High-Throughput Single-Entity Electrochemistry with Microelectrode Arrays.

We describe micro- and nanoelectrode array analysis with an automated version of the array microcell method (AMCM). Characterization of hundreds of electrodes, with diameters ranging from 100 nm to 2 µm, was carried out by using AMCM voltammetry and chronoamperometry. The influence of solvent evaporation on mass transport in the AMCM pipette and the resultant electrochemical response were investigated, with experimental results supported by finite element method simulations. We also describe the application of AMCM to high-throughput single-entity electrochemistry in measurements of stochastic nanoparticle impacts. Collision experiments recorded 3270 single-particle events from 671 electrodes. Data collection parameters were optimized to enable these experiments to be completed in a few hours, and the collision transient sizes were analyzed with a U-Net deep learning model. Elucidation of collision transient sizes by histograms from these experiments was enhanced due to the large sample size possible with AMCM.

Bioactive TNIIIA2 Sequence in Tenascin-C Is Responsible for Macrophage Foam Cell Transformation; Potential of FNIII14 Peptide Derived from Fibronectin in Suppression of Atherosclerotic Plaque Formation.

One of the extracellular matrix proteins, tenascin-C (TN-C), is known to be upregulated in age-related inflammatory diseases such as cancer and cardiovascular diseases. Expression of this molecule is frequently detected, especially in the macrophage-rich areas of atherosclerotic lesions; however, the role of TN-C in mechanisms underlying the progression of atherosclerosis remains obscure. Previously, we found a hidden bioactive sequence termed TNIIIA2 in the TN-C molecule and reported that the exposure of this sequence would be carried out through limited digestion of TN-C by inflammatory proteases. Thus, we hypothesized that some pro-atherosclerotic phenotypes might be elicited from macrophages when they were stimulated by TNIIIA2. In this study, TNIIIA2 showed the ability to accelerate intracellular lipid accumulation in macrophages. In this experimental condition, an elevation of phagocytic activity was observed, accompanied by a decrease in the expression of transporters responsible for lipid efflux. All these observations were mediated through the induction of excessive ß1-integrin activation, which is a characteristic property of the TNIIIA2 sequence. Finally, we demonstrated that the injection of a drug that targets TNIIIA2's bioactivity could rescue mice from atherosclerotic plaque expansion. From these observations, it was shown that TN-C works as a pro-atherosclerotic molecule through an internal TNIIIA2 sequence. The possible advantages of clinical strategies targeting TNIIIA2 are also indicated.

Imaging with Ion Channels.

We describe the incorporation of gated ion channels into probes for scanning ion conductance microscopy (SICM) as a robust platform for collecting spatial information at interfaces. Specifically, a dual-barrel pipet is used, where one barrel controls the pipet position and the second barrel houses voltage-gated transient receptor potential vanilloid 1 (TRPV1) channels excised in a sniffer-patch configuration. Spatially resolved sensing with TRPV1 channels is demonstrated by imaging a porous membrane where a transmembrane potential across the membrane generates local electric field gradients at pores that activate TRPV1 channels when the probe is in the vicinity of the pore. The scanning routine and automated signal analysis demonstrated provide a generalizable approach to employing gated ion channels as sensors for imaging applications.

Investigating the effect of nitrate on juvenile turbot (Scophthalmus maximus) growth performance, health status, and endocrine function in marine recirculation aquaculture systems.

