L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition

Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.     

冬凌草甲素聚乙二醇功能化氧化石墨烯纳米粒的制备及抗结肠癌实验研究

目的制备负载冬凌草甲素(oridonin,ORI)的聚乙二醇功能化氧化石墨烯(PEGylated graphene oxide,GO-PEG)纳米粒(nanoparticles,NPs),并探讨其对结肠癌的抑制作用。方法利用酰胺化反应将端基为氨基的四臂聚乙二醇(PEG)连到氧化石墨烯(GO)上,并通过红外光谱(IR)和差示-热重联用热分析仪(TGA)等对其进行表征;再通过物理共混的方法在GO-PEG上负载抗肿瘤药物ORI,紫外光谱(UV)法测其包封率和载药率,MTT法测定载药体系对人结肠癌细胞SW620和HT29的增殖毒性,并建立荷瘤裸鼠模型考察其体内抗肿瘤活性。结果 IR和TGA测定结果表明PEG已成功偶联到GO上,UV法测得ORI-GO-PEG的包封率和载药率分别为95.81%和48.92%,且在各种生理溶液中具有良好的稳定性。体外细胞毒性实验结果表明,与ORI裸药相比,ORI-GO-PEG-NPs对结肠癌细胞的杀伤能力更强。体内抑瘤实验进一步发现,ORI-GO-PEG-NPs可以更好地抑制体内SW620肿瘤的生长。结论制得的ORI-GO-PEG-NPs具有优良的载药性能和较强的抗结肠癌作用,为今后开发抗肿瘤药物纳米给药系统提供了实验依据。     

Timely follow‐up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium

Timely follow‐up for positive cancer screening results remains suboptimal, and the evidence base to inform decisions on optimizing the timeliness of diagnostic testing is unclear. This systematic review evaluated published studies regarding time to follow‐up after a positive screening for breast, cervical, colorectal, and lung cancers. The quality of available evidence was very low or low across cancers, with potential attenuated or reversed associations from confounding by indication in most studies. Overall, evidence suggested that the risk for poorer cancer outcomes rises with longer wait times that vary within and across cancer types, which supports performing diagnostic testing as soon as feasible after the positive result, but evidence for specific time targets is limited. Within these limitations, we provide our opinion on cancer‐specific recommendations for times to follow‐up and how existing guidelines relate to the current evidence. Thresholds set should consider patient worry, potential for loss to follow‐up with prolonged wait times, and available resources. Research is needed to better guide the timeliness of diagnostic follow‐up, including considerations for patient preferences and existing barriers, while addressing methodological weaknesses. Research is also needed to identify effective interventions for reducing wait times for diagnostic testing, particularly in underserved or low‐resource settings. CA Cancer J Clin 2018;68:199–216 . © 2018 American Cancer Society .     

影响胰腺癌早期诊断的临床因素319例分析

[目的]探讨胰腺癌早期诊断的影响因素。[方法]回顾总结319例胰腺癌病人的临赓堑征，尤基梦首发症状和首沃就诊症状。[结果]首发症状以腹痛、上腹不适、厌食、黄疸多见，出现病，例多分别为．157型、76例、67例、46例。首次就诊时，多数病人症状增多、加重，尤其是出现厌食、黄疸、腰背疼痛、乏力、消瘦等症状的病例明显增加。73例病人首次就诊没有进行必要的辅助检查，102例病人有误诊史。[结论]对于出婴腹痛、上腹不适、厌食、黄疸等症状的病例，要考虑到胰腺癌的可能，及时进行有效的辅助检查，是发现早期胰腺癌、改善病人预后的重要措施。     

扶桑花抗生育成分对早孕小鼠黄体影响的定量研究

本文处用图像分析仪 ,以核浆比和数密度为指标 ,研究了不同浓度的扶桑花提取物—HR 1对早孕小鼠黄本组织学的影响。结果表明 :(1)小鼠黄体细胞的核浆比和数密度 ,随给药剂量 (0、 4、 10、 10 0、10 0 0mg/kg/d)的增加而增加 ,其中 10 0和 10 0 0mg/kg/d两组的黄体细胞核浆比和数密度明显高于对照组(p <0 .0 5) ;(2 )黄体组织学的定性观察显示 ,给药各组的黄体细胞明显退化 ,细胞缩小 ,细胞界限不清。这些结果提示 ,扶桑花提取物的抗早孕作用与妊娠黄体受损有关。     

