A multidimensional analysis of genes mutated in breast and colorectal cancers

A recent study of a large number of genes in a panel of breast and colorectal cancers identified somatic mutations in 1149 genes. To identify potential biological processes affected by these genes, we examined their putative roles based on sequence similarity, membership in known functional groups and pathways, and predicted interactions with other proteins. These analyses identified functional groups and pathways that were enriched for mutated genes in both tumor types. Additionally, the results pointed to differences in molecular mechanisms that underlie breast and colorectal cancers, including various intracellular signaling and metabolic pathways. These studies provide a multidimensional framework to guide further research and help identify cellular processes critical for malignant progression and therapeutic intervention.     

Proteins combination on PHBV microsphere scaffold to regulate Hep3B cells activity and functionality: a model of liver tissue engineering system

The synergistic effects of extracellular matrix (ECM) protein combinations on Hep3B cell proliferation and functions are studied herein. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) microspheres were covalently conjugated with three types of proteins, collagen (type I), laminin, and fibronectin, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide cross linkers. Successful conjugations of protein molecules were verified by the presence of nitrogen peaks in X-ray photoelectron spectroscopy. The densities of grafted proteins were quantified using Micro-BCA kit. A human hepatoma cell line, Hep3B, was then cultured in vitro on the ECM proteins-modified microspheres for 2 weeks. Cell proliferation was estimated using MTT method, and two hepatic functions, albumin secretion and P-450 activity, were evaluated using ELISA and EROD assays, respectively. The results indicated that combination of the three ECM proteins on microsphere surfaces has a significant effect on the proliferation of Hep3B cells, thus better mimicking the in vivo environment for liver tissue engineering.     

Enantioselective acetylcholinesterase inhibition of the organophosphorous insecticides profenofos, fonofos, and crotoxyphos

A large number of organophosphorous insecticides (OPs) are chiral compounds, and yet enantioselectivity in their environmental fate and effects is rarely addressed. In the present study, we isolated individual enantiomers of three OPs, profenofos, fonofos, and crotoxyphos, and evaluated enantioselectivity in their inhibition of acetylcholinesterase (AChE). Acetylcholinesterase inhibition by the enantiomers and racemates was determined in vivo in the aquatic invertebrate Daphnia magna and in Japanese medaka (Oryzias latipes) as well as in vitro with electric eel (Electrophorus electricus) and human recombinant AChEs. The overall results showed variable sensitivity between AChE enzymes from different species as well as variable magnitude of enantioselectivity in enzyme inhibition. The (-)-enantiomer of profenofos was 4.3- to 8.5-fold more inhibitory to AChE in vivo, whereas (-)-fonofos was 2.3- to 29-fold more potent than the corresponding (+)-enantiomer. The (+)-enantiomer of crotoxyphos was 1.1- to 11-fold more inhibitory to AChE than the (-)-enantiomer. In contrast, the in vitro results showed (+)-profenofos to be 2.6- to 71.8-fold more inhibitory than the (-)-enantiomer and (-)-crotoxyphos to be 1.6- to 1.9-fold more active than the (+)-enantiomer. The reversed direction of enantioselectivity observed between the in vivo and in vitro assays suggests enantioselectivity within toxicodynamic processes such as uptake, biotransformation, or elimination. Findings from the present study provide evidence of enantioselectivity in the AChE inhibition of chiral OPs in nontarget organisms and indicate the need to consider enantiomers individually when assessing environmental risk of these chiral pesticides.     

IL-1β promotes the migration of olfactory epithelium neural stem cells through activating matrix metalloproteinase expressions

Background

To investigate the effects of IL-1β on the migration of olfactory epithelium neural stem cells (OENSCs), and to assess the mechanisms.

重症急性胰腺炎治疗护理进展

从非手术治疗（建立有效循环通道、抑制胰腺分泌、防治感染、营养支持、腹腔灌洗、血液灌洗和内镜介入治疗）、手术治疗方面对重症急性胰腺炎的治疗和护理进展进行了综述。     

对门诊血液透析患儿的家庭健康指导

目的 了解门诊血液透析患儿的家庭健康指导效果。方法 对患儿进行饮食指导(包括蛋白质、热量的摄入,保持水电解质平衡);血管通路的维护;皮肤护理;日常生活及心理指导。通过定期随访及采用自行设计的调查表调查门诊透析患儿及家属在进行健康指导前后对透析相关知识掌握程度。结果 健康指导前后患儿及家属对饮食、血管维护、皮肤护理、日常生活习惯等健康知识掌握程度经X~2检验,P均<0.01,有显著性差异。结论 通过健康指导,大大提高了患儿及家属在饮食、血管维护、皮肤护理、日常生活习惯方面的知识,患儿积极主动地配合治疗,为透析或肾移植提供了良好的生理及心理条件。     