Nitrate (NO3-), a potential toxic nitrogenous compound to aquatic animals, is distributed in aquatic ecosystems worldwide. The aim of this study was to investigate the effects of different NO3- levels on growth performance, health status, and endocrine function of juvenile turbot (Scophthalmus maximus) in recirculating aquaculture systems (RAS). Fish were exposed to 0 mg/L (control, CK), 50 mg/L (low nitrate, LN), 200 mg/L (medium nitrate, MN), and 400 mg/L (high nitrate, HN) NO3-N for 60 d in experimental RAS. Cumulative survival (CS) was significantly decreased with increasing NO3- levels in LN, MN, and HN. The lowest CS was 35% in the HN group. Growth parameters, including absolute growth rate, specific growth rate, and feed conversion rate, were significantly different in HN compared with that in the CK. Histological survey of gills and liver revealed dose-dependent histopathological damage induced by NO3- exposure and significant differences in glutamate pyruvate transaminase and glutamate oxalate transaminase in MN and HN compared with that in the CK. The hepatosomatic index in HN was significantly higher than that in the CK. Additionally, NO3- significantly increased bioaccumulation in plasma in LN, MN, and HN compared to that in the CK. Significant decreases in hemoglobin and increases in methemoglobin levels indicated reduced oxygen-carrying capacity in HN. Additionally, qRT-PCR and enzyme-linked immunosorbent assay (ELISA) were developed to investigate key biomarkers involved in the GH/IGF-1, HPT, and HPI axes. Compared with that in the CK, the abundance of GH, GHRb, and IGF-1 was significantly lower in HN, whereas GHRa did not differ between treatments. The plasma T3 level significantly decreased in LN, MN, and HN and T4 significantly decreased in HN. The CRH, ACTH, and plasma cortisol levels were significantly upregulated in HN compared with that in the CK. We conclude that elevated NO3- exposure leads to growth retardation, impaired health status, and endocrine disorders in turbot and the NO3- level for juvenile turbot culture should not exceed 50 mg/L NO3-N in RAS. Our findings indicate that endocrine dysfunction of the GH/IGF-1, HPT, and HPI axes might be responsible for growth inhibition induced by NO3- exposure.

The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice.

Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for 12 weeks. Like fenofibrate, pemafibrate significantly suppressed HFD-induced body weight gain; decreased plasma glucose, insulin and triglyceride (TG) levels; and increased plasma fibroblast growth factor 21 (FGF21). However, compared to the dose of fenofibrate, a relatively low dose of pemafibrate showed these effects. Pemafibrate activated PPARα transcriptional activity in the liver, increasing both hepatic expression and plasma levels of FGF21. Additionally, pemafibrate increased the expression of genes involved in thermogenesis and fatty acid oxidation, including Ucp1, Cidea and Cpt1b in inguinal adipose tissue (iWAT) and the mitochondrial marker Elovl3 in brown adipose tissue (BAT). Therefore, pemafibrate activates thermogenesis in iWAT and BAT by increasing plasma levels of FGF21. Additionally, pemafibrate induced the expression of Atgl and Hsl in epididymal white adipose tissue, leading to the activation of lipolysis. Taken together, pemafibrate suppresses diet-induced obesity in mice and improves their obesity-related metabolic abnormalities. We propose that pemafibrate may be useful for the suppression and improvement of obesity-induced metabolic abnormalities.

Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice.

Peroxisome proliferator-activated receptor α (PPARα) is a well-known therapeutic target for treating hyperlipidemia. K-877 is a novel selective PPARα modulator (SPPARMα) that enhances PPARα transcriptional activity with high selectivity and potency, resulting in reduced plasma lipid levels. This study aimed to evaluate the effects of K-877 on hyperlipidemia in low-density lipoprotein receptor knockout (Ldlr-/-) mice, a mouse model of atherosclerosis. We revealed that K-877 administration significantly decreased plasma triglyceride (TG) and total cholesterol (TC) levels and increased plasma high-density lipoprotein cholesterol (HDL-C) levels in Ldlr-/- mice. K-877 administration to Ldlr-/- mice efficiently increased the gene expression of PPARα and its target genes related to fatty acid oxidation in the liver and small intestine. The same treatment significantly increased ATP-binding cassette a1 gene expression in the liver and small intestine and reduced Niemann Pick C1-like 1 gene expression in the small intestine, suggesting that K-877 administration induced HDL-C production in the liver and small intestine and reduced cholesterol absorption in the small intestine. In conclusion, K-877 administration had pronounced effects on the liver and small intestine in Ldlr-/- mice. K-877 is an attractive PPARα-modulating drug for treating hyperlipidemia that works equally well in both the liver and small intestine.

Intradermal injection of Cutibacterium acnes and staphylococcus: A pustular acne-like murine model.

