One of most important factors for messenger RNA (mRNA) transcription is the spliceosomal component U1 small nuclear RNA (snRNA), which recognizes 5′ splicing donor sites at specific regions in ...pre‐mRNA. Mutations in these sites disrupt U1 snRNA binding and cause abnormal splicing. In this study, we investigated mutations at splice sites in SLC26A4 (HGNC 8818), one of the major causative genes of hearing loss, which may result in the synthesis of abnormal pendrin, the channel protein encoded by the gene. Seventeen SLC26A4 variants with mutations in the U1 snRNA binding sites were assessed by minigene splicing assays, and 11 were found to result in abnormal splicing. Interestingly, eight of the 11 pathogenic mutations were intronic, suggesting the importance of conserved sequences at the intronic splice site. The application of modified U1 snRNA effectively rescued the abnormal splicing for most of these mutations. Although three were cryptic mutations, they were rescued by cotransfection of modified U1 snRNA and modified antisense oligonucleotides. Our results demonstrate the important role of snRNA in SLC26A4 mutations, suggesting the therapeutic potential of modified U1 snRNA and antisense oligonucleotides for neutralizing the pathogenic effect of the splice‐site mutations that may result in hearing loss.
Methionine sulfoxide reductase B3 (MsrB3), which stereospecifically repairs methionine-R-sulfoxide, is an important Msr protein that is associated with auditory function in mammals. MsrB3 deficiency ...leads to profound congenital hearing loss due to the degeneration of stereociliary bundles and the apoptotic death of cochlear hair cells. In this study, we investigated a fundamental treatment strategy in an MsrB3 deficiency mouse model and confirmed the biological significance of MsrB3 in the inner ear using MsrB3 knockout (MsrB3(-/-)) mice.
We delivered a recombinant adeno-associated virus encoding the MsrB3 gene directly into the otocyst at embryonic day 12.5 using a transuterine approach. We observed hearing recovery in the treated ears of MsrB3(-/-) mice at postnatal day 28, and we confirmed MsrB3 mRNA and protein expression in cochlear extracts. Additionally, we demonstrated that the morphology of the stereociliary bundles in the rescued ears of MsrB3(-/-) mice was similar to those in MsrB3(+/+) mice.
To our knowledge, this is the first study to demonstrate functional and morphological rescue of the hair cells of the inner ear in the MsrB3 deficiency mouse model of congenital genetic sensorineural hearing loss using an in utero, virus-mediated gene therapy approach.
Our results provide insight into the role of MsrB3 in hearing function and bring us one step closer to hearing restoration as a fundamental therapy.
Purpose
To examine the association between obesity measured by body mass index (BMI) and waist circumference (WC) according to menopausal status in Korean women.
Methods
We identified 6,467,388 ...women, using the Korean National Health Insurance System Cohort. Cox-proportional hazard models were used to generate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for breast cancer risk in relation to BMI and WC.
Results
In postmenopausal women, the risk of breast cancer increased with BMI. Compared to women with a BMI of 18.5–23 kg/m two, the risk of invasive breast cancer was lower in patients with BMI < 18.5 (aHR 0.82, 95% CI 0.75–0.89), while it increased linearly in those with BMI 23–25 (1.11, 1.08–1.14), BMI 25–30 (1.28, 1.25–1.32), and BMI ≥ 30 (1.54,1.47–1.62). In contrast, the risk of breast cancer decreased with BMI in premenopausal women. Compared to women with a BMI of 18.5–23, the risk of IBC was similar in those with a BMI < 18.5 (1.02, 0.94–1.11) and BMI 23–25 (1.01, 0.97–1.05), but was significantly lower in those with a BMI 25–30 (0.95, 0.91–0.98) and BMI ≥ 30 (0.90, 0.82–0.98). A relative increase with BMI was less profound for carcinoma in situ in postmenopausal women, and a relative decrease was more profound in premenopausal women. An analysis using WC showed almost identical results.
Conclusions
There was a positive relationship between obesity and breast cancer in postmenopausal women, and an inverse association in premenopausal women.
