Project description:<p>This is an evaluation of genetic associations with atazanavir (ATV) discontinuation for bilirubin-related causes within 12 months of treatment. Patients were treated at an HIV primary care clinic in Nashville TN from 1998 to 2012. A previously known SNP in UGT1A1 (rs887829) was used to define metabolizer genotypes (extensive, intermediate, slow metabolizer). Over 500,000 SNPs from genome-wide genotyping were used to define MDS (Multidimensional Scaling) coordinates to account for population stratification. Patients were defined as <b>cases</b> if they discontinued ATV for bilirubin-related causes within 12 months of treatment, otherwise they were defined as <b>controls</b> if they did not stop treatment.</p> <p>Among 321 evaluable patients, 15 (4.6%) had bilirubin-related atazanavir discontinuation within 12 months. Homozygosity for rs887829 T/T was present in 28.1% of black, 21.4% of Hispanic, and 8.6% of white patients. Among all patients the hazard ratio (HR) for bilirubin-related discontinuation with T/T versus C/C genotype was 7.3 (95% C.I.: 1.7 to 31.5; p = 0.007). Among 152 white patients the HR was 14.4 (95% CI: 2.6 to 78.7; p = 0.002), but among 153 black patients the HR was 0.8 (95% C.I. 0.05 to 12.7; p = 0.87).</p>
Project description:We investigated the transcriptional responses of fasting against side effects of irinotecan chemotherapy in both tumor and healthy liver tissue
Project description:Adjuvant tamoxifen therapy for invasive breast cancer improves patient survival but comes with side effects that impact health and quality of life. Partly due to a lack of proven animal models, the tissues and cells that mediate these negative side effects are largely unknown. Here we show that mice undergoing a 28-day course of tamoxifen treatment experience dysregulation of core and skin temperature, changes in bone density, and decreased physical activity, recapitulating several aspects of the human response. Single cell RNA sequencing reveals that tamoxifen induces widespread gene expression changes in the hypothalamus, particularly in neurons and ependymal cells. These effects are largely dependent on estrogen receptor alpha (ERα), as conditional ERα knockout ablated or reversed tamoxifen-induced changes in gene expression, thermoregulation, bone, and movement. These findings provide mechanistic insights into the effects of tamoxifen on the hypothalamus and suggest that hypothalamic ERα mediates several side effects of tamoxifen therapy.
Project description:The efficacy of the epidermal growth factor receptor (EGFR) inhibitors have been demonstrated in patients with non-small cell lung cancer (NSCLC), pancreatic cancer (PC) and colorectal cancer (CRC). Dermatological reactions can cause significant physical and psycho-social discomfort to patients. In the present study, the investigators evaluated the effect of epidermal growth factor (EGF) ointment on EGFR inhibitor-related skin side effects (ERSEs).
Project description:Development of chemotherapy has led to a high survival rate of cancer patients; however, severe side effects of anti-cancer drugs, including organ hypoplasia, persists. This study examined the molecular mechanism of the side effects of cyclophosphamide (CPA), a commonly used anti-cancer drug for the treatment of leukemia, and determined how to suppress the side effects using an organ culture system. Treatment with CPA disturbed the growth of tooth germs by inducing apoptosis and suppressing cellular proliferation and differentiation. Furthermore, organs cultured at low-temperature could avoid the CPA-mediated inhibition of organ morphogenesis and differentiation. Cap analysis of gene expression of CPA-treated tooth germ revealed that the expression of genes related to the G1/S cell cycle checkpoint were down-regulated in the CPA-treated tooth germ cultured at low-temperature. In vitro analysis revealed that low-temperature impeded Rb phosphorylation and caused cell cycle arrest at the G1 phase. This can prevent the CPA-mediated cell damage of DNA replication caused by the cross-linking reaction of CPA. Our results revealed that the side effects of CPA on organ development can be avoided by maintaining a low temperature. Further, this study provides a new screening model for assessing the effects of anticancer drugs on organ development.