不同剂量阿加曲班联合丁苯酞对急性脑梗死患者效果及预后的影响因素分析

摘要 目的：本研究旨在探讨不同剂量阿加曲班联合丁苯酞对急性脑梗死患者效果及预后的影响因素。方法：以自2019年6月到2022年8月在我院收治的90例急诊急性脑梗死为研究对象,采用随机数字表法将其分为高剂量组（给予高剂量阿加曲班联合丁苯酞治疗）和低剂量组（给予低剂量阿加曲班联合丁苯酞治疗）各45例。对比治疗7 d后两组临床疗效及预后,分析治疗前及治疗7 d后两组神经功能[中国卒中量表（CSS）评分、神经功能（NIHSS）评分],根据不同预后将患者分为预后良好组和预后不良组,采用单/多因素Logisitic回归分析急性脑梗死预后的影响因素。结果：（1）将两组的临床疗效纳入研究并实施组间差异性比较,结果显示,高剂量组总有效率高于低剂量组（P＜0.05）。（2）将两组的神经功能采用CSS评分、NIHSS评分评估纳入研究并实施组间差异性比较,结果显示治疗前,两组采用CSS评分、NIHSS评分比较（P＞0.05）;治疗7 d后,高剂量组采用CSS评分、NIHSS评分高于低剂量组（P＜0.05）。（3）将两组的预后采用mRS评分评估纳入研究并实施组间差异性比较,结果显示,高剂量组预后良好2.22%（1/45）高于低剂量组15.56%（7/45）（P＜0.05）。（4）预后良好组患者年龄、治疗前CSS评分及治疗前NIHSS评分与预后不良组存在差异（P＜0.05）。（5）以急性脑梗死预后为因变量,以单因素中对比有差异的指标为自变量,经多因素Logisitic回归分析急性脑梗死预后的影响因素为治疗前CSS评分及治疗前NIHSS 评分。结论：高剂量阿加曲班联合丁苯酞能够有效治疗急性脑梗死患者,而急性脑梗死预后的影响因素为治疗前CSS评分及治疗前NIHSS 评分。     

Disialogangliosides and Their Interaction with Cholera Toxin—Investigation by Molecular Modeling,Molecular Mechanics and Molecular Dynamics

Abstract

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface disialogangliosides (GD1A, GD1B and GD3) in aqueous environment. The molecular mechanics calculation reveals that water mediated hydrogen bonding network plays a significant role in the structural stabilization of GD1A, GD1B and GD3. These water mediated hydrogen bonds not only exist between neighboring residues but also exist between residues that are separated by 2 to 3 residues in between. The conformational energy difference between different conformational states of gangliosides correlates very well with the number of water mediated and direct hydrogen bonds. The spatial flexibility of NeuNAc of gangliosides at the binding site of cholera toxin is worked out. The NeuNAc has a limited allowed eulerian space at the binding site of Cholera Toxin (2.4%). The molecular modeling, molecular mechanics and molecular dynamics of disialo- ganglioside-cholera toxin complex reveal that cholera toxin can accommodate the disialo- ganglioside GD1A in three different modes. A single mode of binding is permissible for GD1B and GD3. Direct and water mediated hydrogen bonding interactions stabilizes these binding modes and play an essential role in defining the order of specificity for different disialogangliosides towards cholera toxin. This study not only provides models for the disialoganglioside-cholera toxin complexes but also identifies the NeuNAc binding site as a site for design of inhibitors that can restrict the pathogenic activity of cholera toxin.     

Discovery of ORN0829, a potent dual orexin 1/2 receptor antagonist for the treatment of insomnia

Here, we present the design, synthesis, and SAR of dual orexin 1 and 2 receptor antagonists, which were optimized by balancing the antagonistic activity for orexin receptors and lipophilicity. Based on the prototype compound 1, ring construction and the insertion of an additional heteroatom into the resulting ring led to the discovery of orexin 1 and 2 receptor antagonists, which were 3-benzoyl-1,3-oxazinane derivatives. Within these derivatives, (−)-3h enabled a high dual orexin receptor antagonistic activity and a low lipophilicity. Compound (−)-3h exhibited potent sleep-promoting effects at a po dose of 1 mg/kg in a rat polysomnogram study, and optimal PK properties with a rapid T_max and short half-lives in rats and dogs were observed, indicating a predicted human half-life of 0.9–2.0 h. Thus, (−)-3h (ORN0829; investigation code name, TS-142) was selected as a viable candidate and is currently in clinical development for the treatment of insomnia.     

Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) Is Upregulated in Breast Epithelial–Mesenchymal Transition and Responds to Oxidative Stress

Breast cancer cells that have undergone partial epithelial–mesenchymal transition (EMT) are believed to be more invasive than cells that have completed EMT. To study metabolic reprogramming in different mesenchymal states, we analyzed protein expression following EMT in the breast epithelial cell model D492 with single-shot LFQ supported by a SILAC proteomics approach. The D492 EMT cell model contains three cell lines: the epithelial D492 cells, the mesenchymal D492M cells, and a partial mesenchymal, tumorigenic variant of D492 that overexpresses the oncogene HER2. The analysis classified the D492 and D492M cells as basal-like and D492HER2 as claudin-low. Comparative analysis of D492 and D492M to tumorigenic D492HER2 differentiated metabolic markers of migration from those of invasion. Glutamine-fructose-6-phosphate transaminase 2 (GFPT2) was one of the top dysregulated enzymes in D492HER2. Gene expression analysis of the cancer genome atlas showed that GFPT2 expression was a characteristic of claudin-low breast cancer. siRNA-mediated knockdown of GFPT2 influenced the EMT marker vimentin and both cell growth and invasion in vitro and was accompanied by lowered metabolic flux through the hexosamine biosynthesis pathway (HBP). Knockdown of GFPT2 decreased cystathionine and sulfide:quinone oxidoreductase (SQOR) in the transsulfuration pathway that regulates H₂S production and mitochondrial homeostasis. Moreover, GFPT2 was within the regulation network of insulin and EGF, and its expression was regulated by reduced glutathione (GSH) and suppressed by the oxidative stress regulator GSK3-β. Our results demonstrate that GFPT2 controls growth and invasion in the D492 EMT model, is a marker for oxidative stress, and associated with poor prognosis in claudin-low breast cancer.     