BACKGROUND: Skin 16S microbiome diversity analysis indicates that the Staphylococcus genus, especially Staphylococcus aureus (S. aureus), plays a crucial role in the inflammatory lesions of acne. However, current animal models for acne do not fully replicate human diseases, especially pustular acne, which limits the development of anti-acne medications. AIMS: The aim is to develop a mouse model for acne, establishing an animal model that more closely mimics the clinical presentation of pustular acne. This will provide a new research platform for screening anti-acne drugs and evaluating the efficacy of clinical anti-acne experimental treatments. METHODS: Building upon the existing combination of acne-associated Cutibacterium acnes (C. acnes) with artificial sebum, we will inject a mixture of S. aureus and C. acnes locally into the dermis in a 3:7 ratio. RESULTS: We found that the acne animal model with mixed bacterial infection better replicates the dynamic evolution process of human pustular acne. Compared to the infection with C. acnes alone, mixed bacterial infection resulted in pustules with a distinct yellowish appearance, resembling pustular acne morphology. The lesions exhibited redness, vascular dilation, and noticeable congestion, along with evident infiltration of inflammatory cells. This induced higher levels of inflammation, as indicated by a significant increase in the secretion of inflammatory factors such as IL-1ß and TNF-α. CONCLUSION: This model can reflect the clinical symptoms and development of human pustular acne, overcoming the limitations of animal models commonly used in basic research to study this situation. It provides support for foundational research and the development of new acne medications.

Covalently bridging graphene edges for improving mechanical and electrical properties of fibers.

Assembling graphene sheets into macroscopic fibers with graphitic layers uniaxially aligned along the fiber axis is of both fundamental and technological importance. However, the optimal performance of graphene-based fibers has been far lower than what is expected based on the properties of individual graphene. Here we show that both mechanical properties and electrical conductivity of graphene-based fibers can be significantly improved if bridges are created between graphene edges through covalent conjugating aromatic amide bonds. The improved electrical conductivity is likely due to extended electron conjugation over the aromatic amide bridged graphene sheets. The larger sheets also result in improved π-π stacking, which, along with the robust aromatic amide linkage, provides high mechanical strength. In our experiments, graphene edges were bridged using the established wet-spinning technique in the presence of an aromatic amine linker, which selectively reacts to carboxyl groups at the graphene edge sites. This technique is already industrial and can be easily upscaled. Our methodology thus paves the way to the fabrication of high-performance macroscopic graphene fibers under optimal techno-economic and ecological conditions.

Comparative efficacy and safety of six photoelectric therapies for the atrophic acne scars: A network meta-analysis.

Objectives This network meta-analysis assessed the relative efficacy and safety of six common photoelectric therapies including 1064-nm neodymium-doped yttrium aluminum garnet (Nd: YAG), fractional carbon dioxide laser(FSCO2), fractional micro-plasma radiofrequency(Plasma), micro-needling fractional radiofrequency (MRF), 1550nm or 1540nm erbium-glass non-ablative fractional laser (NAFL) fractional erbium-doped yttrium aluminum garnet (Er: YAG). Methods A comprehensive search to identify relevant studies was conducted using four electronic databases. Outcome measures were extracted based on subjective and objective indexes, including the dermatologists' evaluation(DE), the patients' overall satisfaction(PS), VAS score, and Postinflammatory hyperpigmentation (PIH). Results Eleven published clinical research studies, involving 405 patients were included in this study. Ranking of DE from large to small is as follows: Nd: YAG, FSCO2, Er: YAG, Plasma, NAFL, MRF. In terms of PS, the rand from high to low can be described as follows: Er: YAG, Nd: YAG, FSCO2, Plasma, NAFL, MRF. In connection with the sequencing of adverse events, pain severity from slight to severe as follows: Er:YAG, Nd:YAG, FSCO2, NAFL, MRF, Plasma. The probability of having PIH are presented in order from lowest to highest as follows: MRF, Plasma, Nd: YAG, NAFL, Er: YAG, FSCO2. Conclusion FSCO2 remains the mainstream of potentially curative treatment, then again Nd: YAG and Er: YAG require greater efforts to prove their superior effectiveness. NAFL might be appropriate for mild and moderate improvement with its strengths of good tolerance while Plasma fits into patients with higher pain thresholds but an expectation of higher results. MRF has not given expression on absolute predominance for the present. Registration PROSPERO CRD42021242160 (available from https://www.crd.york.ac.uk/prospero).

Construction of "peptide-hemin/DNA" hybrid-complexes and their peroxidase activities.

N-Acetylated microperoxidase-11 and G-quadruplex DNA are shown to form a stable "peptide-hemin/DNA" hybrid-complex, in which the peroxidase activity at the interface between hemin and the G-quartet planes exponentially increases with increasing Ka value.

Boosting NAD ameliorates hematopoietic impairment linked to short telomeres in vivo.

Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null (Tert-/-) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert-/- mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert-/- hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert-/- transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.

