Endogenous metabolic markers for predicting the activity of dihydropyrimidine dehydrogenase

Five-fluorouracil (5-FU) is a chemotherapeutic agent that is mainly metabolized by the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). The DPD enzyme activity deficiency involves a wide range of severities. Previous studies have demonstrated the effect of a DPYD single nucleotide polymorphism on 5-FU efficacy and highlighted the importance of studying such genes for cancer treatment. Common polymorphisms of DPYD in European ancestry populations are less frequently present in Koreans. DPD is also responsible for the conversion of endogenous uracil (U) into dihydrouracil (DHU). We quantified U and DHU in plasma samples of healthy male Korean subjects, and samples were classified into two groups based on DHU/U ratio. The calculated DHU/U ratios ranged from 0.52 to 7.12, and the two groups were classified into the 10th percentile and 90th percentile for untargeted metabolomics analysis using liquid chromatography-quantitative time-of-flight-mass spectrometry. A total of 4440 compounds were detected and filtered out based on a coefficient of variation below 30%. Our results revealed that six metabolites differed significantly between the high activity group and low activity group (false discovery rate q-value \u3c 0.05). Uridine was significantly higher in the low DPD activity group and is a precursor of U involved in pyrimidine metabolism; therefore, we speculated that DPD deficiency can influence uridine levels in plasma. Furthermore, the cutoff values for detecting DPD deficient patients from previous studies were unsuitable for Koreans. Our metabolomics approach is the first study that reported the DHU/U ratio distribution in healthy Korean subjects and identified a new biomarker of DPD deficiency

Development of Laser Ruler in Rigid Laryngoscope

ObjectivesThe objective of this study was to develop a new device that provides a simple, noninvasive method of measuring accurate lesion size while using an endoscope.MethodsWe developed a rigid laryngoscope with a built-in laser-ruler using a one-light emitting diode and an acrylic plate. The invention incorporates a built-in laser diode that projects an auto-parallel beam into the optical path of the rigid laryngoscope to form two spots in the field of view.ResultsWhile the interspot distance remains consistent despite changes in focal plane, magnification, or viewing angle of the laryngoscope, projection to an uneven surface introduces certain variations in the shape, and size of the spots, and the distance between the two spots.ConclusionThe device enables a laryngologist to easily measure the distance between landmarks, as well as the change in real size, and the progressive change of vocal fold lesions in an outpatient setting

The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis

Background Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. Methods We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used. Results HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF. Conclusions Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.This work was supported by grants from the National Research Foundation of Korea, (NRF-2018R1A5A2025286, NRF-2020R1A2C3013255, NRF-2020M2D9A2093974, NRF-2020R1I1A1A01070841, NRF-2020M2D9A2093976 and NRF-2022R1A2C3011611), funded by the Korean government (Ministry of Science and ICT)

SPON1 Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer's Disease Mouse Model

Alzheimer's disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (A beta) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of A beta, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of SPON1 in A beta reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express Spon1. iNSCs harboring mouse Spon1 secreted SPON1 protein and reduced the quantity of A beta when co-cultured with A beta -secreting Neuro 2a cells. The human SPON1 gene itself also reduced A beta in HEK 293T cells expressing the human APP transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting SPON1 reduced the amount of A beta and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human APP and PSEN1 transgenes with five AD-linked mutations

Breathing silicon anodes for durable high-power operations

Silicon anode materials have been developed to achieve high capacity lithium ion batteries for operating smart phones and driving electric vehicles for longer time. Serious volume expansion induced by lithiation, which is the main drawback of silicon, has been challenged by multi-faceted approaches. Mechanically rigid and stiff polymers (e.g. alginate and carboxymethyl cellulose) were considered as the good choices of binders for silicon because they grab silicon particles in a tight and rigid way so that pulverization and then break-away of the active mass from electric pathways are suppressed. Contrary to the public wisdom, in this work, we demonstrate that electrochemical performances are secured better by letting silicon electrodes breathe in and out lithium ions with volume change rather than by fixing their dimensions. The breathing electrodes were achieved by using a polysaccharide (pullulan), the conformation of which is modulated from chair to boat during elongation. The conformational transition of pullulan was originated from its a glycosidic linkages while the conventional rigid polysaccharide binders have beta linkagesopen1

Characteristics and efficacy of fish-derived gelatin microparticles as an embolic agent in a rabbit renal model: regulation of the degradation period by molecular weight

PURPOSE:To evaluate the embolic effect of fish-derived gelatin microparticles (GMPs) and compare the degradation periods and biocompatibilities of different molecular weight (MW) GMPs in a rabbit model.METHODS:GMPs were designed to degrade within 21 days (high MW GMP, 15-30 kDa) and 2 days (low MW GMP, 5-15 kDa) in vivo. Renal arteries of 24 rabbits were embolized using both high and low MW GMPs (155-350 µm). Rabbits were sacrificed either immediately after embolization, or after follow-up (F/U) angiogram on days 2 and 21 of embolization, respectively (4 rabbits in each of the 6 subgroups). Pathological changes of recanalized vessels were evaluated using the Banff classification. For the in vitro study, each type of GMP was mixed with normal saline and morphological changes were compared for 14 days.RESULTS:Fish-derived GMPs showed effective embolization. On 2-day F/U angiography, occluded vessels were more recanalized to the peripheral branches in low MW group. On day 21, a parenchymal perfusion defect recovered to a greater extent in low MW group than that in high MW group. Mean Banff scores for intimal arteritis on 2-day F/U and interstitial fibrosis on 21-day F/U were higher in high MW group (1.75 ± 0.58 vs. 0.19 ± 0.4 and 2.56 ± 0.63 vs. 0.88 ± 0.89; P < .001). On in vitro assessment, low MW GMP lost the spherical shape and degraded, and was invisible on microscopy on day 6, whereas high MW GMP was only partially degraded after 2 weeks.CONCLUSION:Fish-derived GMPs showed effective embolization in a rabbit model. Low MW GMPs degraded within 2 days with a low inflammatory response

A Rare Case of Radial Arteriovenous Fistula After Coronary Angiography

The percutaneous transfemoral approach has been routinely used for cardiac catheterization and coronary angioplasty. Local vascular complications following angioplasty are seen in 5% to 10% of patients, especially in those who need prolonged anticoagulation. Transradial access for coronary procedures dramatically reduces access site complications. We report a rare case of radial arteriovenous fistula, which developed after coronary angiography perfomed using the transradial approach