In this study, we tested our hypothesis regarding mechanistic cross-talk between gastrointestinal inflammation and memory loss in a mouse model. Intrarectal injection of the colitis inducer ...2,4,6-trinitrobenzenesulfonic acid (TNBS) in mice caused colitis via activation of nuclear factor (NF)-κB and increase in membrane permeability. TNBS treatment increased fecal and blood levels of lipopolysaccharide (LPS) and the number of Enterobacteriaceae, particularly Escherichia coli (EC), in the gut microbiota composition, but significantly reduced the number of Lactobacillus johnsonii (LJ). Indeed, we observed that the mice treated with TNBS displayed impaired memory, as assessed using the Y-maze and passive avoidance tasks. Furthermore, treatment with EC, which was isolated from the feces of mice with TNBS-induced colitis, caused memory impairment and colitis, and increased the absorption of orally administered LPS into the blood. Treatment with TNBS or EC induced NF-κB activation and tumor necrosis factor-α expression in the hippocampus of mice, as well as suppressed brain-derived neurotrophic factor expression. However, treatment with LJ restored the disturbed gut microbiota composition, lowered gut microbiota, and blood LPS levels, and attenuated both TNBS- and EC-induced memory impairment and colitis. These results suggest that the gut microbiota disturbance by extrinsic stresses can cause gastrointestinal inflammation, resulting in memory impairment.
Lysine-specific demethylase 1 (LSD1), which has been considered as a potential therapeutic target in human cancer, has been known to regulate many biological functions through its non-histone ...substrates. Although LSD1-induced hypoxia-inducible factor alpha (HIF1α) demethylation has recently been proposed, the effect of LSD1 on the relationship between HIF1α post-translational modifications (PTMs) and HIF1α-induced tumor angiogenesis remains to be elucidated. Here, we identify a new methylation site of the HIF1α protein antagonized by LSD1 and the interplay between HIF1α protein methylation and other PTMs in regulating tumor angiogenesis. LSD1 demethylates HIF1α at lysine (K) 391, which protects HIF1α against ubiquitin-mediated protein degradation. LSD1 also directly suppresses PHD2-induced HIF1α hydroxylation, which has a mutually dependent interplay with Set9-mediated HIF1α methylation. Moreover, the HIF1α acetylation that occurs in a HIF1α methylation-dependent manner is inhibited by the LSD1/NuRD complex. HIF1α stabilized by LSD1 cooperates with CBP and MTA1 to enhance vascular endothelial growth factor (VEGF)-induced tumor angiogenesis. Thus, LSD1 is a key regulator of HIF1α/VEGF-mediated tumor angiogenesis by antagonizing the crosstalk between PTMs involving HIF1α protein degradation.
Background
In gallbladder cancer, stage T2 is subdivided by tumour location into lesions on the peritoneal side (T2a) or hepatic side (T2b). For tumours on the peritoneal side (T2a), it has been ...suggested that liver resection may be omitted without compromising the prognosis. However, data to validate this argument are lacking. This study aimed to investigate the prognostic value of tumour location in T2 gallbladder cancer, and to clarify the adequate extent of surgical resection.
Methods
Clinical data from patients who underwent surgery for gallbladder cancer were collected from 14 hospitals in Korea, Japan, Chile and the USA. Survival and risk factor analyses were conducted.
Results
Data from 937 patients were available for evaluation. The overall 5‐year disease‐free survival rate was 70·6 per cent, 74·5 per cent for those with T2a and 65·5 per cent among those with T2b tumours (P = 0·028). Regarding liver resection, extended cholecystectomy was associated with a better 5‐year disease‐free survival rate than simple cholecystectomy (73·0 versus 61·5 per cent; P = 0·012). The 5‐year disease‐free survival rate was marginally better for extended than simple cholecystectomy in both T2a (76·5 versus 66·1 per cent; P = 0·094) and T2b (68·2 versus 56·2 per cent; P = 0·084) disease. Five‐year disease‐free survival rates were similar for extended cholecystectomies including liver wedge resection versus segment IVb/V segmentectomy (74·1 versus 71·5 per cent; P = 0·720). In multivariable analysis, independent risk factors for recurrence were presence of symptoms (hazard ratio (HR) 1·52; P = 0·002), R1 resection (HR 1·96; P = 0·004) and N1/N2 status (N1: HR 3·40, P < 0·001; N2: HR 9·56, P < 0·001). Among recurrences, 70·8 per cent were metastatic.
Conclusion
Tumour location was not an independent prognostic factor in T2 gallbladder cancer. Extended cholecystectomy was marginally superior to simple cholecystectomy. A radical operation should include liver resection and adequate node dissection.