Fetal dose measurements and shielding efficiency assessment in a custom setup of 192Ir brachytherapy for a pregnant woman with breast cancer

PurposeTo assess the radiation dose to the fetus of a pregnant patient undergoing high-dose-rate (HDR) ¹⁹²Ir interstitial breast brachytherapy, and to design a new patient setup and lead shielding technique that minimizes the fetal dose.MethodsRadiochromic films were placed between the slices of an anthropomorphic phantom modeling the patient. The pregnant woman was seated in a chair with the breast over a table and inside a leaded box. Dose variation as a function of distance from the implant volume as well as dose homogeneity within a representative slice of the fetal position was evaluated without and with shielding.ResultsWith shielding, the peripheral dose after a complete treatment ranged from 50 cGy at 5 cm from the caudal edge of the breast to <0.1 cGy at 30 cm. The shielding reduces absorbed dose by a factor of two near the breast and more than an order of magnitude beyond 20 cm. The dose is heterogeneous within a given axial plane, with variations from the central region within 50%. Interstitial HDR ¹⁹²Ir brachytherapy with breast shielding can be more advantageous than external-beam radiotherapy (EBRT) from a radiation protection point of view, as long as the distance to the uterine fundus is higher than about 10 cm. Furthermore, the weight of the shielding here proposed is notably lower than that needed in EBRT.ConclusionsShielded breast brachytherapy may benefit pregnant patients needing localized radiotherapy, especially during the early gestational ages when the fetus is more sensitive to ionizing radiation.     

Probabilistic Analysis of Human Health Risks Associated with Background Concentrations of Inorganic Arsenic: Use of a Margin of Exposure Approach

Substantial evidence exists from epidemiological and mechanistic studies supporting a sublinear or threshold dose–response relationship for the carcinogenicity of ingested arsenic; nonetheless, current regulatory agency evaluations have quantified arsenic risks using default, generic risk assessment procedures that assume a linear, no-threshold dose–response relationship. The resulting slope factors predict risks from U.S. background arsenic exposures that exceed certain regulatory levels of concern, an outcome that presents challenges for risk communication and risk management decisions. To better reflect the available scientific evidence, this article presents the results of a Margin of Exposure (MOE) analysis to characterize risks associated with typical and high-end background exposures of the U.S. population to arsenic from food, water, and soil. MOE values were calculated by comparing a no-observable-adverse-effect-level (NOAEL) derived from the epidemiological literature with exposure estimates generated using a probabilistic (Monte Carlo) model. The plausibility and conservative nature of the exposure and risk estimates evaluated in this analysis are supported by sensitivity and uncertainty analyses and by comparing predicted urinary arsenic concentrations with empirical data. Using the more scientifically supported MOE approach, the analysis presented in this article indicates that typical and high-end background exposures to inorganic arsenic in U.S. populations do not present elevated risks of carcinogenicity.     

Application of Uncertainty Factors in the Priority Substances Program and International Harmonization

The Canadian Environmental Protection Act (CEPA) authorizes the Ministers of the Environment and of Health in Canada to investigate a wide variety of substances that may contaminate the environment and cause adverse effects on the environment and/or on human health. Under the Act, assessments have been completed for 44 environmental contaminants on the first Priority Substances List (PSL) and are relatively advanced for 25 compounds on the second PSL. The principles developed for the application of uncertainty factors in assessment of risks to human health for Priority Substances under CEPA are outlined, with emphasis on those aspects which are somewhat unique and/or evolving. The interface of developments in the Priority Substances program with an initiative of the International Programme on Chemical Safety in this area to effect greater harmonization of approaches is also described.     

Integral dose based inverse optimization objective function promises lower toxicity in head-and-neck

PurposeThe voxels in a CT data sets contain density information. Besides its use in dose calculation density has no other application in modern radiotherapy treatment planning. This work introduces the use of density information by integral dose minimization in radiotherapy treatment planning for head-and-neck squamous cell carcinoma (HNSCC).Materials and methodsEighteen HNSCC cases were studied. For each case two intensity modulated radiotherapy (IMRT) plans were created: one based on dose-volume (DV) optimization, and one based on integral dose minimization (Energy hereafter) inverse optimization. The target objective functions in both optimization schemes were specified in terms of minimum, maximum, and uniform doses, while the organs at risk (OAR) objectives were specified in terms of DV- and Energy-objectives respectively. Commonly used dosimetric measures were applied to assess the performance of Energy-based optimization. In addition, generalized equivalent uniform doses (gEUDs) were evaluated. Statistical analyses were performed to estimate the performance of this novel inverse optimization paradigm.ResultsEnergy-based inverse optimization resulted in lower OAR doses for equivalent target doses and isodose coverage. The statistical tests showed dose reduction to the OARs with Energy-based optimization ranging from ∼2% to ∼15%.ConclusionsIntegral dose minimization based inverse optimization for HNSCC promises lower doses to nearby OARs. For comparable therapeutic effect the incorporation of density information into the optimization cost function allows reduction in the normal tissue doses and possibly in the risk and the severity of treatment related toxicities.