid accumulation and inflammation under hyperlipidemic conditions, leading to reduced plaque burden. Therefore, the pro-atherogenic effects observed in miR-33-deficient mice are likely counterbalanced by protective effects in macrophages, which may be the primary mechanism through which anti-miR-33 therapies reduce atherosclerosis.

The uncontrolled growth of tumor can lead to the formation of area deprived in nutrients. Due to their high genetic instability, tumor cells can adapt and develop resistance to this pro-apoptotic environment. Among the resistance mechanisms, those involved in the resistance to long-term amino acid restriction are not elucidated. A long-term amino acid restriction is particularly deleterious since nine of them cannot be synthetized by the cells. In order to determine how cancer cells face a long-term amino acid deprivation, we developed a cell model selected for its capacity to resist a long-term amino acid limitation. We exerted a selection pressure on mouse embryonic fibroblast to isolate clones able to survive with low amino acid concentration. The study of several clones revealed an alteration of the eiF2α/ATF4 pathway. Compared to the parental cells, the clones exhibited a decreased expression of the transcription factor ATF4 and its target genes. Likewise, the knock-down of ATF4 in parental cells renders them resistant to amino acid deprivation. Moreover, this association between a low level of ATF4 protein and the resistance to amino acid deprivation was also observed in the cancer cell line BxPC-3. This resistance was abolished when ATF4 was overexpressed. Therefore, decreasing ATF4 expression may be one important mechanism for cancer cells to survive under prolonged amino acid deprivation.

The development of genetically encoded self-labeling protein tags such as the HaloTag and SNAP-tag has expanded the utility of chemical dyes in microscopy. Intracellular labeling using these systems requires small, cell-permeable dyes with high brightness and photostability. We recently discovered a general method to improve the properties of classic fluorophores by replacing N,N-dimethylamino groups with four-membered azetidine rings to create the "Janelia Fluor" dyes. Here, we describe the synthesis of the HaloTag and SNAP-tag ligands of Janelia Fluor 549 and Janelia Fluor 646 as well as standard labeling protocols for use in ensemble and single-molecule cellular imaging.