Citations

AbstractFemale Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients.

Zinc (Zn2+) is the second most abundant trace element, but is considered a micronutrient, as it is a cofactor for many enzymes and transcription factors. Whereas Zn2+ deficiency can cause cognitive immune or metabolic dysfunction and infertility, excess Zn2+ is nephrotoxic. As for other ions and solutes, Zn2+ is moved into and out of cells by specific membrane transporters: ZnT, Zip, and NRAMP/DMT proteins. ZIP10 is reported to be localized at the apical membrane of renal proximal tubules in rats, where it is believed to play a role in Zn2+ import. Renal regulation of Zn2+ is of particular interest in light of growing evidence that Zn2+ may play a role in kidney stone formation. The objective of this study was to show that ZIP10 homologs transport Zn2+, as well as ZIP10, kidney localization across species. We cloned ZIP10 from dog, human, and Drosophila ( CG10006), tested clones for Zn2+ uptake in Xenopus oocytes and localized the protein in renal structures. CG10006, rather than foi (fear-of-intimacy, CG6817) is the primary ZIP10 homolog found in Drosophila Malpighian tubules. The ZIP10 antibody recognizes recombinant dog, human, and Drosophila ZIP10 proteins. Immunohistochemistry reveals that ZIP10 in higher mammals is found not only in the proximal tubule, but also in the collecting duct system. These ZIP10 proteins show Zn2+ transport. Together, these studies reveal ZIP10 kidney localization, a role in renal Zn2+ transport, and indicates that CG10006 is a Drosophila homolog of ZIP10.

Abstract Background Early phase clinical trials evaluate the safety and efficacy of new treatments. The exclusion/inclusion criteria in these trials are usually rigorous and may exclude many patients seen in clinical practice. Our objective was to study the comorbidities limiting the participation of patients with breast, colorectal, or lung cancer in clinical trials. Materials and Methods We queried ClinicalTrials.gov on December 31, 2016. We reviewed the eligibility criteria of 1,103 trials. Logistic regression analyses were completed, and exclusion was studied as a binary variable. Results Out of 1,103 trials, 70 trials (6%) excluded patients >75 years of age, and 45% made no reference to age. Eighty-six percent of trials placed restrictions on patients with history of prior malignancies. Regarding central nervous system (CNS) metastasis, 416 trials (38%) excluded all patients with CNS metastasis, and 373 (34%) only allowed asymptomatic CNS metastasis. Regarding chronic viral infections, 347 trials (31%) excluded all patients with human immunodeficiency virus, and 228 trials (21%) excluded all patients with hepatitis B or C infection. On univariate analysis, chemotherapy trials were more likely to exclude patients with CNS metastasis and history of other malignancies than targeted therapy trials. Multivariate analysis demonstrated that industry-sponsored trials had higher odds of excluding patients with compromised liver function. Conclusion Many clinical trials excluded large segments of the population of patients with cancer. Frequent exclusion criteria included patients with CNS metastasis, history of prior malignancies, and chronic viral infections. The criteria for participation in some clinical trials may be overly restrictive and limit enrollment. Implications for Practice The results of this study revealed that most early phase clinic trials contain strict exclusion criteria, potentially excluding the patients who may be more likely to represent the population treated in clinical settings, leaving patients susceptible to unintended harm from inappropriate generalization of trial results. Careful liberalization of the inclusion/exclusion criteria in clinical trials will allow investigators to understand the benefits and drawbacks of the experimental drug for a broader population, and possibly improve recruitment of patients with cancer into clinical trials.