Fluid replacement following dehydration reduces oxidative stress during recovery

To investigate the effects of hydration status on oxidative DNA damage and exercise performance, 10 subjects ran on a treadmill until exhaustion at 80% VO_2max during four different trials [control (C), 3% dehydration (D), 3% dehydration + water (W) or 3% dehydration + sports drink (S)]. Dehydration significantly decreased exercise time to exhaustion (D < C and S). Plasma MDA levels were significantly higher at pre-exercise in D than C. Plasma TAS was significantly lower at pre-exercise in C and S than in D, and was significantly lower in S than D at 60 min of recovery. Dehydration significantly increased oxidative DNA damage during exercise, but fluid replacement with water or sports drink alleviated it equally. These results suggest that (1) dehydration impairs exercise performance and increases DNA damage during exercise to exhaustion; and (2) fluid replacement prolongs exercise endurance and attenuates DNA damage.     

Interaction of soluble pig heart glutamate-aspartate transaminase with various beta,gamma-unsaturated amino acids

beta-Ethylidene-DL-aspartate (beta EA) and beta-methylene-DL-glutamate (beta MG) were synthesized and tested as potential suicide inhibitors of soluble pig heart glutamate-aspartate transaminase (sGAT). beta MG was found to be a) a substrate with a very low turnover number relative to glutamate and b) a competitive inhibitor with respect to aspartate (albeit with a large binding constant). At high concentrations beta MG inactivated the enzyme but only very slowly. beta EA was also found to be a substrate with a very low turnover number; it did not inactivate the enzyme (1 hr, 25 degrees C) even at a high concentration. However, beta EA was found to bind to the enzyme with an affinity comparable to that of aspartate and glutamate. beta-Methylene-DL-aspartate (beta MA) has been shown to rapidly inactivate glutamate-aspartate transaminase. Therefore, it appears that glutamate-aspartate transaminase can bind analogues of aspartate with alkene groups in the beta position. The conjugated carbonyl groups of beta MA and beta EA will enhance Michael addition in comparison with that expected for vinylglycine. On the other hand, the presence of the methyl groups should reduce the electrophilicity of the double bond of beta EA compared to beta MA. This deactivation and/or steric hindrance to Michael attack may account for the inability of beta EA to inactivate sGAT. Therefore, it may be possible to design selective suicide inhibitors of glutamate-aspartate++ transaminase with the following structure: HO2CC(= CHX)CH(CO2H)NH2, where X is an electron-withdrawing group. Ideally, X would increase the reactivity of the double bond while affording a minimum of steric hindrance to susceptible enzyme-bound bases.     

Cox model with interval‐censored covariate in cohort studies

In cohort studies the outcome is often time to a particular event, and subjects are followed at regular intervals. Periodic visits may also monitor a secondary irreversible event influencing the event of primary interest, and a significant proportion of subjects develop the secondary event over the period of follow‐up. The status of the secondary event serves as a time‐varying covariate, but is recorded only at the times of the scheduled visits, generating incomplete time‐varying covariates. While information on a typical time‐varying covariate is missing for entire follow‐up period except the visiting times, the status of the secondary event are unavailable only between visits where the status has changed, thus interval‐censored. One may view interval‐censored covariate of the secondary event status as missing time‐varying covariates, yet missingness is partial since partial information is provided throughout the follow‐up period. Current practice of using the latest observed status produces biased estimators, and the existing missing covariate techniques cannot accommodate the special feature of missingness due to interval censoring. To handle interval‐censored covariates in the Cox proportional hazards model, we propose an available‐data estimator, a doubly robust‐type estimator as well as the maximum likelihood estimator via EM algorithm and present their asymptotic properties. We also present practical approaches that are valid. We demonstrate the proposed methods using our motivating example from the Northern Manhattan Study.     

Polo-like kinase 1 (Plk1) is expressed by cutaneous T-cell lymphomas (CTCLs), and its downregulation promotes cell cycle arrest and apoptosis

Polo-like kinases are serine/threonine kinases crucial for mitosis and DNA integrity. Plk1, the most well studied member of this family, is upregulated in several cancers, as well as in dividing cells with peak expression during G2/M phase. Recently, employing lesional skin from patients with cutaneous T-cell lymphoma (CTCL), we showed that Plk1 was increased mainly in advanced lesions. In this study, employing western blot and quantitative RT-PCR analyses, we demonstrated that Plk1 was overexpressed in multiple CTCL cell lines (HH, Hut78, MyLa, SeAx and SZ4). Further, a genetic knockdown (by short hairpin RNA) or enzyme activity inhibition (via a small molecule inhibitor, GW843682X) was found to result in a decrease in cell growth, viability and proliferation. Plk1 inhibition in CTCL cells also resulted in: (1) increased G2/M phase cell cycle arrest, (2) alteration in key mitotic proteins, (3) apoptosis and (4) multiple mitotic errors. Given our findings, clinical trials of Plk1 inhibitors in CTCL may be a promising area for further translational investigation. We speculate that overexpression of Plk1 may prove to be relevant to the progression and prognosis of CTCL through its direct impact on the regulation of tumor cell proliferation and indirect influence on the acquisition of somatic mutations by proliferating tumor cells.     

