PYK2 is overexpressed in chronic lymphocytic leukaemia: A potential new therapeutic target

Chronic Lymphocytic Leukaemia (CLL) is the most common adult B-cell leukaemia and despite improvement in patients' outcome, following the use of targeted therapies, it remains incurable. CLL supportive microenvironment plays a key role in both CLL progression and drug resistance through signals that can be sensed by the main components of the focal adhesion complex, such as FAK and PYK2 kinases. Dysregulations of both kinases have been observed in several metastatic cancers, but their role in haematological malignancies is still poorly defined. We characterized FAK and PYK2 expression and observed that PYK2 expression is higher in leukaemic B cells and its overexpression significantly correlates with their malignant transformation. When targeting both FAK and PYK2 with the specific inhibitor defactinib, we observed a dose–response effect on CLL cells viability and survival. In vivo treatment of a CLL mouse model showed a decrease of the leukaemic clone in all the lymphoid organs along with a significant reduction of macrophages and of the spleen weight and size. Our results first define a possible prognostic value for PYK2 in CLL, and show that both FAK and PYK2 might become putative targets for both CLL and its microenvironment (e.g. macrophages), thus paving the way to an innovative therapeutic strategy.     

Controlled release of adeno-associated virus from alginate hydrogel microbeads with enhanced sensitivity to ultrasound

Adeno-associated virus (AAV)-based gene therapy holds promise as a fundamental treatment for genetic disorders. For clinical applications, it is necessary to control AAV release timing to avoid an immune response to AAV. Here we propose an ultrasound (US)-triggered on-demand AAV release system using alginate hydrogel microbeads (AHMs) with a release enhancer. By using a centrifuge-based microdroplet shooting device, the AHMs encapsulating AAV with tungsten microparticles (W-MPs) are fabricated. Since W-MPs work as release enhancers, the AHMs have high sensitivity to the US with localized variation in acoustic impedance for improving the release of AAV. Furthermore, AHMs were coated with poly-l -lysine (PLL) to adjust the release of AAV. By applying US to the AAV encapsulating AHMs with W-MPs, the AAV was released on demand, and gene transfection to cells by AAV was confirmed without loss of AAV activity. This proposed US-triggered AAV release system expands methodological possibilities in gene therapy.     

Comparación de los libros de historia de vida digitales y convencionales sobre el estado de ánimo,la comunicación,la cognición y la calidad de vida en personas con demencia en residencias: un estudio piloto

IntroductionPerson-centered care (PCC) includes life story, a form of reminiscence therapy that can be useful in the treatment of dementia. We compared the efficacy of using a digital or conventional life story book (LSB) on depressive symptoms, communication, cognition, and quality of life.Material and methodsThirty one persons with dementia living in 2 PCC nursing homes were randomly assigned to receive reminiscence therapy based on the Neural Actions digital LSB (n = 16) or a conventional LSB (n = 15). Both groups performed 2 weekly sessions of 45 min for 5 weeks. Depressive symptoms were evaluated with the Cornell scale (CSDD); communication with the Holden scale (HCS), cognition with the Mini Mental State Examination (MMSE) and quality of life with the quality of life scale for Alzheimer's (QoL-AD). The results were analyzed using ANOVA of repeated measures with the jamovi 2.3 program.ResultsBoth LSB improved communication skills (η² = 0.115; p < 0.001), with no differences between groups. No effects on quality of life, cognition, or mood were found.ConclusionsIn PCC centres digital or conventional LSB can be useful in the treatment of people with dementia by facilitating communication. Its role on quality of life, cognition or mood is uncertain.     

A carbon-13 nuclear magnetic resonance investigation of the metabolic fluxes associated withy glucose metabolism in human erythrocytes

We have used [2-¹³C]d-glucose and carbon-13 nuclear magnetic resonance (NMR) spectroscopy to investigate metabolic fluxes through the major pathways of glucose metabolism in intact human erythrocytes and to determine the interactions among these pathways under conditions that perturb metabolism. Using the method described, we have been able to measure fluxes through the pentose phosphate pathway, phosphofructokinase, the 2,3-diphosphoglycerate bypass, and phosphoglycerate kinase, as well as glucose uptake, concurrently and in a single experiment. We have measured these fluxes in normal human erythrocytes under the following conditions: (1) fully oxygenated; (2) treated with methylene blue; and (3) deoxygenated. This method makes it possible to monitor various metabolic effects of stresses in normal and pathological states. Not only has ¹³C-NMR spectroscopy proved to be a useful method for measuring in vivo flux through the pentose phosphate pathway, but it has also provided additional information about the cycling of metabolites through the non-oxidative portion of the pentose phosphate pathway. Our evidence from experiments with [1-¹³C]-, [2-¹³C]-, and [3-¹³C]d-glucoses indicates that there is an observable reverse flux of fructose 6-phosphate through the reactions catalyzed by transketolase and transaldolase, even in the presence of a net flux through the pentose phosphate pathway.     

