使用免疫学替代终点加速人乳头瘤病毒疫苗研发的监管考量

基于人乳头瘤病毒(HPV)疫苗临床试验终点的观察和评价的实际困难和疫苗短缺现状,讨论以免疫学替代终点评估HPV疫苗临床试验效力水平的适用场景和应对挑战,通过回顾分析免疫学指标水平与疫苗保护效力间的关系证据,探讨基于免疫学数据加速批准HPV疫苗的监管考量要点,提高HPV疫苗可及性,早日实现消除宫颈癌的目标。     

首种针对妇女的癌症疫苗通过审批

特别注意Gardasil并不能对疫苗中没有包含的不常见的HPV类型提供免疫,因此该疫苗并不能对所有的宫颈癌或者生殖器疣免疫。PAP筛检仍然很重要;接种疫苗并不能替代常规的宫颈癌筛检。该疫苗在还未被HPV感染的女性中最有效。Gardasil并不是为了治疗活性生殖器疣、宫颈癌、CIN、VIN或者VaIN。该疫苗应该在6个月内注射3次。第2次和第3次应该分别在首次注射后的2个月和6个月后注射。在Merck公司的疫苗Gardasil获得FDA批准之后,现在妇女就有对宫颈癌免疫的选择权了。每年大约有620万的美国人感染人乳头瘤病毒(HPV),而且有超过50%的性生…     

预防性人乳头瘤病毒疫苗

人乳头瘤病毒(human papillomavirus,HPV)感染是引起宫颈癌的主要原因,而宫颈癌是妇女的第二常见癌症死因.本文对预防性HPV亚单位疫苗进行了综述,这种疫苗基于HPV核壳蛋白L1能形成病毒样颗粒(VLP),诱生高水平中和抗体.在实验室完成临床前研究后,Merck公司和GlaxoSmithKline公司正着手研发商品疫苗.两种疫苗均以HPV16和HPV18为目标,大约70%宫颈癌由这两个型别引起.Merck公司疫苗还以HPV6和HPV11为目标,大约90%外生殖器疣由这两个型别引起.疫苗有着极高的安全性和极强的免疫原性,能使免疫妇女产生针对持续感染和有关病变的完全的型特异性保护应答.尚待解决的问题包括对高危人群的免疫接种以及疫苗成本能否低到可在发展中国家普遍接种.     

宫颈癌治疗性疫苗临床研究进展

宫颈癌的发生与高危型人乳头瘤病毒( human papillomavirus,HPV)的持续感染有关.随着对HPV及其致病机制的深入研究,已经开发了多种用于宫颈癌生物免疫治疗的疫苗,有些已进入临床试验.此文对已进入临床试验阶段的宫颈癌疫苗的设计策略和临床试验进展做一综述.     

别怕宫颈癌,疫苗可预防

人乳头瘤病毒(Human Pdpillomcavirus,HPV)感染会导致宫颈癌,预防HPV感染就成为重中之重,于是各种宫颈癌疫苗(即HPV疫苗)就诞生了。高危型HPV长期感染是诱发宫颈癌的首要因素,宫颈癌与HPV之间关系明确,使得宫颈癌成为目前唯一病因明确的,可以早期预防、治疗,并有希望彻底根除的癌症——这一发现获得了诺贝尔奖。     

人乳头瘤病毒预防性疫苗临床研究进展

人乳头瘤病毒(human papillomavirus,HPV)持续感染是妇女发生宫颈癌的重要原因之一.目前已鉴定出100多个HPV基因型,它们可分为高危型和低危型两类.在亚洲地区,HPV 16、18、58型与宫颈癌关系最密切.目前已上市的HPV预防性疫苗有CervarixTM和Gardasil(R)疫苗.此文对HPV的基因结构和功能以及已上市的预防性疫苗的安全性和免疫原性做一系统阐述.     

人类乳头状瘤病毒载量与宫颈病变关系研究进展

宫颈癌(cervical cancer)是发生于子宫颈鳞状上皮或腺上皮的一种癌,严重危害患者的身体健康.世界卫生组织(WHO)于1992年宣布人类乳头状瘤病毒(HPV)是引起宫颈癌的首要因素.宫颈癌涂片标本进行HPV-DNA分析时发现HPV检出率为97.7％[1].由此可见HPV感染与宫颈癌发生相关.已知的生殖道HPV亚型有50余种.大多数HPV感染是一过性的,可以在18个月内被免疫功能正常的机体自动清除,仅小部分表现为慢性持续感染.高危型HPV的持续感染可引起相关的妇科肿瘤[2],主要为宫颈癌及其癌前病变.及早发现和有效的治疗对于保护患者健康,甚至挽救生命具有重要的价值.     

宫颈癌,有望消除的癌症

日前,世界卫生组织发布《加速消除宫颈癌全球战略》,首次承诺要消除一种癌症,也就是宫颈癌。该战略提出,到2030年,要实现90%的女孩在15岁之前完成人乳头状瘤病毒疫苗(HPV疫苗)接种的目标。那么,接种HPV疫苗与预防宫颈癌之间有着怎样的关联呢?HPV持续性感染是主要致病因素目前已经明确,人乳头状瘤病毒(HPV)某些亚型持续性感染是导致宫颈癌的最主要因素。     

人乳头瘤病毒及其疫苗研究现状

高危型人乳头瘤病毒(human papillomavirus,HPV)的持续感染是导致妇女宫颈癌的关键因素.随着对HPV及其致病机制研究的深入和免疫学的发展,新型HPV预防性疫苗已在多个国家上市,治疗性疫苗的研究也有新的进展.此文对HPV及HPV疫苗的新进展做一综述.     

妇科门诊就诊者HPV感染危险因素分析及HPV疫苗认知情况调查

目的 分析女性子宫颈人乳头瘤病毒(HPV)感染情况及危险因素,调查其对相关疫苗认知情况。方法 选择漯河市中医院2016年12月至2021年12月妇科门诊自愿接受HPV筛查的2 152例女性,比较HPV阳性感染亚型和感染情况分布,分析HPV感染相关危险因素,调查其对相关疫苗认知情况。结果 入组女性HPV高危型主要为HPV16、HPV58和HPV52,低危型主要为HPV11、HPV6,中国人群常见亚型主要为HPVCP8304、HPV53、HPV66。受检女性HPV总感染率为20.77%,其中单一感染16.31%,高于多重感染4.46%;感染类型由高到低依次为高危亚型、低危亚型和混合感染。女性HPV感染与宫颈癌家族史、初婚年龄≤20岁、流产次数>3次和性伴侣个数≥2个有关。阳性者HPV危害性知识知晓率、HPV预防性疫苗知晓率和HPV疫苗接种意愿均低于阴性者。结论 宫颈癌家族史、初婚年龄≤20岁、流产次数>3次和性伴侣个数≥2个是女性HPV感染的危险因素,应加强对HPV相关知识及疫苗普及,降低宫颈癌发生。     

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.