Ligand-hole localization in oxides with unusual valence Fe

Unusual high-valence states of iron are stabilized in a few oxides. A-site-ordered perovskite-structure oxides contain such iron cations and exhibit distinct electronic behaviors at low temperatures, e.g. charge disproportionation (4Fe4+ → 2Fe3+ + 2Fe5+) in CaCu3Fe4O12 and intersite charge transfer (3Cu2+ + 4Fe3.75+ → 3Cu3+ + 4Fe3+) in LaCu3Fe4O12. Here we report the synthesis of solid solutions of CaCu3Fe4O12 and LaCu3Fe4O12 and explain how the instabilities of their unusual valence states of iron are relieved. Although these behaviors look completely different from each other in simple ionic models, they can both be explained by the localization of ligand holes, which are produced by the strong hybridization of iron d and oxygen p orbitals in oxides. The localization behavior in the charge disproportionation of CaCu3Fe4O12 is regarded as charge ordering of the ligand holes, and that in the intersite charge transfer of LaCu3Fe4O12 is regarded as a Mott transition of the ligand holes

Obstetric history and mammographic density: a population-based cross-sectional study in Spain (DDM-Spain)

High mammographic density (MD) is used as a phenotype risk marker for developing breast cancer. During pregnancy and lactation the breast attains full development, with a cellular-proliferation followed by a lobular-differentiation stage. This study investigates the influence of obstetric factors on MD among pre- and post-menopausal women. We enrolled 3,574 women aged 45–68 years who were participating in breast cancer screening programmes in seven screening centers. To measure MD, blind anonymous readings were taken by an experienced radiologist, using craniocaudal mammography and Boyd’s semiquantitative scale. Demographic and reproductive data were directly surveyed by purpose-trained staff at the date of screening. The association between MD and obstetric variables was quantified by ordinal logistic regression, with screening centre introduced as a random effect term. We adjusted for age, number of children and body mass index, and stratified by menopausal status. Parity was inversely associated with density, the probability of having high MD decreased by 16% for each new birth (P value < 0.001). Among parous women, a positive association was detected with duration of lactation [>9 months: odds ratio (OR) = 1.33; 95% confidence interval (CI) = 1.02–1.72] and weight of first child (>3,500 g: OR = 1.32; 95% CI = 1.12–1.54). Age at first birth showed a different effect in pre- and post-menopausal women (P value for interaction = 0.030). No association was found among pre-menopausal women. However, in post-menopausal women the probability of having high MD increased in women who had their first child after the age of 30 (OR = 1.53; 95% CI = 1.17–2.00). A higher risk associated with birth of twins was also mainly observed in post-menopausal women (OR = 2.02; 95% CI = 1.18–3.46). Our study shows a greater prevalence of high MD in mothers of advanced age at first birth, those who had twins, those who have breastfed for longer periods, and mothers whose first child had an elevated birth weight. These results suggest the influence of hormones and growth factors over the proliferative activity of the mammary gland

Abstract P3-06-08: HDAC6 deacetylates HMGN2 to regulate Stat5a activity and breast cancer growth

Abstract Stat5 is a transcription factor utilized by several cytokine/hormone receptor signaling pathways that promotes transcription of genes associated with proliferation, differentiation, and survival of cancer cells. However, there are currently no clinically approved therapies that target Stat5, despite ample evidence that it contributes to breast cancer pathogenesis. Previous research in our lab has shown that the high mobility group nucleosome binding domain 2 (HGMN2) protein serves as a Stat5 co-activator. The activity of HMGN2 has been previously shown to be regulated by acetylation. Here, we show that deacetylation of HMGN2 on lysine residue K2 by histone deacetylase 6 (HDAC6) promotes Stat5-mediated transcription and breast cancer growth. Conversely, in vitro HDAC6 inhibition by pharmacologic and knock-down approaches enhanced HMGN2 acetylation with a concomitant reduction of in vitro Stat5-mediated signaling and global gene expression, and breast cancer growth. In vitro and in vivo treatment of traditional and patient-derived xenograft models with HDAC6 inhibitors resulted in a highly significant reduction of tumor growth. Translationally, it was also found that high levels of acetylated K2 were present in normal human breast tissue, which was lost in primary breast cancers and lymph node metastases. This suggests that blockade of HMGN2 deacetylation as described above is a novel treatment for breast cancer, given that existing HDAC6 inhibitors have a favorable toxicity profile in Phase I trials of other tumor types. Altogether, these results reveal a novel mechanism through which HDAC6 regulates the transcription of Stat5 target genes and demonstrates the utility of HDAC6 inhibition as a potential breast cancer therapeutic. Citation Format: Clevenger CV, Craig JM, Fiorillo AA, Feeney YB, Harrell JC, Medler TR. HDAC6 deacetylates HMGN2 to regulate Stat5a activity and breast cancer growth [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-06-08.</jats:p

Incidence of surgical rib fixation at chest wall injury society collaborative centers and a guide for expected number of cases (CWIS-CC1)

Purpose: Surgical stabilization of rib fractures (SSRF) improves outcomes in certain patient populations. The Chest Wall Injury Society (CWIS) began a new initiative to recognize centers who epitomize their mission as CWIS Collaborative Centers (CWIS-CC). We sought to describe incidence and epidemiology of SSRF at our institutions. Methods: A retrospective registry evaluation of all patients (age > 15 years) treated at international trauma centers from 1/1/20 to 7/30/2021 was performed. Variables included: age, gender, mechanism of injury, injury severity score, abbreviated injury severity score (AIS), emergency department disposition, length of stay, presence of rib/sternal fractures, and surgical stabilization of rib/sternal fractures. Classification and regression tree analysis (CART) was used for analysis. Results: Data were collected from 9 centers, 26,084 patient encounters. Rib fractures were present in 24% (n = 6294). Overall, 2% of all patients underwent SSRF and 8% of patients with rib fractures underwent SSRF. CART analysis of SSRF by AIS-Chest demonstrated a difference in management by age group. AIS-Chest 3 had an SSRF rate of 3.7, 7.3, and 12.9% based on the age ranges (16–19; 80–110), (20–49; 70–79), and (50–69), respectively (p = 0.003). AIS-Chest > 3 demonstrated an SSRF rate of 9.6, 23.3, and 39.3% for age ranges (16–39; 90–99), (40–49; 80–89), and (50–79), respectively (p = 0.001). Conclusion: Anticipated rate of SSRF can be calculated based on number of rib fractures, AIS-Chest, and age. The disproportionate rate of SSRF in patients age 50–69 with AIS-Chest 3 and age 50–79 with AIS-Chest > 3 should be further investigated, as lower frequency of SSRF in the other age ranges may lead to care inequalities.No Full Tex

Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells

Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/ CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon-gamma was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action