Antecedentes
En el cáncer de vesícula biliar, la ubicación del tumor subdivide el estadio T2 en tumores con invasión del lado peritoneal y del lado del hígado (T2a y T2b). Para los tumores que invaden el lado peritoneal (T2a) se sugiere que se puede obviar la resección hepática sin que ello comprometa el pronóstico. Sin embargo, este argumento no ha sido validado. El estudio tuvo como objetivo investigar el valor pronóstico de la localización del tumor en el cáncer de vesícula biliar T2 y establecer la extensión adecuada de la resección quirúrgica.
Métodos
Se recogieron los datos clínicos de pacientes que se sometieron a cirugía por cáncer de vesícula biliar en 14 hospitales de Corea, Japón, Chile y Estados Unidos. Se realizaron análisis de la supervivencia y de los factores de riesgo.
Resultados
Se dispuso de datos de 937 pacientes para ser evaluados. La tasa de supervivencia global libre de enfermedad a los 5 años fue del 70,6%, y las de T2a y T2b del 74,5% y 65,5% (P = 0,028). Con respecto a la resección hepática, la colecistectomía extendida presentó una tasa mejor de supervivencia libre de enfermedad a los 5 años que la colecistectomía simple (73,0% versus 61,5%, P = 0,012). La tasa de supervivencia libre de enfermedad a los 5 años fue marginalmente mejor para la colecistectomía extendida que para la colecistectomía simple tanto en T2a (76,5% versus 66,1%, P = 0,094) como en T2b (68,2% versus 56,2%, P = 0,084). Las tasas de supervivencia libre de enfermedad a los 5 años no fueron diferentes entre la resección hepática en cuña y la segmentectomía S4b+S5 (74,1% versus 71,5%, P = 0,720). En el análisis multivariable, los factores de riesgo independientes para la recidiva fueron la presencia de síntomas (cociente de riesgos instantáneos, hazard ratio, HR 1,52, P = 0,002), la resección R1 (HR 1,96, P = 0,004) y el estadio N1/N2 (N1 HR 3,40, P < 0,001; N2 HR 9,56, P < 0,001). El 70,8% de las recidivas eran metastásicas.
Conclusión
La localización del tumor no fue un factor pronóstico independiente en el cáncer de vesícula biliar T2. La colecistectomía extendida fue marginalmente superior que la colecistectomía simple. La cirugía radical debe incluir una resección hepática y una linfadenectomía adecuada.
This multinational multicentre cohort study was undertaken to investigate the prognostic value of tumour location in T2 gallbladder cancer and to clarify the adequate extent of surgical resection. Although tumour location influenced prognosis, it was not an independent prognostic factor in T2 gallbladder cancer. T2 gallbladder cancer requires extended cholecystectomy including hepatic resection and lymph node dissection, regardless of the location.
challenges current TNM system
Nuclear fusion is one of the most attractive alternatives to carbon-dependent energy sources1. Harnessing energy from nuclear fusion in a large reactor scale, however, still presents many scientific ...challenges despite the many years of research and steady advances in magnetic confinement approaches. State-of-the-art magnetic fusion devices cannot yet achieve a sustainable fusion performance, which requires a high temperature above 100 million kelvin and sufficient control of instabilities to ensure steady-state operation on the order oftens of seconds2,3. Here we report experiments at the Korea Superconducting Tokamak Advanced Research4 device producing a plasma fusion regime that satisfies most ofthe above requirements: thanks to abundant fast ions stabilizing the core plasma turbulence, we generate plasmas at a temperature of 100 million kelvin lasting up to 20 seconds without plasma edge instabilities or impurity accumulation. A low plasma density combined with a moderate input power for operation is key to establishing this regime by preserving a high fraction of fast ions. This regime is rarely subject to disruption and can be sustained reliably even without a sophisticated control, and thus represents a promising path towards commercial fusion reactors.
Purpose
To assess the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) in liver cancer patients with different times of previous conventional transarterial ...chemoembolization (cTACE) treatments.
Methods
367 liver cancer patients about to receive DEB-TACE treatment were enrolled in this prospective cohort study. All patients were divided into no previous cTACE group (NPC group), 1–2 times previous cTACE group (PC group) and triple or above previous cTACE group (TPC group) according to the times of previous cTACE treatments.
Results
There was no difference in complete response (CR) (
P
= 0.671) and objective response rate (ORR) (
P
= 0.062) among three groups. Additionally, no difference in overall survival (OS) among groups (
P
= 0.899) was found. As to liver function, most liver function indexes were deteriorative at 1 week after DEB-TACE operation, but returned to baseline at 1–3 months after DEB-TACE operation in all three groups, while percentage of abnormal total bile acid (TBA) patients was higher in TPC group than NPC and PC groups at 1–3 month post-DEB-TACE (
P
= 0.018). As for safety profiles, the incidence of pain during DEB-TACE operation was lower in TPC group compared to NPC and PC groups (
P
= 0.005), while no difference of other adverse events was found during and 1 month post-DEB-TACE treatment among three groups.