Long-term follow up of patients with common variable immunodeficiency treated with intravenous immunoglobulin: Reevaluation of intravenous immunoglobulin replacement therapy

Five patients with common variable immunodeficiency treated in our hospital between December 1979 and December 1990 were given six kinds of intravenous immunoglobulin preparations (pepsin treated, S-sulfonated, polyethylene glycol treated, pH4 treated, alkylated, and pH4.25 formulation preparation) for replacement therapy. Duration of the therapy ranged from 7.6 to 11 years. Incidences of fever and acute infections were variable among patients, but no significant differences were seen in the incidences among periods given each preparation. Three cases revealed abnormal pulmonary functions in tests. Adverse reactions were rarely seen in our study periods, and no severe reactions were observed. No significant differences were seen in incidences of adverse reactions. Postinfusion levels of serum complement slightly decreased from preinfusion levels. However, the decrease in complement was not related to any adverse reaction. No long-term complications such as transmission of hepatitis have been observed. Our data suggest that no obvious differences exist between the efficacy and safety of each IVIG preparation. Differences of efficacy of IVIG replacement therapy may be due to the variable pathophysiology of each patient.Abbreviations CVID common variable immunodeficiency - IVIG intravenous immunoglobulin     

Molecular magnetic materials from polyoxometalates

The significance of polyoxometalates in the field of molecular magnetism is discussed. We show that this kind of inorganic complexes provides remarkable examples for the study of the exchange interactions in clusters. On the other hand, we examine the possibility of using these metal oxide anions as magnetic components of molecular materials containing organic tetrathiafulvalenes as electron donor molecules.     

酶类药物现状、问题及展望

随着生物制药的迅速发展,许多酶类药物应运而生,在治疗代谢疾病、心血管疾病、癌症等诸多疾病上发挥着越来越重要的作用。但是酶类药物也存在一些不足,如潜在的免疫原性、较短的体内半衰期,以及较差的组织靶向性,影响了酶类药物的疗效和应用。为克服这些缺点,人们已开发出多种技术,如通过糖基化、聚乙二醇修饰等分子工程技术提升酶蛋白药效,另一方面酶基因疗法也已成功用于多种酶缺陷疾病的治疗。基于酶类药物的迅速发展和广泛的应用前景,本文对酶类药物的现状进行较详细的阐述,并对酶类药物的优势、所存在的问题及未来发展趋势进行分析和评述。     

ELF磁场对3T3细胞生长的影响及其机理的探讨

用细胞分析成像光盘记录系统测量了3T3细胞在某些ELF磁场和温度条件下生长周期的变化.实验结果表明,只有某些频率的ELF磁场才对细胞生长产生影响,磁场对细胞生长的影响还与培养细胞的生化环境有关.温度和ELF磁场都能影响细胞的生长.但二者的机理是不一样的,当撤除ELF磁场后,细胞在短时间内(2天以上)继续保持着ELF场对其生长的影响.而细胞生长周期能在短时间内(2天以内)随着温度的变化而变化.温度引起的细胞生长的变化可能与细胞内的各种生长因子、生物离子的活性有关.ELF磁场引起的细胞生长的变化可能与ELF磁场对细胞膜的影响有关,与细胞内细胞生长必不可少的生物离子(如Ca~(2+))的浓度有关.     

脑部磁刺激场的理论模型

作为脑部磁刺激研究的一项基础工作,建立了刺激磁场中的球形头模型、对方形线圈在其内产生的时变磁场和感应电场进行了理论研究.导出(?).(?).(?)的解析表达式,分析了场的特性和刺激强度的分布规律.为进一步探索时变磁场对人脑的最佳刺激方式和作用机理提供了初步的理论基础.