双特异性抗体在肿瘤治疗中的研究

双特异性抗体(bispecific antibody,BsAb)有两个抗原结合位点,其中一个位点可与靶细胞表面抗原结合,另一个位点则可与载荷物(如效应细胞,分子等)结合。将BsAb应用于肿瘤治疗,发挥抗肿瘤效应的思想已有二十多年历史,随着对效应细胞生物学了解的加深和抗体工程的飞速发展,各种形式的BsAb相继出现,多种BsAb药物已进入临床初期试验或治疗使用阶段。本文就BsAb的各种新形式及其在肿瘤治疗中的应用新进展作简要概述。     

The transcription factor 7-like 2 (TCF7L2) polymorphism may be associated with focal arteriolar narrowing in Caucasians with hypertension or without diabetes: the ARIC Study

Background

To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes.

Materials and methods

In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation.

Results

Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA_1c (P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide.

Conclusion

GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes.     

Acute L-glutamine deprivation compromises VEGF-a upregulation in A549/8 human carcinoma cells

Tumor ischemia participates in angiogenesis and cancer progression through cellular responses to hypoxia and nutrient deprivation. However, the contribution of amino acids limitation to this process remains poorly understood. Using serum-free cell culture conditions, we tested the impact of L-glutamine deprivation on metabolic and angiogenic responses in A549/8 carcinoma cells. In these cells, lowering glutamine concentration modified the cell cycle distribution and significantly induced apoptosis/necrosis. Although glutamine deprivation led to a HIF-independent increase in VEGF-A mRNA, the corresponding protein level remained low and correlated with the inhibition of protein synthesis and activation of the GCN2/eIF2alpha pathway. Limitation of glutamine availability also hampers hypoxia- and hypoglycemia-induced VEGF-A protein upregulation. Thus, glutamine deprivation may have no direct effect on VEGF-dependent angiogenesis, compared to hypoxia or to glucose deprivation, and may instead be detrimental to cancer progression by antagonizing ischemia-induced stresses.     

Sex-specific effects of <Emphasis Type="Italic">ACE</Emphasis> I/D and <Emphasis Type="Italic">AGT</Emphasis>-M235T on pulse pressure: the HyperGEN Study

Evidence shows that an elevated pulse pressure (PP) may lead to an increased risk of cardiovascular morbidity and mortality. There is also evidence that PP is a sexually dimorphic trait, and that genetic factors influence inter-individual variation in PP. The aim of this project was to assess the genotype-by-sex interaction on PP in a sample of mostly hypertensive African American and White participants using candidate genes involved in the renin–angiotensin–aldosterone system. Subjects were participants in the HyperGEN Study, including men (43%) and women (57%) over the age of 55 years (mean age = 65). Candidate gene polymorphisms used were ACE insertion/deletion (1,789 subjects genotyped) and AGT-M235T (1,800 subjects genotyped). We employed linear regression methods to assess the genotype-by-sex interaction. For ACE, genotype-by-sex interaction on PP was detected (P = 0.04): the “D/D” genotype predicted a 2.2 mmHg higher pulse pressure among women, but a 1.2 mmHg lower PP among men, compared to those with an “I” allele, after adjusting for age, weight, height, ethnicity, and antihypertension medication use. A similar interaction was found for systolic blood pressure. The genotype-by-sex interaction was consistent across ethnicity. The interaction was evident among those on antihypertensive medications (P = 0.05), but not among those not taking such medications (P = 0.55). In our analysis of AGT, no evidence of a genotype-by-sex interaction affecting PP, SBP, or DBP was detected. This evidence for a genotype-by-sex interaction helps our understanding of the complex genetic underpinnings of blood pressure phenotypes.     

DSA图像中运动伪影的消除方法

由于病人存在着各种运动(如呼吸、肌肉运动、心脏运动、设备噪声),在成像过程中常会造成图像上出现伪影,干扰医生的正常诊断,为消除这种伪影,本文提出一种基于图像配准思想的全自动消除伪影的方法,该方法能够自动消除DSA图像中的大部分运动伪影,使DSA图像得到较好的增强,并为后面的血管分割和三维重建提供便利,是一种快速有效的方法。     

An anti-infective peptide that selectively modulates the innate immune response

We show that an innate defense-regulator peptide (IDR-1) was protective in mouse models of infection with important Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and Salmonella enterica serovar Typhimurium. When given from 48 h before to 6 h after infection, the peptide was effective by both local and systemic administration. Because protection by IDR-1 was prevented by in vivo depletion of monocytes and macrophages, but not neutrophils or B- and T-lymphocytes, we conclude that monocytes and macrophages are key effector cells. IDR-1 was not directly antimicrobial: gene and protein expression analysis in human and mouse monocytes and macrophages indicated that IDR-1, acting through mitogen-activated protein kinase and other signaling pathways, enhanced the levels of monocyte chemokines while reducing pro-inflammatory cytokine responses. To our knowledge, an innate defense regulator that counters infection by selective modulation of innate immunity without obvious toxicities has not been reported previously.     