Hydrogen produced from renewable resources has been gaining attention and its use is encouraged, as an effort of emission control. Consequently, the development of hydrogen production methods allows ...for fuel cell technologies to be developed in parallel. As a clean system for generating electricity, the reaction between hydrogen and oxygen occurring in a fuel cell produces only water and heat. By recovering heat release, thermal energy can be converted to mechanical work or electric power, improving performance and profitability of the system. This work studies the process integration of a 300 kW Phosphoric Acid Fuel-Cell (PAFC) and the Organic Ranking Cycle (ORC); a combined heat recovery process for generating additional electricity. A thermo-economic analysis is performed to determine the optimal working fluid with minimum payback time and net profit of PAFC/ORC integration. Among 15 working fluids examined, utilizing ammonia for ORC increased additional electricity produced by 6.64%, showing the greatest net profit, approximately 149 K€, and the payback time is reached after 3.3 years. Examined fluids with high critical temperature were water, benzene, and toluene, and obtained great efficiency improvement (about 9–11%) but they were unable to results to profit during 10 years of fuel cell lifetime.
•Optimal working fluid is determined for utilizing PAFC/ORC integration.•PAFC/ORC improves system efficiency for distributed power generation.•A fluid given a great efficiency might not secure the highest profit in lifetime.•Thermo-economic analysis induces optimal working fluid used for decision making.•NH3 is the optimum candidate from standpoint of system efficiency and profitability.
ABSTRACT
The vertebrate skeletal system has various functions, including support, movement, protection, and the production of blood cells. The development of cartilage and bones, the core components ...of the skeletal system, is mediated by systematic inter‐ and intracellular communication among multiple signaling pathways in differentiating progenitors and the surrounding tissues. Recently, Pannexin (Panx) 3 has been shown to play important roles in bone development in vitro by mediating multiple signaling pathways, although its roles in vivo have not been explored. In this study, we generated and analyzed Panx3 knockout mice and examined the skeletal phenotypes of panx3 morphant zebrafish. Panx3‐/‐ embryos exhibited delays in hypertrophic chondrocyte differentiation and osteoblast differentiation as well as the initiation of mineralization, resulting in shortened long bones in adulthood. The abnormal progression of hypertrophic chondrogenesis appeared to be associated with the sustained proliferation of chondrocytes, which resulted from increased intracellular cAMP levels. Similarly, osteoblast differentiation and mineralization were delayed in panx3 morphant zebrafish. Taken together, our results provide evidence of the crucial roles of Panx3 in vertebrate skeletal development in vivo.—Oh, S.‐K., Shin, J.‐O., Baek, J.‐I., Lee, J., Bae, J. W., Ankamerddy, H., Kim, M.‐J., Huh, T.‐L., Ryoo, Z.‐Y., Kim, U.‐K., Bok, J., Lee, K.‐Y. Pannexin 3 is required for normal progression of skeletal development in vertebrates. FASEB J. 29, 4473‐4484 (2015). www.fasebj.org
Objective
This study aims to evaluate physical, psychosocial, and spiritual factors associated with happiness in breast cancer survivors during the reentry period.
Methods
It is a cross‐sectional ...study with 283 nonmetastatic breast cancer survivors who completed treatment within 1 year. We included survivors who completed questionnaires on happiness and health‐related quality of life (QoL) 2 years after cancer diagnosis. Happiness and QoL was measured using the Subjective Happiness Scale and EORTC QLQ‐C30, respectively. Multivariable logistic regression was used to find factors associated with happiness.
Results
The mean age of the study participants was 48.5 ± 7.8 years. Among the 283 survivors, 14.5%, 43.8%, 32.5%, and 2.1% reported being “very happy,” “happy,” “neutral,” and “not happy at all,” respectively. Happy survivors reported a better general health status and QoL (67.6 vs 49.6; P < .01), and fewer symptoms compared to unhappy survivors. Happy survivors were more likely to feel certain about the future (27.2% vs 11.9%, P < .01), have a strong purpose in life (22.4% vs 9.3%, P < .01), and feel hopeful (36.4% vs 8.5%, P < .01) compared to unhappy survivors. In a multivariate model, having purpose (OR = 2.50, 95% CI 1.42‐4.40) and hope (OR = 4.07, 95% CI 2.23‐7.45) in life were found to be associated with happiness.
