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The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor which in certain cancer types drives pro-survival processes that facilitate tumorigenesis, malignant cell migration, invasion, and metastasis. Much of AHR’s pro-tumorigenic action is due to its activation by the oncometabolite, kynurenine. Because of this AHR antagonists are being actively investigated as new anti-tumor therapy. In this study we compared the effects of treatment with the AHR antagonists, BAY2416964 and GNF351, to that of AHR knockout in PyMT murine mammary cancer cells. BAY2416964 and GNF351 effectively inhibited kynurenine-dependent increases in Cyp1a1 and Cyp1b1 mRNA levels. CRISPR/Cas9-generated PyMT AhrKO cells exhibited reduced cell proliferation compared with controls, but treatment with 1 μM BAY2416964 for 96 h had no effect on the proliferation of wildtype cells. To further examine the differences between AHR knockout and short term BAY2416964, we generated long-term BAY2416964 (LT-BAY) cells by exposing wildtype cells to 1 μM BAY2416964 for at least 6 weeks. Similar to AhrKO cells, LT-BAY cells exhibited reduced cell proliferation and migration compared with wildtype cells. No differentially expressed genes (DEGs) were identified in wildtype cells exposed to 1 μM BAY2416964 for 24 h; however, 46.4% of DEGs overlapped between AhrKO and LT-BAY cells including gene regulated cell proliferation. Our data reveal long-term pharmacological inhibition of AHR by BAY2416964 closely resembles AHR loss in a mouse model of breast cancer.

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

We investigated whether a physiological marker of cardiovascular health, pulse pres­sure (PP), and age magnified the effect of the functional COMT Val158Met (rs4680) pol­ymor­phism on 15-year cognitive trajectories (episodic memory [EM], visuospatial ability, and se­man­tic memory) using data from 1585 non-demented adults from the Betula study. A mul­tiple-group growth model was specified to gauge individual differences in change. The allelic variants showed negligible differences across the cognitive markers in average trends. The older portion of the sample selectively age-magnified the effects of Val158Met on EM changes, resulting in greater decline in Val compared to homozygote Met carriers. This effect was attenuated by sta­tistical control for PP. Further, PP mod­erated the effects of COMT on 15-year EM trajectories, resulting in greater decline in Val carriers, even after accounting for the confounding effects of sex, education, cardiovascular diseases (dia­betes, stroke, and hypertension), and chronological age, controlled for practice gains. The effect was still present after excluding individuals with a history of cardiovascular diseases. The effects of cognitive change were not moderated by any other covariates. This report underscores the importance of addressing synergistic effects in nor­mal cognitive aging, as the addition thereof may even place healthy individuals at greater risk for memory decline.

Aim: To assess the prevalence and to investigate the pathogenetic mechanisms of dental and periodontal lesions in children with X-linked hypophosphatemic rickets (XLH) examined at diagnosis or during treatment., Methods: Nine children with XLH (age 7.2 +/- 3.3 years) were enrolled in the study (at diagnosis, n = 2; during treatment with oral inorganic phosphate salts combined with 1,25-dihydroxyvitamin D3, n = 7). Oral examination was performed according to the evidence of carious and gingival lesions. Decayed or filled teeth (dft) index for primary teeth, and the decayed, missing, or filled teeth (DMFT) index for permanent teeth was assessed. All patients with a history of spontaneous dental abscesses underwent orthopantomography examination., Results: d/D ranged from 0 to 9 and f/F from 0 to 3. DMFT/dft index was 0 in the three youngest patients. One patient had enamel hypoplasia and two had enamel dyschromic alterations. Six out of nine patients (67%) had a history of spontaneous fistulae as a consequence of periapical abscesses occurring in the absence of dental decay or history of injury. In these patients, orthopantomographies showed enlarged pulp chambers associated with prominent pulp horns extending up to the dentino-enamel junction in both primary and permanent dentition., Conclusion: XLH patients show some peculiar dentinal abnormalities. Treatment prevents only in part dental and periodontal lesions. Genetic mechanisms have a main role in causing defective dentin mineralisation.