A 9-year-old girl with blisters on the hands and face: An early presentation of variegate porphyria.

Variegate porphyria (VP) is a rare subtype of porphyrias characterized by dysfunction of enzymes in the heme biosynthesis pathway leading to an accumulation of porphyrins and their precursors. The resulting buildup can manifest as neuropsychiatric symptoms and photosensitive blistering eruptions on sun-exposed skin. We report a case of VP in a 9-year-old girl with many confounding medical factors that warranted alternative explanations for her cutaneous lesions. VP has been reported infrequently in the pediatric population and is associated with more severe neuropsychiatric outcomes compared to adult-onset disease.

Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer.

Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to support their enhanced proliferation and other cancer-related characteristics. Here, a systematic analysis of TCGA breast cancer datasets revealed that proteasome subunit transcript levels are elevated in all intrinsic subtypes (luminal, HER2-enriched, and basal-like/triple-negative) when compared to normal breast tissue. Although these observations suggest a pan-breast cancer utility for proteasome inhibitors, our further experiments with breast cancer cell lines and patient-derived xenografts (PDX) pointed to triple-negative breast cancer (TNBC) as the most sensitive subtype to proteasome inhibition. Finally, using TNBC cells, we extended our studies to in vivo xenograft experiments. Our previous work has firmly established a cytoprotective role for the transcription factor NRF1 via its ability to upregulate proteasome genes in response to proteasome inhibition. In further support of this notion, we show here that NRF1 depletion significantly reduced tumor burden in an MDA-MB-231 TNBC xenograft mouse model treated with carfilzomib. Taken together, our results point to TNBC as a particularly vulnerable breast cancer subtype to proteasome inhibition and provide a proof-of-principle for targeting NRF1 as a viable means to increase the efficacy of proteasome inhibitors in TNBC tumors.