Rhomboid protease RHBDL4/RHBDD1 cleaves SREBP-1c at endoplasmic reticulum monitoring and regulating fatty acids.

The endoplasmic reticulum (ER)-embedded transcription factors, sterol regulatory element-binding proteins (SREBPs), master regulators of lipid biosynthesis, are transported to the Golgi for proteolytic activation to tune cellular cholesterol levels and regulate lipogenesis. However, mechanisms by which the cell responds to the levels of saturated or unsaturated fatty acids remain underexplored. Here, we show that RHBDL4/RHBDD1, a rhomboid family protease, directly cleaves SREBP-1c at the ER. The p97/VCP, AAA-ATPase complex then acts as an auxiliary segregase to extract the remaining ER-embedded fragment of SREBP-1c. Importantly, the enzymatic activity of RHBDL4 is enhanced by saturated fatty acids (SFAs) but inhibited by polyunsaturated fatty acids (PUFAs). Genetic deletion of RHBDL4 in mice fed on a Western diet enriched in SFAs and cholesterol prevented SREBP-1c from inducing genes for lipogenesis, particularly for synthesis and incorporation of PUFAs, and secretion of lipoproteins. The RHBDL4-SREBP-1c pathway reveals a regulatory system for monitoring fatty acid composition and maintaining cellular lipid homeostasis.

A redox-active metal-organic compound for lithium/sodium-based dual-ion batteries.

Currently, there is considerable interest in developing new electrode materials to construct the new-generation dual-ion batteries (DIBs) with the potential advantages of higher working voltage, good safety, low cost, and environmental friendliness. Herein, a well-known charge-transfer metal-organic compound, copper-tetracyanoquinodimethane (CuTCNQ), is synthesized and then used as an anode material, which can reversibly store Li+/Na+ ions under the lower working voltage. Consequently, the lithium/sodium-based DIBs (LDIBs/SDIBs) are constructed by coupling CuTCNQ anode with graphite cathode and their working mechanisms are also understood in detail. As expected, LDIBs exhibit a high average potential of 4.26 V, a high initial discharge capacity of 195.4 mAh g-1 at 0.1 A g-1, long cycling performance after 200 cycles with good capacity retention and excellent rate capability of 106.2 mAh g-1 at 5 A g-1. Especially, high average potential of 4.23 V and good rate capability of 34.5 mAh g-1 at 5 A g-1 could be maintained in SDIBs. These results may open a new avenue for using metal-organic compound in the field of high-performance energy-storage devices.

Dynamic hybrid-phase computed tomography simulation in lung stereotactic body radiotherapy: A feasibility study.

To assess the feasibility of dynamic hybrid-phase computed tomography (CTDHP) simulation when patients undergo lung stereotactic body radiation therapy (SBRT). Eighteen non-small-cell lung-cancer patients were immobilised in a stereotactic body frame with abdominal compression. All underwent dynamic hybrid-phase CT scans that were compared with cone-beam CT (CBCT). We also determined the internal target volume (ITV) and evaluated the following four metrics: the "AND" function in the Boolean module of Eclipse, volume overlap (VO), Dice similarity coefficient (DSC), and dose-volume histogram. The average ITV values of 4DCTDHP and 3D-CBCT were respectively 12.82±10.42 and 14.6±12.18 cm3 (n=72, p<0.001), and the average ITV value of AND was 11.7±10.1 cm3. The average planning target volume (PTV) of 4DCTDHP and 3D-CBCT was 25.63±18.04 and 28.00±19.82 cm3 (n=72, p<0.001). The median AND difference between ITV and PTV was significant (p<0.01) and had a significantly linear distribution (R2=0.991 for ITV, R2=0.972 for PTV). The average VO of PTV was greater than that of ITV (0.81±0.096; 0.78±0.11). We also observed that the average DSC in PTV (0.83±0.066) was greater than that in ITV (0.81±0.084). The average results indicated that 97.9%±3.44 of ITVCBCT was covered by 95% of the prescribed dose. The average minimum, maximum and mean percentage doses of ITVCBCT were 87.9%±9.46, 107.3%±1.57, and 101.3%±1.12, respectively. This paper has demonstrated that dynamic hybrid-phase CT simulation for patients undergoing lung SBRT and also published evaluation metrics in scientific analysis. Our approach also has the advantage of adequate margin and fewer phases in CT simulation.

