An Elaborate New Linker System Significantly Enhances the Efficacy of an HER2-Antibody-Drug Conjugate against Refractory HER2-Positive Cancers.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in breast and gastric cancers and this causes poor clinical outcomes. Although both T-DM1 and Enhertu are approved as an HER2-targeting antibody-drug conjugate (ADC), the effects of these drugs are still not satisfactory to eradicate diverse tumors expressing HER2. To address this shortfall in HER2-targeted therapeutics, an elaborate cleavable linker is created and a novel HER2-targeting ADC composed with trastuzumab and monomethyl auristatin F, which is being investigated in a phase 1 clinical trial and is referred to as LegoChem Bisciences-ADC (LCB-ADC). LCB-ADC displays a higher cytotoxic potency than T-DM1 and it also has a higher G2/M arrest ratio. In animal studies, LCB-ADC produces noticeable tumor growth inhibition compared with trastuzumab or T-DM1 in an HER2 high-expressing N87 xenograft tumor. Especially, LCB-ADC shows good efficacy in terms of suppressing tumor growth in a patient-derived xenograft (PDX) model of HER2-positive gastric cancer as well as in T-DM1-resistant models such as HER2 low-expressing HER2 low expressing JIMT-1 xenograft tumor and PDX. Collectively, the results demonstrate that LCB-ADC with the elaborate linker has a higher efficacy and greater biostability than its ADC counterparts and may successfully treat cancers that are nonresponsive to previous therapeutics.

Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the αV138M variant of human pyruvate dehydrogenase.

The pyruvate dehydrogenase multienzyme complex (PDHc) connects glycolysis to the tricarboxylic acid cycle by producing acetyl-CoA via the decarboxylation of pyruvate. Because of its pivotal role in glucose metabolism, this complex is closely regulated in mammals by reversible phosphorylation, the modulation of which is of interest in treating cancer, diabetes, and obesity. Mutations such as that leading to the αV138M variant in pyruvate dehydrogenase, the pyruvate-decarboxylating PDHc E1 component, can result in PDHc deficiency, an inborn error of metabolism that results in an array of symptoms such as lactic acidosis, progressive cognitive and neuromuscular deficits, and even death in infancy or childhood. Here we present an analysis of two X-ray crystal structures at 2.7-Å resolution, the first of the disease-associated human αV138M E1 variant and the second of human wildtype (WT) E1 with a bound adduct of its coenzyme thiamin diphosphate and the substrate analogue acetylphosphinate. The structures provide support for the role of regulatory loop disorder in E1 inactivation, and the αV138M variant structure also reveals that altered coenzyme binding can result in such disorder even in the absence of phosphorylation. Specifically, both E1 phosphorylation at αSer-264 and the αV138M substitution result in disordered loops that are not optimally oriented or available to efficiently bind the lipoyl domain of PDHc E2. Combined with an analysis of αV138M activity, these results underscore the general connection between regulatory loop disorder and loss of E1 catalytic efficiency.

Dexamethasone downregulates SIRT1 and IL6 and upregulates EDN1 genes in stem cells derived from gingivae via the AGE/RAGE pathway.

OBJECTIVES: To evaluate the effects of dexamethasone on the aging of mesenchymal stem cells from human gingiva using next-generation sequencing. RESULTS: Four mRNAs were upregulated and 12 were downregulated when the results of dexamethasone at 24 h were compared with the control at 24 h. Expressions of SIRT1 and IL6 were decreased in dexamethasone at 24 h but expression of EDN1 was increased. CONCLUSIONS: Application of dexamethasone reduced the expression of SIRT1 and IL6 but enhanced the expression of EDN1 of stem cells.

Short-term application of dexamethasone on stem cells derived from human gingiva reduces the expression of RUNX2 and ß-catenin.

Objective Next-generation sequencing was performed to evaluate the effects of short-term application of dexamethasone on human gingiva-derived mesenchymal stem cells. Methods Human gingiva-derived stem cells were treated with a final concentration of 10-7 M dexamethasone and the same concentration of vehicle control. This was followed by mRNA sequencing and data analysis, gene ontology and pathway analysis, quantitative real-time polymerase chain reaction of mRNA, and western blot analysis of RUNX2 and ß-catenin. Results In total, 26,364 mRNAs were differentially expressed. Comparison of the results of dexamethasone versus control at 2 hours revealed that 7 mRNAs were upregulated and 25 mRNAs were downregulated. The application of dexamethasone reduced the expression of RUNX2 and ß-catenin in human gingiva-derived mesenchymal stem cells. Conclusion The effects of dexamethasone on stem cells were evaluated with mRNA sequencing, and validation of the expression was performed with qualitative real-time polymerase chain reaction and western blot analysis. The results of this study can provide new insights into the role of mRNA sequencing in maxillofacial areas.