Conclusions
During the reentry period, breast cancer survivors who are hopeful and have a clear purpose in life are more likely to be happy than those who are not. Setting proper life goals might be beneficial to help breast cancer survivors who experience persistent QoL issues.
•Amikacin results in ototoxicity due to the overproduction of reactive oxygen species.•Galangin prevents amikacin-provoked increase in ROS production in cochlear explants.•Galangin reduced apoptotic ...cell death of hair cells in amikacin-treated cochlear explants.
Amikacin is a semi-synthetic aminoglycoside widely used to treat infections caused by gentamicin-resistant gram-negative organisms and nontuberculous mycobacteria. However, the use of this agent often results in ototoxicity due to the overproduction of reactive oxygen species (ROS). Galangin, a natural flavonoid, has been shown to play a protective role against mitochondrial dysfunction by reducing mitochondrial ROS production.
In this study, the effect of galangin on amikacin-induced ototoxicity was examined using cultures of cochlear explants. Immunofluorescent staining showed that treatment of inner hair cells (IHCs) and outer hair cells (OHCs) with galangin significantly decreased damage induced by amikacin. Moreover, pretreatment with galangin resulted in decreased amikacin-provoked increase in ROS production in both types of hair cells by MitoSOX-red staining. Attenuation of apoptotic cell death was assessed immunohistochemically using active caspase-3 antibody and with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, compared to explants exposed to amikacin alone (P<0.05). These results indicate that galangin protects hair cells in the organ of Corti from amikacin-induced toxicity by reducing the production of mitochondrial ROS.
The results of this study suggest that galangin can potentially be used as an antioxidant and antiapoptotic agent to prevent hearing loss caused by aminoglycoside induced-oxidative stress.
Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. Generally, hormone receptor-positive (HR+) breast cancers have favorable ...prognosis. In order to understand the exact clinical characteristics and prognosis of single HR-positive breast cancer (ER + PR- tumors and ER-PR+ tumors), we compared these tumors to double HR+ tumors as well as HR- negative tumors (ER-PR-).
We examined the clinical and biological features of 6,980 women with invasive ductal carcinoma, and these patients were stratified according to ER and PR expression as double HR+ (ER + PR+), single HR+ (ER + PR- and ER-PR+) and double HR-negative (HR-, ER-PR-) tumors.
In this study, 571 (8.2%) cases were single HR+ tumors, of which 90 (1.3%) were ER-PR+ tumors and 481 (6.9%) were ER + PR- tumors. Our multivariate analysis showed that in patients without HER2 overexpression ER + PR- tumors were associated with an increased risk of recurrence and death compared with ER + PR+ tumors, with a hazard ratio of 2.12 for disease-free survival (DFS) and 4.79 for overall survival (OS). In patients without HER2 overexpression ER-PR+ tumors had increased risk of recurrence and death compared with ER + PR+ tumor, with a hazard ratio of 4.19 for DFS and 7.22 for OS. In contrast, in patients with HER2 overexpression, the difference in survival between single HR+ tumors and double HR+ HR- tumors was not statistically significant. In patients without HER2 overexpression the DFS and OS of ER + PR- and ER-PR+ tumors were not significantly different from those of ER-PR- tumors.
We have identified clinically and biologically distinct features of single HR+ tumors (ER-PR+ and ER + PR-) through comparison with both ER + PR+ and ER-PR- tumors. These differences were only significant in HER2- tumors, not in HER2+ tumors. Single HR+ tumors without HER2 overexpression (ER + PR-HER2- or ER-PR + HER2-) were associated with poorer survival than ER + PR + HER2- tumors, and had comparable poor survival to ER-PR-HER2- tumors (triple-negative breast cancer).
Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes ...and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA. We also observe increased mutation prevalence affecting BRCA1, BRCA2, and TP53 in SMC with an enrichment of a mutation signature linked to homologous recombination repair deficiency in TNBC. Finally, virtual microdissection and multivariate analyses reveal that Korean BC status is independently associated with increased TIL and decreased TGF-β signaling expression signatures, suggesting that younger Asian BCs harbor more immune-active microenvironment than western BCs.
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