Safety and efficacy of vaginal laser therapy for stress urinary incontinence: a meta-analysis.

BACKGROUND: Laser therapy has recently been proposed as a novel treatment for stress urinary incontinence (SUI) due to offering several advantages. This study aimed to evaluate the safety and efficacy of laser treatment of SUI by a meta-analysis. METHODS: The systematic review registration number is INPLASY202080001. A comprehensive search to identify relevant studies was conducted using the PubMed, Embase, Cochrane Library, CNKI, VIP and Wanfang databases with a cutoff date of 1 November, 2020. Outcome measures were extracted based on subjective and objective indexes, including International Consultation on Incontinence Questionnaire-Short Form (ICIQ-UI-SF), Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), and objective measurements "1-hour pad test" (1-hour test under standardized conditions). Score changes before and after treatment were evaluated through meta-analysis. Subgroup analysis was performed according to geographic region, type of urinary incontinence (UI), severity of UI, age, and body mass index (BMI). RESULTS: Sixteen published clinical research studies, involving 899 patients with SUI, were included in this study. After laser treatment, the change in the ICIQ-SF score at 1, 2, and 6 months was -5.49 (95% CI: -6.74--4.24; I2=91%, P<0.01), -4.97 (95% CI: -6.24--3.71), and -5.48 (95% CI: -6.15--4.81), respectively. The improvement in 1-hour pad weight test results at 1, 3, and 12 months post treatment was -5.59 (95% CI: -6.93--4.25), -4.96 (95% CI: -6.73--3.20), and -5.82 (95% CI: -6.77--4.87), respectively. The PISQ-12 score increased by 5.39 (95% CI: 1.20-9.58) following treatment. Subgroup analysis identified the type and severity of UI as the potential source of heterogeneity. Adverse effects were reported in 6 of the 16 trials and affected only a small number of patients. Most adverse events were mild or moderate and required no medical intervention or resolved in a few days. CONCLUSIONS: Vaginal laser therapy appears to be a safe, effective, and minimally invasive treatment option for SUI that can be well tolerated by patients.

Conjugated microporous polyarylimides immobilization on carbon nanotubes with improved utilization of carbonyls as cathode materials for lithium/sodium-ion batteries.

Aromatic polyimide (PI)-based compounds have been widely studied for lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs) due to their higher specific energy density, economical, environmentally friendly and adjustable redox potential window. However, their solubility in aprotic electrolytes, inherently poor conductivity and low active site utilization limit their application in large-scale energy storage system (ESS). Here, we synthesized two aromatic PI-based conjugated microporous polymers (CMPs) and integrated them with multi-walled carbon nanotubes (CNT) (TAPT-NTCDA@CNT and TAPT-PMDA@CNT) for using as cathode materials for LIBs and SIBs. The aromatic PI-based CMP can effectively utilize the redox activity site due to its abundant π-conjugated redox active units, stable imide bond, high specific surface area and clear pore structure. As expected, the optimum TAPT-NTCDA@CNT exhibits good rate performance (89.7 mAh g-1 at 2000 mA g-1) and long cycle stability (87.3% capacity retention after 500 cycles) in LIBs. Also, TAPT-NTCDA@CNT can provide a higher initial capacity of 91.1 mAh g-1 in SIBs at 30 mA g-1. This work provides key insights for the further development of other new organic electrodes for other advanced rechargeable batteries.

Both of marine fish species Oryzias melastigma and Pagrus major all failing in early localization at embryo stage by vasa RNA.

Germ cells are essential for gonadal development. As precursors of germ cells, primordial germ cells (PGCs) are particularly important for germline formation. However, the research on distribution patterns of PGCs in marine fish is very limited, especially for economic species. The vasa gene has been widely used as marker to identify PGCs origination and migration because of vasa RNA is a component of germ plasm. In this study, we isolated full-length vasa cDNA (Omvas and Pmvas) from marine medaka (Oryzias melastigma) and red seabream (Pagrus major), detected vasa transcripts in different tissues by RT-PCR and described vasa expression patterns during embryogenesis and gametogenesis by in situ hybridization. At the same time, we also explored the relationship between early distribution of germ plasm components and species evolution. The results demonstrated that deduced amino acid sequence of Omvas and Pmvas shared several conserved motifs of Vasa homologues and high identity with other teleost, and vasa transcripts were exclusively detected in early germ cells of gonad. During embryogenesis, vasa RNA of both fishes, like medaka (Oryzias latipes), failed to localize at cleavage furrows and distributed uniformly throughout each blastomere. This study firstly discovered that the marine economic fish, red seabream, lost vasa RNA early specific localization at cleavage furrows and distinctive distribution in germ cells. In addition, compared with other teleost, we found that early distribution of germ plasm might not relate to species evolution. This will improve our understanding of vasa localization modes in teleost, and facilitate fish germ cell manipulation.

