Age-related terminal duct lobular unit involution in benign tissues from Chinese breast cancer patients with luminal and triple-negative tumors

Abstract Background Terminal duct lobular unit (TDLU) involution is a physiological process of breast tissue aging characterized by a reduction in the epithelial component. In studies of women with benign breast disease, researchers have found that age-matched women with lower levels of TDLU involution are at increased risk of developing breast cancer. We previously showed that breast cancer cases with core basal phenotype (CBP; estrogen receptor negative [ER−], progesterone receptor-negative [PR−], human epidermal growth factor receptor 2-negative [HER2−], cytokeratins (CK 5 or CK5/6)-positive [CK5/6+] and/or epidermal growth factor receptor-positive [EGFR+]) tumors had significantly reduced TDLU involution compared with cases with luminal A (ER+ and/or PR+, HER2−, CK5/6−, EGFR−) tumors from a population-based case-control study in Poland. We evaluated the association of TDLU involution with tumor subtypes in an independent population of women in China, where the breast cancer incidence rate, prevalence of known risk factors, and mammographic breast density are thought to be markedly different from those of Polish women. Methods We performed morphometric assessment of TDLUs by using three reproducible semiquantitative measures that inversely correlate with TDLU involution (TDLU count/100 mm2, TDLU span in micrometer, and acini count/TDLU) by examining benign tissue blocks from 254 age-matched luminal A and 250 triple-negative (TN; ER−, PR−, HER2−, including 125 CBP) breast cancer cases treated in a tertiary hospital in Beijing, China. Results Overall, we found that TN and particularly CBP cases tended to have greater TDLU measures (less involution) than luminal A cases in logistic regression models accounting for age, body mass index, parity, and tumor grade. The strongest association was observed for tertiles of acini count among younger women (aged <50 years) (CBP vs. luminal A; ORtrend 2.11, 95% CI 1.22–3.67, P = 0.008). Conclusions These data extend previous findings that TN/CBP breast cancers are associated with reduced TDLU involution in surrounding breast parenchyma compared with luminal A cases among Chinese women, providing further support for differences in the pathogenesis of these tumor subtypes

Evidence for an association of HLA-DRB1*15 and DRB1*09 with leprosy and the impact of DRB1*09 on disease onset in a Chinese Han population

<p>Abstract</p> <p>Background</p> <p>Human leukocyte antigens (HLAs) have been proposed to modulate the immune response to <it>Mycobacterium leprae</it>. The association of HLA-DRB1 with leprosy has been reported in several populations, but not in a Chinese population.</p> <p>Methods</p> <p>The polymerase chain reaction-sequence-specific oligonucleotide probe with Luminex100 (PCR-SSOP-Luminex) method was used to genotype HLA-DRB1 alleles in 305 leprosy patients and 527 healthy control individuals.</p> <p>Results</p> <p>The HLA-DRB1*15 allele was significantly more prevalent among leprosy patients than healthy controls, whereas the frequency of the HLA-DRB1*09 allele was lower among leprosy patients, especially those with early-onset disease.</p> <p>Conclusion</p> <p>HLA-DRB1 alleles are associated with leprosy susceptibility in a Chinese population. The HLA-DRB1*09 allele was found to be protective exclusively in a subset of early-onset leprosy patients.</p

Role of copper ion in regulating ligand binding in a myoglobin-based cytochrome c oxidase model

Cytochrome c oxidase (CcO), the terminal enzyme in the mitochondrial respiratory chain, catalyzes the four-electron reduction of dioxygen to water in a binuclear center comprised of a high-spin heme (heme a3) and a copper atom (CuB) coordinated by three histidine residues. As a minimum model for CcO, a mutant of sperm whale myoglobin, named Cu BMb, has been engineered, in which a copper atom is held in the distal heme pocket by the native E7 histidine and two nonnative histidine residues. In this work, the role of the copper in regulating ligand binding in CuBMb was investigated. Resonance Raman studies show that the presence of copper in CO-bound CuBMb leads to a CcO-like distal heme pocket. Stopped-flow data show that, upon the initiation of the CO binding reaction, the ligand first binds to the Cu+; it subsequently transfers from Cu+ to Fe2+ in an intramolecular process, similar to that reported for CcO. The high CO affinity toward Cu+ and the slow intramolecular CO transfer rate between Cu+ and Fe2+ in the CuBMb/Cu + complex are analogous to those in Thermus thermophilus CcO (TtCcO) but distinct from those in bovine CcO (bCcO). Additional kinetic studies show that, upon photolysis of the NO-bound CuBMb/Cu+ complex, the photolyzed ligand transiently binds to Cu+ and subsequently rebinds to Fe2+, accounting for the 100% geminate recombination yield, similar to that found in TtCcO. The data demonstrate that the Cu BMb/Cu+ complex reproduces essential structural and kinetic features of CcO and that the complex is more akin to TtCcO than to bCcO. © 2010 American Chemical Society

Regulatory Role of Glu546 in Flavin Mononucleotide  Heme Electron Transfer in Human Inducible Nitric Oxide Synthase

Nitric oxide (NO) production by mammalian NO synthase (NOS) is believed to be regulated by the docking of the flavin mononucleotide (FMN) domain in one subunit of the dimer onto the heme domain of the adjacent subunit. Glu546, a conserved charged surface residue of the FMN domain in human inducible NOS (iNOS), is proposed to participate in the interdomain FMN/heme interactions [Sempombe et al. <i>Inorg. Chem.</i> <b>2011</b>, <i>50</i>, 6869–6861]. In the present work, we further investigated the role of the E546 residue in the FMN–heme interdomain electron transfer (IET), a catalytically essential step in the NOS enzymes. Laser flash photolysis was employed to directly measure the FMN–heme IET kinetics for the E546N mutant of human iNOS oxygenase/FMN (oxyFMN) construct. The temperature dependence of the IET kinetics was also measured over the temperature range of 283–304 K to determine changes in the IET activation parameters. The E546N mutation was found to retard the IET by significantly raising the activation entropic barrier. Moreover, pulsed electron paramagnetic resonance data showed that the geometry of the docked FMN/heme complex in the mutant is basically the same as in the wild type construct, whereas the probability of formation of such a complex is about twice lower. These results indicate that the retarded IET in the E546N mutant is not caused by an altered conformation of the docked FMN/heme complex, but by a lower population of the IET-active conformation. In addition, the negative activation entropy of the mutant is still substantially lower than that of the holoenzyme. This supports a mechanism by which the FMN domain can modify the IET through altering probability of the docked state formation