肺癌患者癌因性疲乏与希望水平的相关性

目的了解肺癌患者癌因性疲乏(cancer-related fatigue,CRF)和希望水平状况,并探讨两者之间的相关性。方法便利抽样法选取长春市3所三级甲等医院住院的203例肺癌患者,采用一般情况调查表、Piper疲乏自我评估修订量表、Herth希望量表对其进行调查。结果肺癌患者CRF总体得分为(5.63±0.902)分,属于中度疲乏;其中,得分最高的是躯体感知疲乏维度,得分为(6.93±1.105)分,得分最低的是认知疲乏维度,得分为(4.05±1.127)分。肺癌患者希望总分为(36.22±2.641)分,总体处于中等以上水平,其中65%的患者希望得分位于高等水平。肺癌患者CRF总分与希望水平呈负相关,且CRF各个维度与希望水平呈负相关。结论肺癌患者CRF普遍存在,应重视患者的CRF现状。临床工作中,需科学全面评估患者的希望水平,制定合理的心理干预措施,提高患者的希望水平,进而缓解CRF症状。     

军人创伤后应激障碍与适应障碍的视觉和听觉诱发电位研究

目的 探讨军人创伤后应激障碍和适应障碍的视觉诱发电位和听觉诱发电位的特征。方法 对33例创伤后应激障碍患者和34例适应障碍患者及30名健康军人(对照组)，应用Nicolet Bravo型脑电生理仪及光、声刺激，完成视觉诱发电位和听觉诱发电位检测。结果 应激障碍组和适应障碍组Cz脑区视觉诱发电位／P2波幅较对照组为低，应激障碍组Pz脑区视觉诱发电位／P3波幅分别较对照组和适应障碍组为低；应激障碍组Oz脑区听觉诱发电位／P3潜伏期较对照组延迟，Cz脑区听觉诱发电位／P2波幅分别较对照组和适应障碍组为低，Cz脑区听觉诱发电位／P3波幅分别较对照组和适应障碍组为高。结论 应激障碍和适应障碍的诱发电位有一定的特征，值得进一步随访观察。     

Early Clinical Experience With AZD4831, A Novel Myeloperoxidase Inhibitor,Developed for Patients With Heart Failure With Preserved Ejection Fraction

We evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics of AZD4831, a novel oral myeloperoxidase (MPO) inhibitor, in a randomized, single‐blind, placebo‐controlled study, following once‐daily multiple ascending dosing to steady‐state in healthy subjects. Target engagement was measured as specific MPO activity in plasma following ex vivo zymosan stimulation of whole blood. Except for generalized maculopapular rash in 4 of 13 subjects receiving the 2 highest doses, 15 and 45 mg AZD4831, no clinically relevant safety and tolerability findings were observed. AZD4831 was rapidly absorbed and plasma concentrations declined slowly with an elimination half‐life of ~ 60 hours. A dose/concentration‐effect relationship between MPO inhibition vs. AZD4831 exposure was established with > 50% MPO inhibition in plasma at concentrations in the low nanomolar range. Steady‐state levels were achieved within 10 days. Taken together, the PK profile, the sustained dose/concentration‐dependent MPO inhibition, and available clinical data support further clinical development of AZD4831 in patients with heart failure with preserved ejection fraction.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Myeloperoxidase (MPO) is reported to play a role in atherogenesis in humans and MPO plasma levels predict outcome of cardiovascular disease. In patients with chronic heart failure (HF), elevated plasma MPO levels are associated with more advanced HF. Additionally, elevated plasma MPO levels within an HF subject seem to be predictive of increased adverse clinical outcomes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ This was the first once‐daily multiple ascending dosing study of the MPO inhibitor AZD4831 in healthy subjects to explore safety, tolerability, pharmacokinetics, and pharmacodynamics at steady‐state conditions.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ AZD4831 has a long half‐life consistent with once daily dosing. Except for incidence of generalized maculopapular rash at the highest doses, no clinically relevant safety and tolerability findings were observed

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Target engagement was established and a dose/concentration‐effect relationship between MPO inhibition vs. AZD4831 exposure was observed with half‐maximal inhibitory concentration values in the lower nanomolar range. The study showed that AZD4831 is a suitable drug candidate for further evaluation in patients with heart failure with preserved ejection fraction.

