The Proteoglycan Glypican-1 as a Possible Candidate for Innovative Targeted Therapeutic Strategies for Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers, with a 5-year survival rate of 7% and 80% of patients diagnosed with advanced or metastatic malignancies. Despite recent advances in diagnostic testing, surgical techniques, and systemic therapies, there remain limited options for the effective treatment of PDAC. There is an urgent need to develop targeted therapies that are able to differentiate between cancerous and non-cancerous cells to reduce side effects and better inhibit tumor growth. Antibody-targeted strategies are a potentially effective option for introducing innovative therapies. Antibody-based immunotherapies and antibody-conjugated nanoparticle-based targeted therapies with antibodies targeting specific tumor-associated antigens (TAA) can be proposed. In this context, glypican-1 (GPC1), which is highly expressed in PDAC and not expressed or expressed at very low levels in non-malignant lesions and healthy pancreatic tissues, is a useful TAA that can be achieved by a specific antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy. In this review, we describe the main clinical features of PDAC. We propose the proteoglycan GPC1 as a useful TAA for PDAC-targeted therapies. We also provide a digression on the main developed approaches of antibody-based immunotherapy and antibody-conjugated nanoparticle-based targeted therapy, which can be used to target GPC1.     

Coagulation Factor XIIIa and Activated Protein C Activate Platelets via GPVI and PAR1

Platelet and coagulation activation are highly reciprocal processes driven by multi-molecular interactions. Activated platelets secrete several coagulation factors and expose phosphatidylserine, which supports the activation of coagulation factor proteins. On the other hand, the coagulation cascade generates known ligands for platelet receptors, such as thrombin and fibrin. Coagulation factor (F)Xa, (F)XIIIa and activated protein C (APC) can also bind to platelets, but the functional consequences are unclear. Here, we investigated the effects of the activated (anti)coagulation factors on platelets, other than thrombin. Multicolor flow cytometry and aggregation experiments revealed that the ‘supernatant of (hirudin-treated) coagulated plasma’ (SCP) enhanced CRP-XL-induced platelet responses, i.e., integrin α_IIbβ₃ activation, P-selectin exposure and aggregate formation. We demonstrated that FXIIIa in combination with APC enhanced platelet activation in solution, and separately immobilized FXIIIa and APC resulted in platelet spreading. Platelet activation by FXIIIa was inhibited by molecular blockade of glycoprotein VI (GPVI) or Syk kinase. In contrast, platelet spreading on immobilized APC was inhibited by PAR1 blockade. Immobilized, but not soluble, FXIIIa and APC also enhanced in vitro adhesion and aggregation under flow. In conclusion, in coagulation, factors other than thrombin or fibrin can induce platelet activation via GPVI and PAR receptors.     

Assembly of the Multi-Subunit Cytochrome bc1 Complex in the Yeast Saccharomyces cerevisiae

The cytochrome bc₁ complex is an essential component of the mitochondrial respiratory chain of the yeast Saccharomyces cerevisiae. It is composed of ten protein subunits, three of them playing an important role in electron transfer and proton pumping across the inner mitochondrial membrane. Cytochrome b, the central component of this respiratory complex, is encoded by the mitochondrial genome, whereas all the other subunits are of nuclear origin. The assembly of all these subunits into the mature and functional cytochrome bc₁ complex is therefore a complicated process which requires the participation of several chaperone proteins. It has been found that the assembly process of the mitochondrial bc₁ complex proceeds through the formation of distinct sub-complexes in an ordered sequence. Most of these sub-complexes have been thoroughly characterized, and their molecular compositions have also been defined. This study critically analyses the results obtained so far and highlights new possible areas of investigation.     

湖北城市建设职业技术学院藏龙岛校区设计构想

该文从设计理念、空间特色及单体建筑设计的几个方面,简要地介绍了湖北城市建设职业技术学院藏龙岛校区的设计构思。     

Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense RNF213 Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review

Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband’s carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118–4122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.     

A Novel Homozygous Variant in DYSF Gene Is Associated with Autosomal Recessive Limb Girdle Muscular Dystrophy R2/2B

Mutations in the DYSF gene, encoding dysferlin, are responsible for Limb Girdle Muscular Dystrophy type R2/2B (LGMDR2/2B), Miyoshi myopathy (MM), and Distal Myopathy with Anterior Tibialis onset (MDAT). The size of the gene and the reported inter and intra familial phenotypic variability make early diagnosis difficult. Genetic analysis was conducted using Next Gene Sequencing (NGS), with a panel of 40 Muscular Dystrophies associated genes we designed. In the present study, we report a new missense variant c.5033G>A, p.Cys1678Tyr ({"type":"entrez-nucleotide","attrs":{"text":"NM_003494","term_id":"1675063869"}}NM_003494) in the exon 45 of DYSF gene related to Limb Girdle Muscular Dystrophy type R2/2B in a 57-year-old patient affected with LGMD from a consanguineous family of south Italy. Both healthy parents carried this variant in heterozygosity. Genetic analysis extended to two moderately affected sisters of the proband, showed the presence of the variant c.5033G>A in both in homozygosity. These data indicate a probable pathological role of the variant c.5033G>A never reported before in the onset of LGMDR2/2B, pointing at the NGS as powerful tool for identifying LGMD subtypes. Moreover, the collection and the networking of genetic data will increase power of genetic-molecular investigation, the management of at-risk individuals, the development of new therapeutic targets and a personalized medicine.     

CAD系统设计中的形式化方法与功能命题

本文结合作者多年的研究实践,对CAD系统功能设计理论和方法进行研究,并在此基础上提出和建立CAD系统功能设计的数学模型,其中包括：(1)介绍需求分析的形式化描述和表示方法,建立需求空间结构;(2)提出复合功能、设计逻辑、功能与参数依赖及交互效率等新概念,并分别建构复合功能的构造和效率命题;(3)阐述这些理论和方法在自行开发的专业化系统中的应用。     

Adaptive river segmentation in SAR images

There is difficulty for distinguishing of river and shadow in Synthetic Aperture Radar (SAR) images. A method of river segmentation in SAR images based on wavelet energy and gradient is proposed in this paper. It mainly includes two algorithms: coarse segmentation and refined segmentation. Firstly, The river regions are coarsely segmented by the wavelet energy feature,and then refined segmented accurately by the gradient threshold which is got adaptively. The experimental results show the validity of the method, which provides a good foundation for targets detection above the river.     

Corium spreading and coolability: CSC Project

In the context of severe accidents, large R&D efforts throughout the world are currently directed towards ex-vessel corium behaviour. Among the mitigation means which can be envisaged, the European industries and utilities are considering the implementation of a core-catcher outside the reactor pressure vessel in order to prevent basemat erosion and to stabilize and control the corium within the containment. The CSC project focused on two key phenomena for external core-catcher efficiency, reliability and safety: spreading and coolability. An experimental programme, covering different scenarios and including both simulant and real materials provided a lot of results which now constitute a large database and which enabled the qualification of computer codes.