Conclusion
DEB-TACE treatment was equally efficient and tolerated in liver cancer patients with different times of previous cTACE treatments.
Development of efficient and durable oxygen evolution reaction (OER) catalysts has a direct impact on the water splitting efficiency and cost effectiveness. In this work, we report the successful ...synthesis of a new Ni(OH)
2
structure, strain-stabilized Ni(OH)
2
nanoribbons (NR-Ni(OH)
2
) two to three layers thick, with widths of 2-5 nm,
via
an electro-oxidation route. Conventional Ni(OH)
2
usually has negligible OER activity, while NR-Ni(OH)
2
shows high activity for the oxygen evolution reaction and an overpotential of 162 millivolts and furthermore exhibits long-term stability in alkaline electrolyte. The substantial reduction in the overpotential of NR-Ni(OH)
2
is due to its easier OOH* adsorption by the active four-coordinated Ni edge sites. The enhanced catalytic activity of NR-Ni(OH)
2
makes it an excellent candidate for industrial applications.
Development of efficient and durable oxygen evolution reaction (OER) catalysts has a direct impact on the water splitting efficiency and cost effectiveness.
Many psychology studies are statistically underpowered. In part, this may be because many researchers rely on intuition, rules of thumb, and prior practice (along with practical considerations) to ...determine the number of subjects to test. In Study 1, we surveyed 291 published research psychologists and found large discrepancies between their reports of their preferred amount of power and the actual power of their studies (calculated from their reported typical cell size, typical effect size, and acceptable alpha). Furthermore, in Study 2, 89% of the 214 respondents overestimated the power of specific research designs with a small expected effect size, and 95% underestimated the sample size needed to obtain .80 power for detecting a small effect. Neither researchers' experience nor their knowledge predicted the bias in their self-reported power intuitions. Because many respondents reported that they based their sample sizes on rules of thumb or common practice in the field, we recommend that researchers conduct and report formal power analyses for their studies.
Background and purpose
We investigated the effect of celecoxib, a selective inhibitor of cyclo‐oxygenase 2, in patients with intracerebral hemorrhage (ICH).
Methods
We conducted a multicenter, ...randomized, controlled, and open with blinded end‐point trial of 44 Korean patients 18 years or older with ICH within 24 h of onset. The intervention group (n = 20) received celecoxib (400 mg twice a day) for 14 days. The control group (n = 24) received the standard medical treatment for ICH. The primary end‐point was the number of patients with a change in the volume of perihematomal edema (PHE) from the 1st to the 7th ± 1 day (cut‐off value, 20%).
Results
The time from onset to computed tomography scan slightly differed between groups (177 ± 160 min for control vs. 297 ± 305 min for the celecoxib group; P = 0.10). In the primary end‐point analysis using cut‐off values, there was a significant shift to reduced expansion of PHE in the celecoxib group (P = 0.005). With respect to the secondary end‐points, there was also a significant shift to reduced expansion of ICH in the celecoxib group (P = 0.046). In addition, the expansion rate of PHE at follow‐up tended to be higher in the control group than in the celecoxib group (90.6 ± 91.7% vs. 44.4 ± 64.9%; P = 0.058).
Conclusions
In our small, pilot trial, administration of celecoxib in the acute stage of ICH was associated with a smaller expansion of PHE than that observed in controls.
Soil acidification is a major problem in soils of intensive Chinese agricultural systems. We used two nationwide surveys, paired comparisons in numerous individual sites, and several long-term ...monitoring-field data sets to evaluate changes in soil acidity. Soil pH declined significantly (P < 0.001) from the 1980s to the 2000s in the major Chinese crop-production areas. Processes related to nitrogen cycling released 20 to 221 kilomoles of hydrogen ion (H⁺) per hectare per year, and base cations uptake contributed a further 15 to 20 kilomoles of H⁺ per hectare per year to soil acidification in four widespread cropping systems. In comparison, acid deposition (0.4 to 2.0 kilomoles of H⁺ per hectare per year) made a small contribution to the acidification of agricultural soils across China.
The cellular prion protein (PrP
) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that ...PrP
degradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock 70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrP
accumulation and tumorigenicity in vivo. PrP
was degraded via the proteasome pathway mediated by the ubiquitin-protein E3 ligase glycoprotein 78 (GP78), which interacts directly with PrP
. However, hypoxia-induced HSPA1L interacted with GP78 and inhibited its functions. HSPA1L knockdown facilitated the interaction of GP78 and PrP
, thereby increasing PrP
ubiquitination. Thus, GP78 was identified as the ubiquitinase for PrP
, thereby revealing an essential mechanism that controls PrP
levels in CRC. Our results suggest that the HSPA1L/HIF-1α/GP78 axis has a crucial role in PrP
accumulation during tumor progression.
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