Cardiovascular disease (CVD) remains the major cause of death in the industrialized countries, despite significant advancement in clinical cardiology during the past 2 decades. Beyond optimal control of traditional risk factors, such as lipids, blood pressure, and glucose, targeting novel molecular pathways may further improve outcome in high‐risk patients with CVD by exerting direct beneficial effects on macrovascular and microvascular structure and function.Recently, the PROMIS study in heart failure with preserved ejection fraction (HFpEF) was reported and provided evidence that coronary microvascular dysfunction is highly prevalent in patients with HFpEF and that it correlates with several key features in this patient population, including disease severity, systemic endothelial dysfunction, as well as diastolic dysfunction. ¹ To date, no or limited pharmacological therapies are available for treatment of patients with HFpEF and a novel pharmacological intervention improving both macrovascular and microvascular status in these patients would be beneficial.Myeloperoxidase (MPO) is mainly present in granules of neutrophils, constituting 5% of the dry weight of the cells. In addition to neutrophils, there are also data suggesting the presence of MPO in monocytes and macrophages. MPO generates reactive chlorinating species, such as hypochlorous acid, the active component of bleach, which possesses potent bactericidal and viricidal activities and reacts with electron‐rich moieties of a large range of biomolecules. ² These actions mainly occur in the phagolysosome, but also in the extracellular compartment, as MPO can be released following neutrophil degranulation.Multiple lines of evidence suggest that MPO may play a role in atherogenesis in humans ² , ³ , ⁴ and MPO plasma levels predict outcome of CVD. ³ , ⁴ , ⁵ In chronic heart failure (HF), elevated plasma MPO levels are associated with more advanced disease. Additionally, elevated plasma MPO levels within an HF subject seem to be predictive of increased adverse clinical outcomes. ⁶ In addition, individuals with inherited low MPO activity are protected from leukocyte activation‐induced deterioration of vascular function. ⁷ Direct MPO administration in anaesthetized pigs increased the tone of conductance and resistance vessels and adversely affected myocardial blood flow, thereby strengthening the concept that MPO indeed acts as a modulator of vascular tone in vivo and identifying MPO as a systemic regulator of vasomotion in humans and thus a potential therapeutic target. Furthermore, the degree of MPO‐deficiency was correlated to improved vascular function, such that 50% difference in MPO activity was associated with a 5% absolute difference in flow mediated dilatation. ⁷ As published by Rudolph et al. in 2010, MPO is also involved in structural remodeling of the myocardium, leading to an increased vulnerability to atrial fibrillation. ⁸ Overall, recent evidence suggests that MPO may provide a mechanistic link among inflammation, oxidative stress, vascular dysfunction, and impaired cardiac remodeling. Thus, it is hypothesized that an MPO inhibitor (MPOi) will improve both macrovascular and microvascular status in patients with CVD.There is an offset between the MPOi concentration required to inhibit the MPO in the phagolysosome vs. that required to inhibit extracellular MPO activity. ⁹ From a biological perspective, we hypothesize that it is the extracellular MPO activity that causes the pathological microvascular dysfunction observed in CVD, whereas the intragranular MPO plays a physiological role in host defense.AZD4831 is a novel, potent, and selective MPOi with an in vitro half‐maximal inhibitory concentration of 0.7 nM for human MPO. The pharmacokinetics (PKs), safety, and tolerability, and the effect on uric acid, a down‐stream biomarker of MPO inhibition, following single ascending doses (SADs) in healthy volunteers has been reported. ¹⁰ The human plasma protein binding is 65%, and in vitro studies have indicated that CYP3A4/CYP3A5 is the predominant CYP isoform involved in the metabolism of AZD4831, although other elimination pathways are predicted to contribute to the overall elimination (i.e., non‐CYP450 mediated metabolism as well as renal clearance). ¹⁰ Here, we report the results from the first multiple ascending dose study with the objective to evaluate safety, tolerability, PKs, and pharmacodynamics of AZD4831 in healthy subjects. As an exploratory objective, plasma 4ß‐hydroxycholesterol levels were measured for assessment of potential CYP3A4/A5 induction.