Dermatan Sulfate Affects the Activation of the Necroptotic Effector MLKL in Breast Cancer Cell Lines via the NFκB Pathway and Rac-Mediated Oxidative Stress.

Dermatan sulfate (DS) is a glycosaminoglycan characterized by having a variable structure and wide distribution in animal tissues. We previously demonstrated that some structural variants of DS were able to rapidly induce moderate necroptosis in luminal breast cancer cells when used at a high concentration. We have now investigated the mechanisms underlying the DS-mediated activation of the necroptotic executor MLKL using immunofluorescence, Western blotting and pharmacological inhibition. The two main processes, by which DS influences the phosphorylation of MLKL, are the activation of NFκB, which demonstrates a suppressive impact, and the induction of oxidative stress, which has a stimulatory effect. Moreover, the triggering of the redox imbalance by DS occurs via the modulatory influence of this glycosaminoglycan on the rearrangement of the actin cytoskeleton, requiring alterations in the activity of small Rho GTP-ase Rac1. All of these processes that were elicited by DS in luminal breast cancer cells showed a dependence on the structure of this glycan and the type of cancer cells. Furthermore, our results suggest that a major mechanism that is involved in the stimulation of necroptosis in luminal breast cancer cells by high doses of DS is mediated via the effect of this glycan on the activity of adhesion molecules.

Alterations in the Structure, Composition, and Organization of Galactosaminoglycan-Containing Proteoglycans and Collagen Correspond to the Progressive Stages of Dupuytren's Disease.

Dupuytren's disease (DD) is a prevalent fibroproliferative disorder of the hand, shaped by genetic, epigenetic, and environmental influences. The extracellular matrix (ECM) is a complex assembly of diverse macromolecules. Alterations in the ECM's content, structure and organization can impact both normal physiological functions and pathological conditions. This study explored the content and organization of glycosaminoglycans, proteoglycans, and collagen in the ECM of patients at various stages of DD, assessing their potential as prognostic indicators. This research reveals, for the first time, relevant changes in the complexity of chondroitin/dermatan sulfate structures, specifically an increase of disaccharides containing iduronic acid residues covalently linked to either N-acetylgalactosamine 6-O-sulfated or N-acetylgalactosamine 4-O-sulfated, correlating with the disease's severity. Additionally, we noted an increase in versican expression, a high molecular weight proteoglycan, across stages I to IV, while decorin, a small leucine-rich proteoglycan, significantly diminishes as DD progresses, both confirmed by mRNA analysis and protein detection via confocal microscopy. Coherent anti-Stokes Raman scattering (CARS) microscopy further demonstrated that collagen fibril architecture in DD varies importantly with disease stages. Moreover, the urinary excretion of both hyaluronic and sulfated glycosaminoglycans markedly decreased among DD patients.Our findings indicate that specific proteoglycans with galactosaminoglycan chains and collagen arrangements could serve as biomarkers for DD progression. The reduction in glycosaminoglycan excretion suggests a systemic manifestation of the disease.

Design and evaluation of a bilayered dermal/hypodermal 3D model using a biomimetic hydrogel formulation.

Due to the limitations of the current skin wound treatments, it is highly valuable to have a wound healing formulation that mimics the extracellular matrix (ECM) and mechanical properties of natural skin tissue. Here, a novel biomimetic hydrogel formulation has been developed based on a mixture of Agarose-Collagen Type I (AC) combined with skin ECM-related components: Dermatan sulfate (DS), Hyaluronic acid (HA), and Elastin (EL) for its application in skin tissue engineering (TE). Different formulations were designed by combining AC hydrogels with DS, HA, and EL. Cell viability, hemocompatibility, physicochemical, mechanical, and wound healing properties were investigated. Finally, a bilayered hydrogel loaded with fibroblasts and mesenchymal stromal cells was developed using the Ag-Col I-DS-HA-EL (ACDHE) formulation. The ACDHE hydrogel displayed the best in vitro results and acceptable physicochemical properties. Also, it behaved mechanically close to human native skin and exhibited good cytocompatibility. Environmental scanning electron microscopy (ESEM) analysis revealed a porous microstructure that allows the maintenance of cell growth and ECM-like structure production. These findings demonstrate the potential of the ACDHE hydrogel formulation for applications such as an injectable hydrogel or a bioink to create cell-laden structures for skin TE.

A biological guide to glycosaminoglycans: current perspectives and pending questions.

Mammalian glycosaminoglycans (GAGs), except hyaluronan (HA), are sulfated polysaccharides that are covalently attached to core proteins to form proteoglycans (PGs). This article summarizes key biological findings for the most widespread GAGs, namely HA, chondroitin sulfate/dermatan sulfate (CS/DS), keratan sulfate (KS), and heparan sulfate (HS). It focuses on the major processes that remain to be deciphered to get a comprehensive view of the mechanisms mediating GAG biological functions. They include the regulation of GAG biosynthesis and postsynthetic modifications in heparin (HP) and HS, the composition, heterogeneity, and function of the tetrasaccharide linkage region and its role in disease, the functional characterization of the new PGs recently identified by glycoproteomics, the selectivity of interactions mediated by GAG chains, the display of GAG chains and PGs at the cell surface and their impact on the availability and activity of soluble ligands, and on their move through the glycocalyx layer to reach their receptors, the human GAG profile in health and disease, the roles of GAGs and particular PGs (syndecans, decorin, and biglycan) involved in cancer, inflammation, and fibrosis, the possible use of GAGs and PGs as disease biomarkers, and the design of inhibitors targeting GAG biosynthetic enzymes and GAG-protein interactions to develop novel therapeutic approaches.

Cadmium induces chondroitin sulfate synthase 1 via protein kinase Cα and elongates chondroitin/dermatan sulfate chains in cultured vascular endothelial cells.

Cadmium is an environmental pollutant and a risk factor for atherosclerosis. In the atherosclerotic intima, dermatan sulfate chains accelerate accumulation and oxidation of LDL cholesterol. The major type of dermatan sulfate proteoglycan that is synthesized by vascular endothelial cells is biglycan. In the present study, we analyzed the effect of cadmium on the biglycan synthesis using cultured bovine aortic endothelial cells. Cadmium did not induce biglycan mRNA and core protein expression; however, it elongated the chondroitin/dermatan sulfate chains of biglycan. Among elongation enzymes of the chondroitin/dermatan sulfate chain, chondroitin sulfate synthase 1 (CHSY1) mRNA and protein expression were dose- and time-dependently upregulated by cadmium depending on protein kinase Cα. This finding suggests that CHSY1-dependent elongation of chondroitin/dermatan sulfate chains of biglycan may exacerbate cadmium-induced atherosclerosis.

The effect of the sulfation patterns of dermatan and chondroitin sulfate from vertebrates and ascidians on their neuritogenic and neuroprotective properties.

Neurodegeneration is caused by the progressive loss of the structure and function of neurons, leading to cell death, and it is the main cause of many neurodegenerative diseases. Many molecules, such as glycosaminoglycans (GAGs), have been studied for their potential to prevent or treat these diseases. They are widespread in nature and perform an important role in neuritogenesis and neuroprotection. Here we investigated the neuritogenic and neuroprotective role of Phallusia nigra dermatan sulfate (PnD2,6S) and compared it with two distinct structures of chondroitin sulfate (C6S) and dermatan sulfate (D4S). For this study, a neuro 2A murine neuroblastoma cell line was used, and a chemical lesion was induced by the pesticide rotenone (ROT). We observed that PnD2,6S + ROT had a better neuritogenic effect than either C6S + ROT or D4S + ROT at a lower concentration (0.05 µg/mL). When evaluating the mitochondrial membrane potential, PnD2,6S showed a neuroprotective effect at a concentration of 0.4 µg/mL. These data indicate different mechanisms underlying this neuronal potential, in which the sulfation pattern is important for neuritogenic activity, while for neuroprotection all DS/CS structures had similar effects. This finding leads to a better understanding the chemical structures of PnD2,6S, C6S, and D4S and their therapeutic potential.

Dermatan Sulfate/Chitosan Nanoparticles Loaded with an Anti-Inflammatory Peptide Increase the Response of Human Colorectal Cancer Cells to 5-Fluorouracil.

The gold standard drug for colorectal cancer (CRC) treatment, 5-Fluorouracil (5-FU), induces pharmacological tolerance in long-term management. The transcriptional factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) plays a key role in 5-FU resistance. The aim of this work is to study the capability of polyelectrolytes complex nanoparticles of dermatan sulfate (DS) and chitosan (CS), loaded with the anti-inflammatory tripeptide IRW, to sensitize colorectal cancer cells to 5-FU. Fluorescence and flow cytometry studies confirmed the recognition by the nanoformulation, of the cluster of differentiation 44 (CD44) receptor, involved in the initiation and progression of colorectal tumors. Dynamic light scattering (DLS) and flow cytometry reinforced the importance of DS and CD44 receptor in the interaction, as the addition of DS or anti-CD44 antibody blocked the binding. Moreover, the nanoformulation also interacts with 3D colon cancer cultures, namely colonospheres, enriched in cancer stem cells (CSC), subpopulation responsible for drug resistance and metastasis. To evaluate the consequences of this interaction, the subcellular distribution of the transcriptional factor NFκB, is determined by immunofluorescence analysis. Internalization and the intracellular release of IRW inhibited nuclear translocation of NFκB and increased cellular sensitivity to 5-FU. Altogether, the nanoformulation could provide a selective delivery platform for IRW distribution to colorectal tumors, being an innovative strategy toward overcoming 5-FU resistance in CRC therapy.

Enzymatic comparison of two homologous enzymes reveals N-terminal domain of chondroitinase ABC I regulates substrate selection and product generation.

Chondroitinase ABC-type I (CSase ABC I), which can digest both chondroitin sulfate (CS) and dermatan sulfate (DS) in an endolytic manner, is an essential tool in structural and functional studies of CS/DS. Although a few CSase ABC I have been identified from bacteria, the substrate-degrading pattern and regulatory mechanisms of them have rarely been investigated. Herein, two CSase ABC I, IM3796 and IM1634, were identified from the intestinal metagenome of CS-fed mice. They show high sequence homology (query coverage: 88.00%, percent identity: 90.10%) except for an extra peptide (Met1-His109) at the N-terminus in IM1634, but their enzymatic properties are very different. IM3796 prefers to degrade 6-O-sulfated GalNAc residue-enriched CS into tetra- and disaccharides. In contrast, IM1634 exhibits nearly a thousand times more activity than IM3796 and can completely digest CS/DS with various sulfation patterns to produce disaccharides, unlike most CSase ABC I. Structure modeling showed that IM3796 did not contain an N-terminal domain composed of two ß-sheets, which is found in IM1634 and other CSase ABC I. Furthermore, deletion of the N-terminal domain (Met1-His109) from IM1634 caused the enzymatic properties of the variant IM1634-T109 to be similar to those of IM3796, and conversely, grafting this domain to IM3796 increased the similarity of the variant IM3796-A109 to IM1634. In conclusion, the comparative study of the new CSase ABC I provides two unique tools for CS/DS-related studies and applications and, more importantly, reveals the critical role of the N-terminal domain in regulating the substrate binding and degradation of these enzymes.

Molecular Dynamics-Based Comparative Analysis of Chondroitin and Dermatan Sulfates.

Glycosaminoglycans (GAGs) are a class of linear anionic periodic polysaccharides containing disaccharide repetitive units. These molecules interact with a variety of proteins in the extracellular matrix and so participate in biochemically crucial processes such as cell signalling affecting tissue regeneration as well as the onset of cancer, Alzheimer's or Parkinson's diseases. Due to their flexibility, periodicity and chemical heterogeneity, often termed "sulfation code", GAGs are challenging molecules both for experiments and computation. One of the key questions in the GAG research is the specificity of their intermolecular interactions. In this study, we make a step forward to deciphering the "sulfation code" of chondroitin sulfates-4,6 (CS4, CS6, where the numbers correspond to the position of sulfation in NAcGal residue) and dermatan sulfate (DS), which is different from CSs by the presence of IdoA acid instead of GlcA. We rigorously investigate two sets of these GAGs in dimeric, tetrameric and hexameric forms with molecular dynamics-based descriptors. Our data clearly suggest that CS4, CS6 and DS are substantially different in terms of their structural, conformational and dynamic properties, which contributes to the understanding of how these molecules can be different when they bind proteins, which could have practical implications for the GAG-based drug design strategies in the regenerative medicine.

Glycomics by ion mobility tandem mass spectrometry of chondroitin sulfate disaccharide domain in biglycan.

Biglycan (BGN), a small leucine-rich repeat proteoglycan, is involved in a variety of pathological processes including malignant transformation, for which the upregulation of BGN was found related to cancer cell invasiveness. Because the functions of BGN are mediated by its chondroitin/dermatan sulfate (CS/DS) chains through the sulfates, the determination of CS/DS structure and sulfation pattern is of major importance. In this study, we have implemented an advanced glycomics method based on ion mobility separation (IMS) mass spectrometry (MS) and tandem MS (MS/MS) to characterize the CS disaccharide domains in BGN. The high separation efficiency and sensitivity of this technique allowed the discrimination of five distinct CS disaccharide motifs, of which four irregulated in their sulfation pattern. For the first time, trisulfated unsaturated and bisulfated saturated disaccharides were found in BGN, the latter species documenting the non-reducing end of the chains. The structural investigation by IMS MS/MS disclosed that in one or both of the CS/DS chains, the non-reducing end is 3-O-sulfated GlcA in a rather rare bisulfated motif having the structure 3-O-sulfated GlcA-4-O-sulfated GalNAc. Considering the role played by BGN in cancer cell spreading, the influence on this process of the newly identified sequences will be investigated in the future.

Chemistry and Function of Glycosaminoglycans in the Nervous System.

Proteoglycans, and especially their GAG components, participate in numerous biologically significant interactions with growth factors, chemokines, morphogens, guidance molecules, survival factors, and other extracellular and cell-surface components. These interactions are often critical to the basic developmental processes of cellular proliferation and differentiation, as well as to both the onset of disease sequelae and prevention of disease progression. In many tissues, proteoglycans and especially their glycosaminoglycan (GAG) components are mediators of these processes. The GAG family is characterized by covalently linked repeating disaccharides forming long unbranched polysaccharide chains. Thus far in higher eukaryotes, the family consists of chondroitin sulfate (CS), heparin/heparan sulfate (HS), dermatan sulfate (DS), keratan sulfate (KS) and hyaluronan (HA). All GAG chains (except HA) are characteristically modified by varying amounts of esterified sulfate. One or more GAG chains are usually found in nature bound to polypeptide backbones in the form of proteoglycans; HA is the exception. In the nervous system, GAG/proteoglycan-mediated interactions participate in proliferation and synaptogenesis, neural plasticity, and regeneration. This review focuses on the structure, chemistry and function of GAGs in nervous system development, disease, function and injury response.

Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases.

The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome). The newly directed attention to the impact of ARSB in human pathobiology indicates a broader, more pervasive effect, encompassing roles as a tumor suppressor, transcriptional mediator, redox switch, and regulator of intracellular and extracellular-cell signaling. By controlling the degradation of chondroitin 4-sulfate and dermatan sulfate by removal or failure to remove the 4-sulfate residue at the non-reducing end of the sulfated glycosaminoglycan chain, ARSB modifies the binding or release of critical molecules into the cell milieu. These molecules, such as galectin-3 and SHP-2, in turn, influence crucial cellular processes and events which determine cell fate. Identification of ARSB at the cell membrane and in the nucleus expands perception of the potential impact of decline in ARSB activity. The regulation of availability of sulfate from chondroitin 4-sulfate and dermatan sulfate may also affect sulfate assimilation and production of vital molecules, including glutathione and cysteine. Increased attention to ARSB in mammalian cells may help to integrate and deepen our understanding of diverse biological phenomenon and to approach human diseases with new insights.

Kinetic and Structural Aspects of Glycosaminoglycan-Monkeypox Virus Protein A29 Interactions Using Surface Plasmon Resonance.

Monkeypox virus (MPXV), a member of the Orthopoxvirus genus, has begun to spread into many countries worldwide. While the prevalence of monkeypox in Central and Western Africa is well-known, the recent rise in the number of cases spread through intimate personal contact, particularly in the United States, poses a grave international threat. Previous studies have shown that cell-surface heparan sulfate (HS) is important for vaccinia virus (VACV) infection, particularly the binding of VACV A27, which appears to mediate the binding of virus to cellular HS. Some other glycosaminoglycans (GAGs) also bind to proteins on Orthopoxviruses. In this study, by using surface plasmon resonance, we demonstrated that MPXV A29 protein (a homolog of VACV A27) binds to GAGs including heparin and chondroitin sulfate/dermatan sulfate. The negative charges on GAGs are important for GAG-MPXV A29 interaction. GAG analogs, pentosan polysulfate and mucopolysaccharide polysulfate, show strong inhibition of MPXV A29-heparin interaction. A detailed understanding on the molecular interactions involved in this disease should accelerate the development of therapeutics and drugs for the treatment of MPXV.

Functions of chondroitin/dermatan sulfate containing GalNAc4,6-disulfate.

Chondroitin sulfate (CS) and dermatan sulfate (DS) containing GalNAc4,6-disulfate (GalNAc4S6S) were initially discovered in marine animals. Following the discovery, these glycosaminoglycans have been found in various animals including human. In the biosynthesis of CS/DS containing GalNAc4S6S, 3 groups of sulfotransferases are involved; chondroitin 4-sulfotransferases (C4STs), dermatan 4-sulfotransferase-1 (D4ST-1), and GalNAc 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST). GalNAc4S-6ST and its products have been shown to play important roles in the abnormal pathological conditions such as central nervous system injury, cancer development, abnormal tissue fibrosis, development of osteoporosis, and infection with viruses or nematodes. CS/DS containing GalNAc4S6S has been shown to increase with the functional differentiation of mast cells, macrophages, and neutrophils. Genetic approaches using knockout or knockdown of GalNAc4S-6ST, blocking of the epitopes containing GalNAc4S6S by specific antibodies and chemical technology that enabled the synthesis of oligosaccharides with defined sulfation patterns, have been applied successfully to these investigations. These studies contributed significantly to the basic understanding of the functional roles of CS/DS containing GalNAc4S6S in various abnormal conditions and appear to provide promising clues to the development of possible measures to treat them.

ROS-triggered nanoinducer based on dermatan sulfate enhances immunogenic cell death in melanoma.

Due to its complexity, diversity and heterogeneity, melanoma is a kind of malignant tumor. It has been proved that the enhancement of anti-tumor immune response such as immunogenic cell death (ICD) is an important therapeutic strategy. In previous studies, we confirmed that dermatan sulfate (DS) from skin tissue could specifically homing to melanoma B16F10 cells. In this study, we propose a nanoinducer (DOX/ADS NP) based on a functional DS for melanoma. This nanosystem is composed of DS as framework, aromatic thioketal derivative (ATK) as functional grafting unit and doxorubicin (DOX) designed as an ICD inducer. Through the intermolecular interaction between DOX and ATK, DOX/ADS NP with specific-homing, high-loading and ROS-triggering release was obtained via self-assemble. Compared with free DOX and non-functionalized nanomedicine, DOX/ADS NP could release DOX into B16F10 cells better, and strongly induce the translocation of calreticulin (CRT) to the cell membrane. CRT is a marker of ICD, also as a "eat me" signal to stimulate the maturation and antigen presentation of dendritic cells. Therefore, a series of subsequent immune responses were activated: maturation of dendritic cells, T cells proliferation, increased tumor-infiltrating CTLs and the ratio of CTLs to Tregs, and up-regulated cytotoxic cytokine expression. In conclusion, DOX/ADS NP promoted ICD-associated immune response through more specific targeting effect and sensitive responsive DOX release, achieving better inhibitory effect on melanoma than free DOX and other nanoformulation. This biomimetic ICD nanoinducer based on DS is expected to provide new strategies and references for the treatment of melanoma.

Extracellular endosulfatase Sulf-2 harbors a chondroitin/dermatan sulfate chain that modulates its enzyme activity.

Sulfs represent a class of unconventional sulfatases which provide an original post-synthetic regulatory mechanism for heparan sulfate polysaccharides and are involved in multiple physiopathological processes, including cancer. However, Sulfs remain poorly characterized enzymes, with major discrepancies regarding their in vivo functions. Here we show that human Sulf-2 (HSulf-2) harbors a chondroitin/dermatan sulfate glycosaminoglycan (GAG) chain, attached to the enzyme substrate-binding domain. We demonstrate that this GAG chain affects enzyme/substrate recognition and tunes HSulf-2 activity in vitro and in vivo. In addition, we show that mammalian hyaluronidase acts as a promoter of HSulf-2 activity by digesting its GAG chain. In conclusion, our results highlight HSulf-2 as a proteoglycan-related enzyme and its GAG chain as a critical non-catalytic modulator of the enzyme activity. These findings contribute to clarifying the conflicting data on the activities of the Sulfs.

Dermatan Sulfate Affects Breast Cancer Cell Function via the Induction of Necroptosis.

Dermatan sulfate (DS) is widespread in the extracellular matrix (ECM) of animal tissues. This glycosaminoglycan is characterized by a variable structure, which is reflected in the heterogeneity of its sulfation pattern. The sulfate groups are responsible for the binding properties of DS, which determine an interaction profile of this glycan. However, the detailed role of DS in biological processes such as the neoplasm is still poorly understood. The aim of the study was to assess the effects of the structural variants of DS on breast cancer cells. We found that DS isoforms from normal and fibrotic fascia as well as from intestinal mucosa were able to quickly induce oxidative stress in the cytoplasm and affect the mitochondrial function in luminal breast cancer cells. Moreover, the variants caused the necroptosis of the cells most likely via the first of these mechanisms. This death was responsible for a reduction in the viability and number of breast cancer cells. However, the dynamics and intensity of all of the DS variants-triggered effects were strongly dependent on the cell type and the structure of these molecules. The most pronounced activity was demonstrated by those variants that shared structural features with the DS from the tumor niche.

Correlation analysis of Trial of Org 10172 in acute stroke treatment classification and National Institutes of Health Stroke Scale score in acute cerebral infarction with risk factors

SUMMARY OBJECTIVE: The aim of this study was to investigate the correlation between the Trial of Org 10172 in acute stroke treatment classification and the National Institutes of Health Stroke Scale score of acute cerebral infarction as well as acute cerebral infarction's risk factors. METHODS: The clinical data of 3,996 patients with acute cerebral infarction hospitalized in Hebei Renqiu Kangjixintu Hospital from January 2014 to November 2018 were analyzed retrospectively. According to Trial of Org 10172 in acute stroke treatment, they were divided into five groups: arteriosclerosis, cardio cerebral embolism, arterial occlusion, other causes, and unknown causes. Through questionnaire design, routine physical examination, and physical and chemical analysis of fasting venous blood samples, the risk factors were evaluated, and the correlation between Trial of Org 10172 in acute stroke treatment classification and National Institutes of Health Stroke Scale classification was analyzed using multivariate logistic regression. In addition, the relationship between National Institutes of Health Stroke Scale score and risk factors in different groups was compared, and the correlation between Trial of Org 10172 in acute stroke treatment classification and National Institutes of Health Stroke Scale score was analyzed. RESULTS: Multivariate logistic regression analysis showed that diabetes, atrial fibrillation or stroke history, age, and education level were related to Trial of Org 10172 in acute stroke treatment classification. In the National Institutes of Health Stroke Scale comparison, the scores of the cardio cerebral embolism group were significantly higher than those of the other four groups, and patients with diabetes, atrial fibrillation, or stroke history had a high share, especially atrial fibrillation (33.06%). CONCLUSIONS: The nerve function defect is more serious after acute cerebral infarction with cardiogenic cerebral embolism, indicating a poor prognosis.

Exploring the sulfate patterns of chondroitin sulfate/dermatan sulfate and keratan sulfate in human pancreatic cancer.

This study was designed to explore the sulfation patterns of chondroitin sulfate (CS)/dermatan sulfate (DS), and keratan sulfate (KS) and the expression of carbohydrate sulfotransferases (CHSTs) in 26 pancreatic tumor and normal tissues. CS/DS and KS profiles were simultaneously determined. Pancreatic tumor tissues exhibited increased ΔDi-0S, ΔDi-4S, and ΔDi-6S levels, with absolute ΔDi-4S content being highest, followed by ΔDi-6S. However, as for the contents of KS-6S and KS-6S,6'S, there were no significant regular change. The expression levels of CHST1 and CHST4 were 37 and 15 times higher than those in normal tissues. PCA and OPLS-DA revealed that ΔDi-4S and ΔDi-6S levels could be reliably used to differentiate between healthy and cancerous tissues. The up-regulation of CHST3, CHST12, CHST13, and CHST15 was directly correlated with C-4 and C-6 sulfation. These data provide a foundation for future studies of the role of ΔDi-4S and ΔDi-6S in the progression of pancreatic cancer.

[Danaparoid Sodium Controlled Chronic Disseminated Intravascular Coagulation Associated with Chronic Aortic Dissection and Patent False Lumen for a Long Term:Report of a Case].

The management of chronic disseminated intravascular coagulation( DIC) caused by aortic dissection has not yet been established. We report the successful treatment of a case of aortic dissection with a patent false lumen using danaparoid sodium for acute exacerbation of chronic DIC. 2,000 U danaparoid sodium per day has been stabilizing the coagulative and fibrinolytic parameters and has been relieving bleeding tendencies with no side effects for a long term.