Water transfer via ectomycorrhizal fungal hyphae to conifer seedlings

Little is known about water transfer via mycorrhizal hyphae to plants, despite its potential importance in seedling establishment and plant community development, especially in arid environments. Therefore, this process was investigated in the study reported in this paper in laboratory-based tripartite mesocosms containing the shrub Arctostaphylos viscida (manzanita) and young seedlings of sugar pine (Pinus lambertiana) and Douglas-fir (Pseudotsuga menziesii). The objectives were to determine whether water could be transported through mycorrhizal symbionts shared by establishing conifers and A. viscida and to compare the results obtained using two tracers: the stable isotope deuterium and the dye lucifer yellow carbohydrazide. Water containing the tracers was added to the central compartment containing single manzanita shrubs. The fungal hyphae were then collected as well as plant roots from coniferous seedlings in the other two compartments to determine whether water was transferred via fungal hyphae. In addition, the length of the hyphae and degree of mycorrhizal colonisation were determined. Internal transcribed spacer–restriction fragment length polymorphism (ITS-RFLP) analysis was used to identify the fungal species involved in dye (water) transfer. Results of the stable isotope analysis showed that water is transferred via mycorrhizal hyphae, but isotopically labelled water was only detected in Douglas-fir roots, not in sugar pine roots. In contrast, the fluorescent dye was transported via mycorrhizal hyphae to both Douglas-fir and sugar pine seedlings. Only 1 of 15 fungal morphotypes (identified as Atheliaceae) growing in the mesocosms transferred the dye. Differences were detected in the water transfer patterns indicated by the deuterium and fluorescent dye tracers, suggesting that the two labels are transported by different mechanisms in the same hyphae and/or that different fungal taxa transfer them via different routes to host plants. We conclude that both tracers can provide information on resource transfer between fungi and plants, but we cannot be sure that the dye transfer data provide accurate indications of water transfer rates and patterns. The isotopic tracer provides more direct indications of water movement and is therefore more suitable than the dye for studying water relations of plants and their associated mycorrhizal fungi.     

Influence of landscape and vegetation characteristics on herpetofaunal assemblages in Gulf Coastal Plain pine forests

Longleaf pine (Pinus palustris) savanna characterized by open-canopy, diverse herbaceous vegetation, and high amounts of bare soil once covered much of the southeastern United States Coastal Plain. The unique structural and vegetative conditions of this ecosystem support endemic reptiles and amphibians that have declined as longleaf pine forests have been lost or degraded. Private working pine (Pinus spp.) forests managed for timber production now occur throughout the southeastern United States and have replaced much of the historical longleaf pine savanna. The examination of herpetofaunal (reptile, amphibian) communities in private working loblolly pine (P. taeda) landscapes, particularly in the western Gulf Coastal Plain is lacking. Using repeated field surveys and hierarchical community occupancy models, we examined occupancy and species richness of herpetofauna across 81 sites spanning gradients of management practices, vegetative conditions, and soil composition in northwestern Louisiana, USA, 2017–2019. Young pine stands (<6 yr) exhibited structural characteristics most similar to mature longleaf pine reference sites (>30 yr), while mid-aged stands (13–26 yr) often featured closed canopy and dense midstory. Vegetation conditions varied widely depending on landscape characteristics and site-specific disturbance regimes. We documented 43 species of herpetofauna, including 9 open-pine-associated species. Occupancy of open-pine-associated herpetofauna was positively associated with open-canopy and understory conditions, and sandy soil area. Sites providing open-canopy conditions were often occupied by open-pine-associated species regardless of overstory type and disturbance method. Overall richness of herpetofauna was greatest at sites with moderate canopy cover outside of sandy soil regions. Working pine landscapes in the western Gulf Coastal Plain can support diverse herpetofaunal assemblages, including open-pine-associated species, when management practices maintain open-canopy conditions on sandy, upland soils. More broadly, our results provide insight into how forest management practices affect herpetofauna and may guide practices that can contribute to conservation value of working pine forests.     

Length–weight relationships for 85 fish species from Guam

Length–weight relationships (LWRs) were developed for 85 reef and bottom‐fish species from Guam. These are the first published LWRs for Guam, and include new LWRs for nine species lacking these relationships in FishBase.