Estimation of effects of factors related to preschooler body mass index using quantile regression model.

PURPOSE: The purpose of this study was to investigate Korean preschoolers' obesity-related factors through an ecological approach and to identify Korean preschoolers' obesity-related factors and the different effects of ecological variables on body mass index and its quantiles through an ecological approach. METHODS: The study design was cross-sectional. Through convenience sampling, 241 cases were collected from three kindergartens and seven nurseries in the Seoul metropolitan area and Kyunggi Province in April 2013 using self-administered questionnaires from preschoolers' mothers and homeroom teachers. RESULTS: Results of ordinary least square regression analysis show that mother's sedentary behavior (p < .001), sedentary behavior parenting (p = .039), healthy eating parenting (p = .027), physical activity-related social capital (p = .029) were significant factors of preschoolers' body mass index. While in the 5% body mass index distribution group, gender (p = .031), preference for physical activity (p = .015), mother's sedentary behavior parenting (p = .032), healthy eating parenting (p = .005), and teacher's sedentary behavior (p = .037) showed significant influences. In the 25% group, the effects of gender and preference for physical activity were no longer significant. In the 75% and 95% group, only mother's sedentary behavior showed a statistically significant influence (p < .001, p = .012 respectively). CONCLUSION: Efforts to lower the obesity rate of preschoolers should focus on their environment, especially on the sedentary behavior of mothers, as mothers are the main nurturers of this age group.

sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin.

A sequence within the E2 domain of soluble amyloid precursor protein (sAPP) stimulates iron efflux. This activity has been attributed to a ferroxidase activity suggested for this motif. We demonstrate that the stimulation of efflux supported by this peptide and by sAPPα is due to their stabilization of the ferrous iron exporter, ferroportin (Fpn), in the plasma membrane of human brain microvascular endothelial cells (hBMVEC). The peptide does not bind ferric iron explaining why it does not and thermodynamically cannot promote ferrous iron autoxidation. This peptide specifically pulls Fpn down from the plasma membrane of hBMVEC; based on these results, FTP, for ferroportin-targeting peptide, correctly identifies the function of this peptide. The data suggest that in stabilizing Fpn via the targeting due to the FTP sequence, sAPP will increase the flux of iron into the cerebral interstitium. This inference correlates with the observation of significant iron deposition in the amyloid plaques characteristic of Alzheimer's disease.

Zoledronic acid prevents bone loss in premenopausal women with early breast cancer undergoing adjuvant chemotherapy: a phase III trial of the Korean Cancer Study Group (KCSG-BR06-01).

To determine whether zoledronic acid (ZA) can prevent bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer. In this randomized, open-label, phase III multicenter trial, premenopausal women >40 years were randomly assigned to ZA treatment (4 mg IV, every 6 months) or observation after surgery. All patients were treated with four cycles of AC followed by four cycles of taxane. Between March 2007 and May 2008, we assessed a total of 112 premenopausal women, all of whom developed amenorrhea at 1 year after chemotherapy. The mean percent change of BMD in the lumbar spine (LS) was -1.1% in the ZA group versus -7.5% in observation group at 12 months. Differences in percent change of BMD from baseline between the two groups were 6.4% for the LS, and 3.6% for the femoral neck. The mean levels of bone turnover at 12 months were significantly lower in the ZA group. ZA was generally well tolerated. Infusion of ZA 4 mg every 6 months effectively prevented bone loss within the first year in premenopausal women receiving adjuvant chemotherapy for early breast cancer. Regular BMD measurements and early bisphosphonate therapy should be considered in these patients.

Korean ethnicity as compared with white ethnicity is an independent favorable prognostic factor for overall survival in non-small cell lung cancer before and after the oral epidermal growth factor receptor tyrosine kinase inhibitor era.

