NRF2 is a transcription factor serving as a master regulator of the expression of many genes involved in cellular responses to oxidative and other stresses. In the absence of stress, NRF2 is constantly synthesized but maintained at low levels as it is targeted by KEAP1 for ubiquitination and proteasome-mediated degradation. NRF2 binds KEAP1 mainly through a conserved “ETGE” motif that has also been found in several other proteins, such as DPP3, which has been shown to bind KEAP1 and enhance NRF2 function upon overexpression. Here we demonstrate the interaction between endogenous DPP3 and endogenous KEAP1. We further show that the DPP3-KEAP1 interaction is strongly induced by hydrogen peroxide and that DPP3 is required for timely NRF2 induction and nuclear accumulation in the estrogen receptor (ER)-positive MCF7 breast cancer cells. Moreover, we present evidence that the binding of DPP3 to KEAP1 stabilizes the latter. Finally, we show that DPP3 is overexpressed in breast cancer and that elevated levels of DPP3 mRNA correlate with increased NRF2 downstream gene expression and poor prognosis, particularly for ER-positive breast cancer. Our studies reveal novel insights into the regulation of NRF2 and identify DPP3 and an NRF2 transcriptional signature as potential biomarkers for breast cancer prognosis and treatment.

The BRCA1-PALB2-BRCA2 axis plays an essential role in DNA homologous recombination repair, defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage and how tumors develop from these cells remain poorly defined. Here, we analyzed several aspects of the DNA damage response in multiple tissues of-mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage. Following ionizing radiation, the mutant mice displayed higher levels of DNA breaks and stronger induction of p53 and p21, but continued DNA synthesis, reduced apoptosis, and accelerated tumor development. The differences in p21 induction, DNA synthesis, and apoptosis between wild-type and mutant mice were substantially more pronounced in the mammary gland than in the intestine, suggesting a potential contributing factor to the increased risk and the tissue specificity of /-associated tumor development. Moreover, the mutant mice showed higher levels of reactive oxygen species and constitutive activation of NF-κB, an antiapoptotic transcription factor inducible by both DNA damage and oxidative stress. Treatment of the mutant mice with an inhibitor of NF-κB reactivated apoptosis and delayed tumor development following radiation. Thus, our results also suggest a prosurvival and pro-oncogenic role of NF-κB in -mutant cells. This study explores novel tumor suppression mechanisms of the BRCA1-PALB2 DNA damage response pathway and implicates NF-κB activation as a protumorogenic event and possible therapeutic target. .

Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ablation of either Palb2 or Brca2 with Brca1 led to delayed tumor formation. Whole-exome sequencing (WES) revealed both similarities and differences between Brca1 and Palb2 or Brca2 null tumors. Analyses of mouse mammary glands and cultured human cells showed that combined loss of BRCA1 and PALB2 led to high levels of reactive oxygen species (ROS) and increased apoptosis, implicating oxidative stress in the delayed tumor development in Brca1;Palb2 double CKO mice. The functional complementarity between BRCA1 and PALB2/BRCA2 and the role of ROS in tumorigenesis require further investigation.

Background There is a global decline in interest in careers in renal medicine. This is concerning given the increasing global burden of kidney disease. Previous studies in the USA and Australia have identified factors such as a poor work–life balance, lack of role models and the challenging nature of the speciality as possible reasons behind recruitment struggles. This study aimed to identify factors associated with declining interest among trainees in the UK. Methods We conducted a survey of 150 National Health Service Foundation trainees (interns) and Core Medical Trainees in Health Education West Midlands. Participants completed a 14-part paper-based questionnaire capturing data on trainee demographics, medical school and postgraduate exposure to renal medicine and perceptions of a career in renal medicine. Results There was limited early clinical exposure to renal medicine both in terms of time spent in the speciality and perceived exposure to the range of domains of the speciality. Trainees perceived the speciality as complex with a heavy workload. Very few trainees considered the speciality to be lifestyle oriented. There was also disinterest in taking on the associated general medicine commitments of the training programme. Job experience and identification of role models increased the likelihood of consideration of the speciality. Conclusion This survey has identified key areas to drive interest in the speciality, including early engagement, enthusiastic supervision and increased training flexibility. Urgent attention is required to address these areas and make renal medicine careers more appealing.

ObjectiveTo investigate the relationship between parathyroid gland weight and high-density lipoprotein (HDL) levels in patients with primary hyperparathyroidism (PHPT).MethodsIn this retrospective case control study, we reviewed 329 PHPT patients aged from 20 to 85 years who had a parathyroidectomy at Robert Wood Johnson University Hospital. The patients were divided into 5 quintiles according to their parathyroid gland weight: 68 patients had a parathyroid gland weight <0.3 g, 66 patients had a gland weight 0.3–0.45 g, 67 patients had a gland weight 0.45–0.7 g, 63 patients had a gland weight 0.7–1.25 g, and 65 patients had a gland weight ≥1.25 g.ResultsBody Mass Index (BMI) trended to be higher across the quintiles of parathyroid gland weight (P = 0.003). Serum calcium and PTH levels were significantly increased across parathyroid gland quintiles (p < 0.0001). HDL levels tended to be lower across the increasing quintiles of parathyroid gland weight (P = 0.01). There was a negative relationship between log parathyroid gland weight and HDL in patients with PHPT in a simple linear regression (r = −0.160, P = 0.003). The negative association remained significant after adjustment for age and BMI (r = −0.114, P = 0.039). Furthermore, parathyroid gland weight was significantly associated with levels of triglyceride (r = 0.126, P = 0.02), but this relationship lost its significance after adjustment for age and BMI (r = 0.082, P ˃ 0.05).ConclusionsPHPT patients with heavier parathyroid glands tended to have higher BMI and lower HDL levels.

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An interesting feature of ionizing radiation, especially Gamma and X-rays as a DNA damaging factor is the range of lesions it induces. γ-H2AX foci are documented to represent DNA double-strand breaks (DSBs) as a biomarker for radiation-induced damage. Study design 42 adult male mice Albino BALB/c, had been divided randomly into 6 groups of seven mice each. Group 1 received a standard saline solution untreated also, do not expose to radiation. Group 2 mice received vitamin C (VC) (200 mg/kg.day) intra-peritoneal (i.p.) injected for 8 days without radiation. Group 3 control was exposed to γ-radiation. Group 4 control was exposed to X-ray radiation. Group 5 mice had been administrated with vitamin C in the identical dose of group 2 for 8 days, then exposed to (4 Gy) of γ-ray. Group 6 was administrated with vitamin dose in the same above and the same period, then exposed to (4 Gy) of X-ray. All groups had been sacrificed by cervical dislocation at (1, 3, and 24 h). Post radiation testis mice tissues were collected. A significant difference (P 0.05) between the group of vitamin C and with a control group exposed to both (γ, X-rays) in foci forming, but there is no significant difference (P 0.05) between γ and X- rays for the control and vitamin C groups. The results demonstrate that vitamin C is a good radioprotective agent for testis mice tissues; the effect of (γ and X-rays) had almost the same results on the mice testicle tissues with the same dose.

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