婴儿晚发性Vit K缺乏症的早期诊治及预防

目的：介绍婴儿晚发性vitK缺乏症早期诊治及预防的重要性。方法：选择186例婴儿晚发性vitK缺乏症患者,分析该病病因,临床特征,死亡率与就诊时间的关系。结果：24h之内就诊者24人,全部痊愈,－48h就诊者78例,死亡2例（占2．56％）,－72h就诊者36例,死亡12例（占33．33％）,超过72h就诊者48例,死亡23例（占58．3％）。结论：该病早期诊治能降低死亡率,而该病是可以预防的,提出对所有新生儿常规补充vitK以预防本病的发生。     

Expression of periostin according to endometrial cancer grade

While various molecular profiling methods have been described for the early diagnosis and prognostic process of endometrial cancer, the most common gynaecological cancer, the data obtained remain insufficient. The present study aimed to investigate the protein and gene expression of periostin and its role as a new biomarker in the diagnosis, treatment and prognosis of endometrial cancer. A total of 15 patients diagnosed with endometrial cancer at the Department of Pathology, Zeynep Kamil Training and Research Hospital (Istanbul, Turkey) and 15 patients who were operated on for non-tumour-related reasons, between December 2019 and May 2020, were included in the study. The cases diagnosed with endometrial cancer were divided into three groups: International Federation of Gynaecology and Obstetrics grades I, II and III. Pathology tumour blocks were selected for enzyme-linked immunosorbent assay and PCR studies in which periostin gene expression and protein levels were measured, respectively. A significant increase in periostin gene expression was observed in the endometrial cancer samples compared with that in the controls (3.40±0.66 vs. 2.23±0.47). The protein level of periostin in the tissues was found to be higher in the endometrial cancer samples than that in the control group (1.59±0.31 vs. 0.94±0.22). The levels of periostin protein and gene expression detected in the endometrial cancer samples increased as the grade increased. To the best of our knowledge, the current study is the first to determine the levels of periostin protein and gene expression in endometrial cancer. The results suggested that periostin may be used as a biomarker in the determination of higher histological grade in endometrial cancer.     

Initial Abdominal CT and Laboratory Findings Prior to Diagnosis of Crohn’s Disease in Children

PurposeTo identify initial abdominal computed tomography (CT) and laboratory findings prior to a diagnosis of Crohn’s disease (CD) in children.Materials and MethodsIn this retrospective study, patients (≤18 year-old) who were diagnosed with CD from 2004 to 2019 and had abdominal CT just prior to being diagnosed with CD were included in the CD group. Patients (≤18 years old) who were diagnosed with infectious enterocolitis from 2018 to 2019 and had undergone CT prior to being diagnosed with enterocolitis were included as a control group. We assessed the diagnostic performances of initial CT and laboratory findings for the diagnosis of CD using logistic regression and the area under the curve (AUC).ResultsIn total, 107 patients (50 CD patients, 57 control patients) were included, without an age difference between groups (median 13 years old vs. 11 years old, p=0.119). On univariate logistic regression analysis, multisegmental bowel involvement, mesenteric vessel engorgement, higher portal vein/aorta diameter ratio, longer liver longitudinal diameter, lower hemoglobin (≤12.5 g/dL), lower albumin (≤4 g/dL), and higher platelet (>320×10³/µL) levels were significant factors for CD. On multivariate analysis, multisegmental bowel involvement [odds ratio (OR) 111.6, 95% confidence interval (CI) 4.778–2605.925] and lower albumin levels (OR 0.9, 95% CI 0.891–0.993) were significant factors. When these two features were combined, the AUC value was 0.985 with a sensitivity of 96% and specificity of 100% for differentiating CD.ConclusionMultisegmental bowel involvement on CT and decreased albumin levels can help differentiate CD from infectious enterocolitis in children prior to a definite diagnosis of CD.