Optimal Interfacial Engineering with Different Length of Alkylammonium Halide for Efficient and Stable Perovskite Solar Cells

Recently, two‐dimensional (2D) structure on three‐dimensional (3D) perovskites (graded 2D/3D) has been reported to be effective in significantly improving both efficiency and stability. However, the electrical properties of the 2D structure as a passivation layer on the 3D perovskite thin film and resistance to the penetration of moisture may vary depending on the length of the alkyl chain. In addition, the surface defects of the 2D itself on the 3D layer may also be affected by the correlation between the 2D structure and the hole conductive material. Therefore, systematic interfacial study with the alkyl chain length of long‐chained alkylammonium iodide forming a 2D structure is necessary. Herein, the 2D interfacial layers formed are compared with butylammonium iodide (BAI), octylammonium iodide (OAI), and dodecylammonium iodide (DAI) iodide on a 3D (FAPbI₃)_0.95(MAPbBr₃)_0.05 perovskite thin film in terms of the PCE and humidity stability. As the length of the alkyl chain increased from BA to OA to DA, the electron‐blocking ability and humidity resistance increase significantly, but the difference between OA and DA is not large. The PSC post‐treated with OAI has slightly higher PCE than those treated with BAI and DAI, achieving a certified stabilized efficiency of 22.9%.     

Different Survival of Barcelona Clinic Liver Cancer Stage C Hepatocellular Carcinoma Patients by the Extent of Portal Vein Invasion and the Type of Extrahepatic Spread

Portal vein invasion (PVI) and extrahepatic spread (ES) are two tumor-related factors that define advanced stage in the Barcelona Clinic Liver Cancer (BCLC) staging system (BCLC stage C), and the recommended first line therapy in this stage is sorafenib. However, the extent of PVI and the type of ES may affect patient prognosis as well as treatment outcome. This study analyzed survival of BCLC stage C HCC patients in order to see whether sub-classification of BCLC stage C is necessary. A total of 582 treatment naïve, BCLC stage C HCC patients [age: 54.3 ± 10.8 years, males = 494 (84.9%), hepatitis B virus (458, 78.7%)], defined by PVI and/or ES, were analyzed. Extent of PVI was divided into none, type I-segmental/sectoral branches, type II-left and/or right portal vein, and type III-main portal vein trunk. Type of ES was divided into nodal and distant metastasis. The extent of PVI and type of ES were independent factors for survival. When patients were sub-classified according to the extent of PVI and type of ES, the median survival was significantly different [11.7 months, 5.7 months, 4.9 months and 2.3 months for C1 (PVI-O/I without distant ES), C2 (PVI-II/III without distant ES), C3 (PVI-0/I with distant ES), and C4 (PVI-II/III with distant ES), respectively, P = 0.01]. Patients’ survival was different according to the treatment modality in each sub-stage. Sub-classification of BCLC stage C according to the extent of PVI and type of ES resulted in a better prediction of survival. Also, different outcome was observed by treatment modalities in each sub-stage. Sub-classification of BCLC stage C is required to minimize heterogeneity within the same tumor stage, that will help better predict survival and to select optimal treatment strategies.     

Neuronox versus BOTOX in the Treatment of Post-Stroke Upper Limb Spasticity: A Multicenter Randomized Controlled Trial

Background

Botulinum toxin type A is widely used for treating spasticity. Neuronox (Neu-BoNT/A), a newly manufactured botulinum toxin a, has not yet been investigated for its efficacy and safety in the treatment of post-stroke upper limb spasticity.

Objective

We evaluated the efficacy and safety of Neuronox (Neu-BoNT/A) compared with BOTOX (onabotulinum toxin A) for treating post-stroke upper limb spasticity.

Methods

In total, 196 stroke patients with moderate to severe upper limb spasticity were randomly assigned to either Neuronox or BOTOX intervention. The wrist flexors were mandatory and elbow, finger, and thumb flexors were optional muscles to be injected. Assessments were performed at baseline and 4, 8, and 12 weeks after the intervention. The primary outcome measure was the change from baseline of the Modified Ashworth Scale (MAS) at the wrist flexors at week 4. Secondary outcome measures included the change of MAS at each visit, response rate, Disability Assessment Scale (DAS), Carer Burden Scale, and Global Assessment of treatment benefit.

Results

Primary outcome measures were -1.39±0.79 and -1.56±0.81 in the Neuronox and BOTOX groups, respectively. The difference was within the noninferiority margin of 0.45 (95% upper limit=0.40). There were no significant differences between the groups in the secondary outcome and safety measures, except the change of the MAS at the elbow flexors at week 12 (-0.88±0.75 in the Neuronox group, -0.65±0.74 in the BOTOX group; P=0.0429). Both groups showed significant improvements in the MAS, DAS, and Carer Burden Scale at weeks 4, 8, and 12.

Conclusion

Neuronox showed equivalent efficacy and safety compared with BOTOX for treating post-stroke upper limb spasticity.

Trial Registration

ClinicalTrials.gov NCT01313767