BACKGROUND: We have previously demonstrated, using a regional California Cancer Registry database, that Asian ethnicity is an independent favorable prognostic factor for overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS: Retrospective population-based analysis of Korean and US white patients with NSCLC with known smoking status from Samsung Cancer Center, Seoul, South Korea, and a Southern California Regional Cancer Registry between 1998 and 2005 with follow-up through February 2008 to allow for even case ascertainment periods before and after 2002, when epidermal growth factor receptor tyrosine kinase inhibitors were introduced in Korea and considered as the year of reference. RESULTS: A total of 4622 Korean and 8846 US white patients were analyzed. Median age of diagnosis was 63 years versus 71 years for Korean and white patients, respectively (P < 0.0001). A total of 34.5% of Korean compared with 8.2% white patients were never-smokers. There was significant OS improvement in never-smokers when compared with ever-smokers among either Korean patients (p < 0.0141) or US white (p < 0.0397), respectively. There was significant improvement in OS among Korean patients from 2002 to 2005 compared with 1998-2001 (p < 0.0001) but not among US white patients (p = 0.5641). Except for stage II patients (p = 0.0723), univariate analysis revealed Korean patients had improved OS compared with US white patients among stages I, III, and IV, respectively (all p < 0.0001). Multivariate analysis revealed Korean ethnicity (versus white; hazard ratio (HR) = 0.869; p < 0.0001) was an independent favorable factor for OS. The adjusted HR for OS Korean ethnicity when compared with white ethnicity improved during 2002-2005 (HR = 0.795; p < 0.0001) compared with 1998-2001 (HR = 0.889; p = 0.0013). CONCLUSIONS: These results suggest that Korean ethnicity compared with US white ethnicity is an independent favorable prognostic factor for OS in NSCLC. In addition, greater survival benefit among Korean patients with NSCLC was noted in the postepidermal growth factor receptor tyrosine kinase inhibitor era (2002 and after) compared with US white ethnicity.

Triazaspirodimethoxybenzoyls as selective inhibitors of mycobacterial lipoamide dehydrogenase .

Mycobacterium tuberculosis (Mtb) remains the leading single cause of death from bacterial infection. Here we explored the possibility of species-selective inhibition of lipoamide dehydrogenase (Lpd), an enzyme central to Mtb's intermediary metabolism and antioxidant defense. High-throughput screening of combinatorial chemical libraries identified triazaspirodimethoxybenzoyls as high-nanomolar inhibitors of Mtb's Lpd that were noncompetitive versus NADH, NAD(+), and lipoamide and >100-fold selective compared to human Lpd. Efficacy required the dimethoxy and dichlorophenyl groups. The structure of an Lpd-inhibitor complex was resolved to 2.42 A by X-ray crystallography, revealing that the inhibitor occupied a pocket adjacent to the Lpd NADH/NAD(+) binding site. The inhibitor did not overlap with the adenosine moiety of NADH/NAD(+) but did overlap with positions predicted to bind the nicotinamide rings in NADH and NAD(+) complexes. The dimethoxy ring occupied a deep pocket adjacent to the FAD flavin ring where it would block coordination of the NADH nicotinamide ring, while the dichlorophenyl group occupied a more exposed pocket predicted to coordinate the NAD(+) nicotinamide. Several residues that are not conserved between the bacterial enzyme and its human homologue were predicted to contribute both to inhibitor binding and to species selectivity, as confirmed for three residues by analysis of the corresponding mutant Mtb Lpd proteins. Thus, nonconservation of residues lining the electron-transfer tunnel in Mtb Lpd can be exploited for development of species-selective Lpd inhibitors.

Spontaneous pneumothorax developed in patients with bronchiolitis obliterans after unrelated hematopoietic stem cell transplantation: case report and review of the literature.

Spontaneous pneumothorax following unrelated hematopoietic stem cell transplantation developed in our 2 patients with bronchiolitis obliterans. Bronchiolitis obliterans is a form of obstructive airway disease and is considered a manifestation of chronic graft-versus-host disease (GVHD). Both of the patients were the recipients of marrow from HLA-matched unrelated donors after a preparative regimen with total body irradiation. Chronic GVHD after transplantation is a common feature in these cases. In contrast to other patients with pneumothorax described in the literature, our patients did not develop bullae. We describe a pneumothorax secondary to bronchiolitis obliterans that complicated the posttransplantation course.

Washout of a yeast population during continuous treatment of salad-oil-manufacturing wastewater.

During continuous treatment of salad-oil-manufacturing wastewater using yeast isolates, a large loss of biomass was observed, which subsequently reduced the treatment efficiency. The correlation between biomass washout and loss of species was monitored using the microbiological characteristics of the effluent and the aeration tank. Of the five yeast species, only Candida tropicalis ultimately remained in the aeration tank possibly because it had the best settleability. Addition of nitrogen to the final effluent stimulated the activity of this yeast, which resulted in a treatment efficiency similar to that of the mixed yeast system.