表皮生长因子受体及其抑制剂的研究

表皮生长受体因子属于受体酪氨酸激酶家族成员,其过度表达和/或基因突变与多种肿瘤的形成具有密切的联系。近年来,小分子表皮生长因子受体酪氨酸激酶抑制剂的开发已成为肿瘤治疗领域中的研究热点。这里就表皮生长因子受体及其小分子抑制剂进行简要综述。     

表皮生长因子受体酪氨酸激酶家族与肿瘤治疗

表皮生长因子受体(EGFR,ErbB)酪氨酸激酶家族在多种肿瘤中有表达或高表达.在特异性配体的诱导下能够发生家族成员的二聚化,从而激活细胞内下游信号转导途径,调控细胞的增殖、分化、迁移等生物效应.异常的ErbB受体信号与肿瘤的发生、发展有着密切的关系.随着EGFR的人源化单抗Erbitux和针对EGFR的小分子抑制剂Tarceva的成功上市,以ErbB受体为靶点的抗肿瘤药物成为了近年来肿瘤治疗研究中的热点领域.     

巨噬细胞集落刺激因子受体激酶及其抑制剂的研究进展

巨噬细胞集落刺激因子受体（c-Fms）是原癌基因c-fms的编码产物,属于Ⅲ型受体酪氨酸激酶家族成员。巨噬细胞集落刺激因子与c-Fms结合,激活其酪氨酸激酶,在单核巨噬细胞系的存活、增殖、分化以及胚胎发育过程中发挥着重要的作用。c-Fms及其配体的过度表达,引起该受体介导的细胞信号通路异常激活,参与了肿瘤形成和炎症发生过程。因此,靶向c-Fms激酶的抑制剂能抑制受体的磷酸化,阻断受体介导的细胞信号通路,是治疗肿瘤、关节炎等疾病的潜在药物。     

人源化抗HER2单克隆抗体Pertuzumab

人表皮生长因子受体2（HER2）为受体酪氨酸激酶家族成员,是多种肿瘤细胞的重要生长调节因子,其过度表达对肿瘤的发生和恶性转化有促进作用,而HER2单体无活性,必须经配体结合后与自身或HER家族其他成员形成二聚体才能被激活。因此,HER2已成为肿瘤治疗研究中的一个潜在有效的靶标。目前临床上开发使用的HER2特异性靶向药物主要有两类,即人源化抗体和小分子酪氨酸激酶抑制剂。     

肿瘤分子靶向治疗的研究进展

近年来，随着分子生物学技术的提高和对肿瘤发病机制从细胞、分子水平的进一步认识，分子靶向治疗已成为肿瘤医学的发展方向。其中以受体酪氨酸激酶为治疗靶点的分子靶向治疗受到国内外肿瘤界的普遍关注。它的ErbB受体家族通过基因扩增、过度表达和突变导致信号传导的增加与很多肿瘤及其不良预后呈正相关。     

蛋白酪氨酸激酶信号转导途径与抗肿瘤药物

细胞信号转导(signal transduction)在细胞的代谢、分裂、分化、生物功能及死亡过程中起着重要作用，肿瘤的发生和发展与细胞信号转导过度激活有关。本文简要阐述了蛋白酪氨酸激酶(protein tyrosine kinases，PTKs)介导的信号转导途径，分别介绍了受体酪氨酸激酶介导的Ras/Raf/MAPK和PI-3K/Akt途径，非受体酪氨酸激酶介导的Src、Bcr-Abl和JAK/STAT途径。以此5条信号转导通路中参与的重要蛋白分子为靶点，统计和介绍了相关的已经上市或处于临床研究的抗肿瘤药物。     

前列腺腺癌中EGF,EGFR,PCNA的表达及其相关性研究

目的：探讨前列腺腺癌中ＥＧＦ、ＥＧＦＲ、ＰＣＮＡ的表达及其相关性。方法：采用Ｓ－Ｐ免疫组织化学方法,检测６２例前列腺腺癌中表皮生长因子（ＥＧＦ）及其受体（ＥＧＦＲ）、增殖细胞核抗原（ＰＣＮＡ）的表达情况。结果：６２例前列腺腺中,ＰＧＦ阳性３９例,ＥＧＦＲ阳性４５例,细胞增殖活跃２１例。不同组织级和细胞级的前列腺腺癌中ＥＧＦ、ＥＧＦＲ、ＰＣＮＡ的表达未见明显差异（Ｐ〉０．０５）．ＥＧＦ阳性表达的前列     

联合抗肿瘤策略：抑制表皮生长因子受体和血管生成

肿瘤的发生和发展与酪氨酸激酶（TK）受体的过表达有关，如表皮生长因子受体（EGFR，ErbB家族）在很多实体瘤中均高表达。体外实验表明，抗EGFR治疗能使肿瘤细胞增殖减弱，抑制细胞生长，但不能使其减少和凋亡；而在体内模型中，抗EGFR治疗导致肿瘤变小，暗示EGFR信号转导影响肿瘤细胞的生物学效应，以及肿瘤一宿主相互作用，如血管生成。     

EGFR酪氨酸激酶及其抑制剂的研究进展

表皮生长因子受体(EGFR)酪氨酸激酶是细胞外信号传递到细胞内的重要枢纽,它在信号传导、细胞增殖、分化以及各种调节机制中发挥重要作用,并在多种癌细胞中过度表达。许多研究表明,抑制EGFR酪氨酸激酶活性,可抑制肿瘤生长。本文对EGFR酪氨酸激酶及其几种小分子抑制剂在肿瘤治疗中的研究进展作一综述。     

表皮生长因子受体家族单克隆抗体耐药机制的研究进展

表皮生长因子受体（EGFR）家族广泛存在于体内各种细胞中,其异常活化与多种人类上皮组织肿瘤的发生、发展密切相关,因此已成为肿瘤治疗的重要靶点之一。目前靶向EGFR家族的药物包括小分子酪氨酸激酶抑制剂和单克隆抗体（简称单抗）类药物,特别是单抗类药物近年来在临床上获得了广泛的应用。但是,越来越多的临床资料表明,大量患者对这类药物表现出原发性耐药或获得性耐药。目前靶向EGFR家族单抗类药物产生耐药的原因主要包括：受体结构改变、血管生成、多种受体酪氨酸激酶的活化、EGFR的亚细胞定位、EGFR下游效应分子的持续激活和EGFR家族生长因子表达的上调等。本文就靶向EGFR家族单抗类药物耐药机制的研究进展进行综述。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.