Evolutionary ecology of the visual opsin gene sequence and its expression in turbot (Scophthalmus maximus).

BACKGROUND: As flatfish, turbot undergo metamorphosis as part of their life cycle. In the larval stage, turbot live at the ocean surface, but after metamorphosis they move to deeper water and turn to benthic life. Thus, the light environment differs greatly between life stages. The visual system plays a great role in organic evolution, but reports of the relationship between the visual system and benthic life are rare. In this study, we reported the molecular and evolutionary analysis of opsin genes in turbot, and the heterochronic shifts in opsin expression during development. RESULTS: Our gene synteny analysis showed that subtype RH2C was not on the same gene cluster as the other four green-sensitive opsin genes (RH2) in turbot. It was translocated to chromosome 8 from chromosome 6. Based on branch-site test and spectral tuning sites analyses, E122Q and M207L substitutions in RH2C, which were found to be under positive selection, are closely related to the blue shift of optimum light sensitivities. And real-time PCR results indicated the dominant opsin gene shifted from red-sensitive (LWS) to RH2B1 during turbot development, which may lead to spectral sensitivity shifts to shorter wavelengths. CONCLUSIONS: This is the first report that RH2C may be an important subtype of green opsin gene that was retained by turbot and possibly other flatfish species during evolution. Moreover, E122Q and M207L substitutions in RH2C may contribute to the survival of turbot in the bluish colored ocean. And heterochronic shifts in opsin expression may be an important strategy for turbot to adapt to benthic life.

Evaluating the benefit of adjuvant radiotherapy after extensive lymph node dissection for gastric cancer: a single-institute retrospective study.

OBJECTIVE: This study aimed to evaluate whether adjuvant radiotherapy (RT) can improve the treatment outcome of patients with locally advanced gastric cancer who underwent extensive lymph node dissection (ELND). MATERIALS AND METHODS: This retrospective study included patients with gastric cancer pathological stages IIA-IIIC at Taipei Tzu Chi Hospital between 2008 and 2015. Patients (a) aged >80 years, (b) with distant metastasis at diagnosis, (c) with coexisting malignancies, (d) who did not complete the prescribed RT course, and (e) who died 1 month after surgery were excluded. Among 420 patients diagnosed with gastric cancer, 98 were included. RESULTS: The median follow-up was 24.5 months. Of 39 patients who underwent adjuvant RT, 38 also received adjuvant chemotherapy (CT). Of 59 patients who did not receive adjuvant RT, only 34 received adjuvant CT. ELND was performed in 67.3% of the patients. The 5-year overall survival (OS) rate was 40%. In the univariate analyses, adjuvant CT regimen, 5-fluorouracil + leucovorin, was associated with worst outcome, while TS-1 was associated with better survival outcome (P = 0.018). The number of involved lymph nodes was strongly related to the OS and disease-free survival (DFS) (P < 0.001). We tried using different numbers of involved lymph nodes as a cutoff point and found that adjuvant RT significantly improved both OS and DFS in patients whose involved lymph nodes were ≥4 (OS, P = 0.017; DFS, P = 0.015). In multivariate analyses, better DFS was associated with negative surgical margin (P = 0.04), earlier disease stage (P = 0.001), adjuvant radiotherapy (P = 0.045), and adjuvant CT regimen TS-1 (P = 0.001). CONCLUSION: Adjuvant RT could improve DFS of patients with locally advanced gastric cancer with or without ELND. When the number of involved lymph nodes is ≥4, adjuvant RT is strongly suggested.

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition.

BACKGROUND & AIMS: cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. METHODS: CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR-/- mice. These mice were fed with a Western diet to develop atherosclerosis. RESULTS: CREB3L3 ablation in LDLR-/- mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly up-regulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)-mediated lipogenic and cholesterogenic genes and regulates intestinal liver X receptor-regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi and vice versa. CONCLUSIONS: CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions.