HA Level Research Articles

High prevalence of CD44 and its ligand low molecular weight hyaluronan in plasma of HNSCC patients: clinical significance.

This study aims to evaluate the role of cancer stem cell marker, CD44, and its ligand HA as potential molecular biomarker for early detection of HNSCC. The expression profile (mRNA/Protein) of CD44 variants were analysed in primary HNSCC lesions and plasma of the patients. Then, prevalence of HA variants was analysed in plasma of the patients. The mRNA expression of CD44 variants, CD44S and CD44v3, were significantly high in both early (stage I/II) and late (stage III/IV) invasive lesions, with predominant expression of CD44v3 in the late-stage lesions. In plasma of HNSCC patients, increased levels of SolCD44, CD44-ICD and unique 62 KD CD44 variants with respect to standard CD44S were seen, in comparison to their prevalence in plasma of normal individuals. The abundance of CD44-ICD and 62 KD variants were significantly high in plasma of late stage HNSCC patients. Interestingly, significantly high level of low molecular weight HA(LMW HA) with respect to high molecular weight HA(HMW HA) was seen in plasma of HNSCC patients irrespective of clinical stages. On the contrary, high HMW HA level in plasma of normal individuals was seen. The high level of LMW HA in plasma of HNSCC patients might be due to combinatorial effect of increased mRNA expression of HA synthesizing enzyme HAS1/2/3 and HA degrading enzyme HYAL1/2, as seen in the primary HNSCC samples. Thus, our data revealed the importance of specific CD44 and HA variants in plasma of HNSCC patients during its development as potential non-invasive molecular biomarker of the disease.

Absent ventriculo-atrial conduction during right ventricular apical pacing but nodal response during para-Hisian pacing – What is the mechanism?

A 13-year-old-girl presented with one episode of pre-syncope while standing in a train. Her ECG was suggestive of preexcitation. Echocardiography revealed structurally normal heart without any ventricular hypertrophy. During electrophysiology study, her ventriculo-atrial (VA) conduction was absent even on isoprenaline. However, a para-Hisian pacing maneuver (PHP) revealed consistent VA conduction with a nodal response. This finding indicated that the VA dissociation at baseline was at infra-Hisian (VH) level and conduction at HA level was intact. In addition, this finding is coherent with a speculation of a fasciculo-ventricular pathway (FVP) resulting in such an ECG pattern in her. Pacing from various atrial sites (right atrium, coronary sinus) exhibited nearly fixed preexcitation and short non-varying HV interval confirmatory of FVP. Testing for a PRKAG mutation was advised for her.

Steady state plasma and tissue distribution of low molecular weight hyaluronic acid after oral administration in mice

The oral administration is probably the most used and largely applicable method, even if absorption across the intestinal epithelium is a limiting factor that can invalidate the achievement of a therapy. The aim of this study was to assess the steady state bioavailability of very low molecular weight hyaluronic acid (vLMW-HA) and its distribution in different districts of mice. Adult female C57BL6/J mice (n = 26) were divided in three groups and orally treated for 7 days with: saline solution (SHAM-HA), high dose of vLMW-HA (5 kDa; 500 mg/kg/day; HD-vLMW-HA), and low dose of vLMW-HA (5 kDa; 100 mg/kg/day; LD-vLMW-HA). HA content was quantified in plasma, skin, bladder, gut, rectum, vagina, and eyes with ELISA assay at the end of treatment. HA level significantly increased after treatment with HD-vLMW-HA in all analyzed tissues and plasma. Therefore, vLMW-HA easy absorption and distribution after the oral intake opens new possibilities for future biomedical applications.

Cyclic solubilization and release of polycyclic aromatic hydrocarbons (PAHs) using gemini photosensitive surfactant combined with micro-nano bubbles: a promising enhancement technology for groundwater remediation

Polycyclic aromatic hydrocarbons (PAHs) have posed serious risks to the groundwater environment. Surfactant-enhanced remediation (SER) is a promising strategy, as it can increase the solubilization efficiency of PAHs contaminants. However, this technology is still hampered due to low efficiency and high cost for the separation of pollutants after solubilization. Through the combination of micro-nano bubbles (MNBs) with a gemini photosensitive surfactant (N1, N2-bis[4-[4-[(4-butylphenyl) azo] phenoxy] butyl]-N1, N2-tetramethylethane-1,2-diammonium bromide, AzoPBT), herein we present a significantly enhanced efficiency of phenanthrene (Phe) solubilization and surfactant cycling. Notably, the presence of MNBs was conducive to the dissolution and release of Phe by reducing the CMC and γ of trans-AzoPBT (from 0.52 mmol/L and 28.94 mN·m−1 to 0.39 mmol/L and 27.88 mN·m−1) and increasing the difference of interfacial properties between trans and cis-AzoPBT, which was owing to the electrostatic interaction. Groundwater chemical parameters, i.e., ions, pH and organic matter would affect the solubilization ability of trans-AzoPBT. Mg2+ and Ca2+ inhibited the solubilization while SO42− promoted the solubilization, depending on their radius, electronic quantity and solution pH. A change in the HA level up to 8 mg/L had a negatively effect on the solubilization ability. High release rate (69.39 %) of cis-AzoPBT for Phe and high recovery rate (89.37 %) for tans-AzoPBT were obtained in the AzoPBT/MNBs mixed aqueous solution. Compared to MNBs combined with conventional cationic surfactants, AzoPBT/MNBs mixed aqueous solution exhibited better synergistic solubilization performance, and the apparent solubility of Phe increased from 26.74 % to 31.61 %. Overall, this study demonstrates the enhanced solubilization of PAHs by photosensitive surfactants combined with MNBs, which provides valuable insights of the effective utilization of surfactants in the remediation of PAHs-contaminated groundwater with SER technology.

Serum syndecan-1, hyaluronan and thrombomodulin levels in patients with lupus nephritis.

We investigated circulating syndecan-1, HA and thrombomodulin levels in patients with biopsy-proven Class III/IV ± V LN and their clinico-pathological associations. Patients with non-renal SLE or non-lupus chronic kidney disease, and healthy subjects served as controls. Serum syndecan-1, HA and thrombomodulin levels were determined by ELISAs. Syndecan-1, HA and thrombomodulin levels were significantly higher during active LN compared with remission (P < 0.01, for all), and correlated with the level of proteinuria, estimated glomerular filtration rate, anti-dsDNA antibodies, complement 3 and serum creatinine. Longitudinal studies showed that syndecan-1 and thrombomodulin levels increased prior to clinical renal flare by 3.6 months, while HA level increased at the time of nephritic flare, and the levels decreased in parallel with treatment response. Receiver operating characteristic curve analysis showed that syndecan-1 and thrombomodulin levels distinguished patients with active LN from healthy subjects, LN patients in remission, patients with active non-renal lupus and patients with non-lupus chronic kidney disease (receiver operating characteristic area under curve of 0.98, 0.91, 0.82 and 0.95, respectively, for syndecan-1; and area under curve of 1.00, 0.84, 0.97 and 0.79, respectively, for thrombomodulin). HA level distinguished active LN from healthy subjects, LN patients in remission and non-lupus chronic kidney disease (receiver operating characteristic area under curve of 0.82, 0.71 and 0.90, respectively) but did not distinguish between renal vs non-renal lupus. Syndecan-1 and thrombomodulin levels correlated with the severity of interstitial inflammation, while HA level correlated with chronicity grading in kidney biopsies of active LN. Our findings suggest potential utility of serum syndecan-1, thrombomodulin and HA levels in clinical management, and their potential contribution to LN pathogenesis.

Dynamic thiol/disulphide homeostasis as indicator of oxidative stress in automotive workers

Purpose: To examine thiol-disulphide homeostasis auto painters.Materials and methods: A total of 115 male workers, including 60 auto painters workers and 55 reference group, of the painting and assembly line units respectively, were included in the study. Thiol-disulphide parameters and ischaemia-modified albumin (IMA) of groups were determined. Urinary hippuric acid, (HA) phenol, hexanedione, trichloroacetic acid, arsenic and blood lead and manganese were analysed.Results: The median urinary HA level was significantly higher in auto painters when compared to the reference group [(2461 (1212) vs. 520 (513) µgr/L), (p < 0.001)] . The mean disulphide level [19.7 (4.3) vs 0.15.1(4.1) μmol/L, (p < 0.001)], the disulphide/native thiol ratio [4.72 (1.47) vs. 3.13 (1.21, (p < 0.001)] and the disulphide/total thiol ratio [4.31 (1.23) vs. 2.94 (1.06), (p < 0.001)] were higher in auto painters when compared to the reference group. There was a statistically significant positive correlation between urinary HA and disulphide concentrations (r = 0.536 and p < 0.001), disulphide/native thiol ratio (r = 0.564 and p < 0.001) and the disulphide/total thiol ratio (r = 0.564 and p < 0.001) and IMA (r = 0.396 and p < 0.001).Conclusion: The results presented in this study showed that oxidative stress can be associated with occupational exposure to toluene denoted by alteration of thiol disulphide homeostasis and ischaemia-modified albumin levels.

Circulating miRNAs as footprints for liver fibrosis grading in schistosomiasis.

BackgroundChronic infection with Schistosoma japonicum or S. mansoni results in hepatic fibrosis of the human host. Staging fibrosis is crucial for the prognosis and to determine the rapid need of treatment in patients with schistosomiasis.MethodsTo establish whether there is a correlation between circulating microRNA (miRNA) level and fibrosis progression in schistosomiasis, ten miRNAs were selected to assess their potential in grading schistosomiasis liver fibrosis. This was done firstly in two mouse strains (C57BL/6 and BALB/c) to determine the temporal expression profiles in serum over the course of S. japonicum infection, and then within a cohort of 163 schistosomiasis japonica patients with different grades of liver fibrosis.FindingFour miRNAs (miR-150-5p, let-7a-5p, let-7d-5p and miR-146a-5p) were able to distinguish patients with mild versus severe fibrosis. The level of serum miR-150-5p showed the most promising potential for grading hepatic fibrosis in schistosomiasis. The diagnostic performance of miR-150-5p in discriminating mild from severe fibrosis is comparable with that of the ELF test and serum HA level. In addition, the serum levels of the four miRNAs rebounded in infected C57BL/6 mice, after 6 months post treatment, following the regression of liver fibrosis, thereby providing further support for the utility of these miRNAs in grading schistosomal hepatic fibrosis.Interpretation.Circulating miRNAs can be a supplementary tool for assessing hepatic fibrosis in human schistosomiasis.FundNational Health and Medical Research Council (NHMRC) of Australia (APP1102926, APP1037304 and APP1098244).

Relationship between the endothelial glycocalyx and the extent of coronary atherosclerosis

To investigate the correlation between the EG and the severity of coronary atherosclerosis. A total of193 subjects were divided into two groups. A SDF video microscope with a glycocalyx thickness measurement system was used to visualize the sublingual microcirculation. The levels of HA in the peripheral circulation and coronary circulation were determined via enzyme-linked immunosorbent assay. The number of coronary artery lesions and the Gensini score were used to evaluate the severity of the coronary atherosclerosis. EG thickness in the coronary heart disease (CHD) group (242.18±10.10nm) was lower than that in the NON-CHD group (251.78±10.59nm, P<0.001). There was a negative correlation between the EG thickness and the number of coronary lesions and the Gensini score. The level of intracoronary HA in the CHD group (48.60, 126.27) was higher than that in the NON-CHD group (20.60, 34.45, P<0.001), and it was positively correlated with the number of coronary lesions and the Gensini score. EG damage was correlated with the occurrence and development of coronary atherosclerosis. The EG thickness in the capillaries of the oral submucosa and the intracoronary HA level can be used as auxiliary indexes to assess the severity of coronary atherosclerosis.

Hyaluronic Acid Is a Biomarker for Allograft Dysfunction and Predicts 1-Year Graft Loss After Liver Transplantation

BackgroundAllograft dysfunction after liver transplantation has a profound impact on the risks of death and retransplantation within the first year. We tested whether elevated hyaluronic acid (HA; a glycosaminoglycan cleared by hepatic sinusoidal endothelium) levels may predict excess risk of graft loss. MethodsThis was a retrospective single-center prognostic cohort study. Patients with either a plasma sample before transplantation, an early post-transplantation sample nearest day 30 (range 10–89 d, 80% within days 15–60), or both were included. Plasma HA was measured with the use of enzyme-linked immunosorbent assays. The primary end point was 1-year graft loss (all-cause mortality and retransplantation). A secondary end point was biliary stricture. ResultsIn this study, 169 of 196 patients who received a liver transplant in the study period were included. Pre-transplantation HA (n = 152) did not predict graft loss. Post-transplantation HA (n = 124) was higher among patients with graft loss (median, 177 μg/L [interquartile range (IQR), 89–465] vs 54 μg/L [IQR 37–93]) and was a strong predictor of this outcome (hazard ratio per 50 μg/L, 1.24 [95% confidence interval [CI], 1.14–1.34]). The discriminatory ability of HA was high (area under the receiver operating characteristic curve, 0.86 [95% CI, 0.77–0.94]) and noninferior to other liver function tests. When adjusted for known risk factors of graft loss, HA remained an independent predictor of graft loss. ConclusionsHigh post-transplantation plasma HA level was a strong predictor of 1-year all-cause mortality and retransplantation, whereas pre-transplantation levels were not, despite variety in the time span of blood sampling. Prospective studies are warranted to assess the utility of HA in liver transplantation.

Effects of humic substances on Fe(II) sorption onto aluminum oxide and clay

We studied the effects of humic substances (HS) on the sorption of Fe(II) onto Al-oxide and clay sorbents at pH 7.5 with a combination of batch kinetic experiments and synchrotron Fe K-edge EXAFS analyses. Fe(II) sorption was monitored over the course of 4 months in anoxic clay and Al-oxide suspensions amended with variable HS types (humic acid, HA; or fulvic acid, FA) and levels (0, 1, and 4 wt%), and with differing Fe(II) and HS addition sequences (co-sorption and pre-coated experiments, where Fe(II) sorbate was added alongside and after HS addition, respectively). In the Al-oxide suspensions, the presence of HS slowed down the kinetics of Fe(II) sorption, but had limited, if any, effect on the equilibrium aqueous Fe(II) concentrations. EXAFS analyses revealed precipitation of Fe(II)–Al(III)-layered double hydroxide (LDH) phases as the main mode of Fe(II) sorption in both the HA-containing and HA-free systems. These results demonstrate that HS slow down Fe(II) precipitation in the Al-oxide suspensions, but do not affect the composition or stability of the secondary Fe(II)–Al(III)-LDH phases formed. Interference of HS with the precipitation of Fe(II)–Al(III)-LDH was attributed to the formation organo-Al complexes HS limiting the availability of Al for incorporation into secondary layered Fe(II)-hydroxides. In the clay systems, the presence of HA caused a change in the main Fe(II) sorption product from Fe(II)–Al(III)-LDH to a Fe(II)-phyllosilicate containing little structural Al. This was attributed to complexation of Al by HA, in combination with the presence of dissolved Si in the clay suspension enabling phyllosilicate precipitation. The change in Fe(II) precipitation mechanism did not affect the rate of Fe(II) sorption at the lower HA level, suggesting that the inhibition of Fe(II)–Al(III)-LDH formation in this system was countered by enhanced Fe(II)-phyllosilicate precipitation. Reduced rates of Fe(II) sorption at the higher HA level were attributed to surface masking or poisoning by HA of secondary Fe(II) mineral growth at or near the clay surface. Our results suggest that HS play an important role in controlling the kinetics and products of Fe(II) precipitation in reducing soils, with effects modulated by soil mineralogy, HS content, and HS properties. Further work is needed to assess the importance of layered Fe(II) hydroxides in natural reducing environments.

Effectiveness of clinical pathway for treatment of advanced schistosomiasis hepatic fibrosis

Objective To assess the effectiveness of the clinical pathway for the treatment of advanced schistosomiasis hepatic fibrosis. Methods The duration of hospital stay, gross hospitalization expense, individual-paid expense, interior diameter of portal vein, levels of four serum hepatic fibrosis-related parameters (PIIIP, CIV, HA, and LN), and activities of ALT, AST and γ-GT were assessed and compared between the advanced schistosomiasis patients receiving the clinical pathway and ones receiving non-clinical pathway. Results There were 142 advanced schistosomiasis patients with hepatic fibrosis receiving the clinical pathway of anti-hepatic fibrosis. Compared with the patients receiving non-clinical pathway, the gross hospitalization expenses reduced by 11.2% (t = 6.310, P < 0.05), and the individual-paid expenses reduced by 16.1% (t = 4.326, P < 0.05). The mean HA level was twice higher than the normal range, with a positive rising from 70.4% to 83.1%, and the abnormal rates of CIV and γ-GT were 64.1% and 28.9% respectively. Conclusions The clinical pathway can drastically reduce the treatment expenses in advanced schistosomiasis patients with hepatic fibrosis. However, the patients have a trend towards the persistent disease progression. Therefore, the researches of more effective therapeutic methods for advanced schistosomiasis hepatic fibrosis are urgently needed.

Fibrosis 4 Score Versus Hyaluronic Acid as Non-Invasive Tools for Assessment of HCV-Related Hepatic Fibrosis: Correlation with Quantitative Morphometric Analysis of Liver Biopsy

1.1.Background & Aims: Unlike the ordinal METAVIR system, morphometry can be used for quantitative assessment of hepatitis C virus (HCV)-related liver fibrosis. However, due to its invasive nature, we tried to study two non-invasive tools for this assessment; namely FIB-4 score and HA level. 1.2.Patients & methods: This study enrolled 99 chronic HCV patients with examination of their biopsy specimens by METAVIR system. Morphometry was performed by the fully automated Leica Qwin image processor and software 2004, Germany. Serum hyaluronic acid was measured using ELISA-based technique and FIB-4 score was calculated using Sterling’s formula. 1.3.Results: Fibrosis percentage quantified by morphometry increases as fibrosis advances. Also, it has significantly positive correlation with serum level of HA (r= .248, p=0.013), as well as FIB4-score (r=.481, p< 0.0001). The cut off values of morphometry fibrosis percentage, FIB-4 score, and HA level for diagnosis of advanced fibrosis (F≥3) are 8.35%, 1.63, and 46.5 ng/ml, respectively. Their diagnostic accuracy has AUC of 0.88, 0.91, & 0.73, respectively. Their sensitivity and specificity are 83% & 91% for morphometry, 83% & 90% for Fib-4 score, and 67% & 85% for HA level. Sensitivities of morphometry and FIB-4 score were not significantly different (p=0.549) while both were significantly better than that of HA (p=0.003 and 0.015, respectively). 1.4.Conclusion: Morphometry is a precise tool for measuring advanced hepatic fibrosis. Although there was significant positive correlation between morphometry fibrosis percent, serum hyaluronic acid level and FIB-4 score, both morphometry and FIB-4 score were better diagnostic tests for advanced fibrosis than HA.

Hyaluronic Acid Predicts Postoperative Large Amount of Ascites after Liver Resection for Patients with Hepatocellular Carcinoma

Background/Aims: Postoperative large amount of ascites (PLA) is a postoperative complication in patients undergoing liver resection (LR) for hepatocellular carcinoma (HCC) and can lead to poor prognosis. The purpose of this study is to investigate predictor and prognosis of patients with PLA. Methods: Four hundred HCC patients undergoing LR were divided into 2 groups: Group A, patients without PLA; Group B, patients with PLA. Statistical analysis was performed to assess the clinical features associated with PLA and to compare the survival between Groups A and B. Results: Multivariate analysis revealed that body mass index (≤22 kg/m²), albumin (≤3.5 g/dl), hyaluronic acid (HA; >200 ng/ml), bleeding (>620 ml) and total intraoperative in-out balance (>5.0 ml/kg/h) were associated with PLA. HA (>200 ng/ml) was the most useful predictor of PLA, because the area under the receiver operating characteristic curve of HA was the highest among these 5 features. The relapse-free, cancer-specific and overall survival rates were poorer in Group B than in Group A. Conclusion: The serum HA level (>200 ng/ml) is a useful predictor of PLA in HCC patients undergoing LR. As PLA leads to poor prognosis, the surgical method for HCC patients with an elevated serum HA level should be carefully considered.

Abstract B86: Pegylated recombinant human hyaluronidase PH20 (PEGPH20) enhances nab-paclitaxel plus gemcitabine efficacy in human pancreatic cancer xenografts

Abstract Hyaluronan (HA) over-accumulation in the extracellular matrix (ECM) of many solid tumors is associated with tumor progression and poor prognosis. Accordingly, an HA-degrading enzyme, PEGPH20, is being developed to deplete tumor-associated HA in the ECM. In preclinical animal models, enzymatic removal of ECM HA with PEGPH20 is associated with remodeling of the tumor stroma, reduction of tumor interstitial fluid pressure, expansion of tumor blood vessels and facilitated delivery of chemotherapy. As pancreatic ductal adenocarcinoma (PDA) has been identified as a cancer type that accumulates high levels of HA, and the combination of albumin-bound paclitaxel (nab-paclitaxel, NAB) and gemcitabine (GEM) has been shown to improve survival in patients with metastatic pancreatic cancer (Von Hoff 2013), preclinical studies were conducted using human PDA xenograft models to investigate whether PEGPH20 enhanced the anti-tumor activity of NAB and GEM. In brief, nude mice were inoculated with human BxPC3 PDA cells, or with HA-high BxPC3/HAS3 cells, a cell line engineered to over-express HA, adjacent to the right tibial periosteum. Tumor growth was monitored via ultrasonography. When tumors reached ~350 mm3, mice were staged into 8 treatment groups: (1) vehicle control; (2) PEGPH20 alone, 4.5 mg/kg; (3) NAB alone, 10 mg/kg; (4) GEM alone, 180 mg/kg; (5) NAB plus PEGPH20; (6) GEM plus PEGPH20; (7) NAB plus GEM; and (8) NAB plus GEM plus PEGPH20. Vehicle, PEGPH20 and/or NAB was administered intravenously starting on study day 0, and then dosed twice weekly for four weeks. GEM was administered intraperitoneally starting on study day 1 and then dosed weekly for three weeks. Histology of tumors confirmed HA removal in all PEGPH20 treated groups. In the parental BxPC3 model, the addition of PEGPH20 increased the anti-tumor efficacy of NAB plus GEM by 15% (81% vs. 66%, respectively) and extended median survival time (MST) by &amp;gt;31% (68d vs. 52d, respectively); whereas in the HA-high BxPC3/HAS3 model, PEGPH20 increased the anti-tumor efficacy of NAB plus GEM by 34% (104% vs. 70%) and extended MST by &amp;gt;125% (72d vs. 32d, respectively). As Jacobetz et al. (2013) have shown that PEGPH20 treatment increases the intratumoral delivery of GEM in genetically engineered mouse PDA models; we evaluated whether PEGPH20 also improves intratumoral accumulation of paclitaxel in the BxPC3/HAS3 model vs. NAB alone. The co-administration of PEGPH20 with NAB increased intratumoral paclitaxel accumulation by &amp;gt;43% one hour following a single administration. Further, PEGPH20 enhanced NAB plus GEM mediated reduction in the PDA serum biomarkers CA19-9 and CEA in both models. As KRAS mutations occur in 90% of non neuro-endocrine pancreatic tumors (Thomas 2007), and BxPC3 cells are KRAS WT, we repeated these studies in KRAS mutant/HA-low AsPC1 xenografts, and engineered KRAS mutant/HA-high AsPC1/HAS3 PDA xenografts. Mice were inoculated and tumor growth was monitored as described above. Animals were then staged into 8 groups and then dosed when tumors reached ~350 mm3. The PEGPH20 dose in these studies was reduced to 37.5 μg/kg to approximate dosing in ongoing clinical trials (NCT01839487). As predicted by tumor HA level, the addition of PEGPH20 did not increase the anti-tumor efficacy or survival in the HA-low parental AsPC1 model. In the HA-high AsPC1/HAS3 model, the addition of PEGPH20 increased the anti-tumor efficacy of NAB plus GEM by 25% (78% vs. 53%, respectively) and extended MST by &amp;gt;31% (74d vs. 48d, respectively). Taken together, the data suggest that PEGPH20-mediated HA removal significantly increases the anti-tumor efficacy of NAB plus GEM in HA-high mouse models of PDA. Clinical trials are currently ongoing to evaluate PEGPH20 plus NAB plus GEM in stage IV patients with metastatic pancreatic cancer (NCT01839487). Citation Format: Ryan J. Osgood, James F. Skipper, Jessica A. Cowell, Yanling Chen, Li Zhu, Michael E. Bledsoe, Susan J. Zimmerman, David W. Kang, H. Michael Shepard, Daniel C. Maneval, Curtis B. Thompson. Pegylated recombinant human hyaluronidase PH20 (PEGPH20) enhances nab-paclitaxel plus gemcitabine efficacy in human pancreatic cancer xenografts. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B86.

Protective Effect of Ischemic Preconditioning on Hepatic Ischemia-Reperfusion Injury in Rats

Aim: Ischemic preconditioning (IPC) protects tissue against ischemia and reperfusion (I/R) injury. The aim of this study was to examine the impact of IPC on protection of hepatocytes after prolonged I/R injury. Methods: Twenty-four Wistar rats were randomly divided into ischemic preconditioning group (IP), ischemia/reperfusion group (IR) and sham operation group (SO). A model of partial liver ischemia/reperfusion was used, in which rats were subjected to liver ischemia for 90 min prior to reperfusion. The animals in the IP group underwent ischemic preconditioning for 10 min prior to the ischemia/reperfusion challenge. After 3 h of reperfusion, serum and liver tissue in each group were collected to detect the level of serum ALT, AST, HA, MDA and liver histopathology. Results: Compared with IR group, IP group showed a significantly lower ALT, AST, HA and MDA level in 3 h. Proliferation index (PI) was significantly increased in IP group compared with IR group. Conclusion: Ischemic preconditioning can protect liver cells against ischemia/reperfusion injury, which may be related to cell proliferation during early ischemic reperfusion.

Material on the basis of partially crosslinked solution of HA derivative for synovial fluid viscosupplementation

Material on the basis of partially crosslinked solution of HA derivative for synovial fluid viscosupplementation

Preoperative serum hyaluronic acid level as a prognostic factor in patients undergoing hepatic resection for hepatocellular carcinoma

Hyaluronic acid (HA) probably plays a critical role in tumorigenesis. The clinical significance of serum HA concentration in patients with hepatocellular carcinoma (HCC) remains to be elucidated. This study analysed the relationship between preoperative serum HA levels and prognosis after hepatic resection in patients with HCC. Consecutive patients who underwent hepatic resection for HCC between September 1999 and March 2012 were included in this retrospective study. Serum HA levels were measured within 4 weeks before surgery by an immunoturbidimetric automated latex assay. The cut-off level for preoperative serum HA was validated using a time-dependent receiver operating characteristic (ROC) curve analysis. The prognostic impact of preoperative serum HA levels was analysed using Cox proportional hazards models. A total of 506 patients of median age 66 years (405 men, 80·0 per cent) were analysed. The median length of follow-up was 32 months. High serum HA levels (100 ng/ml or above) were associated with shorter recurrence-free survival (P < 0·001) (hazard ratio (HR) 1·50, 95 per cent confidence interval 1·17 to 1·93; P = 0·002) and overall survival (P = 0·001) (HR 1·46, 1·03 to 2·07; P = 0·033). In patients with HCC without severe liver fibrosis, serum HA level was correlated with multiple tumours (P = 0·039), early recurrence (P = 0·033), and poor recurrence-free (P < 0·001) and overall (P = 0·024) survival. High preoperative serum HA levels predict poor prognosis in patients with HCC after hepatic resection, and may serve as a future biomarker.

Biochemical and Immunogenetic Diagnostic Markers Less Commonly Used for Predicting the Efficacy of Chronic Hepatitis C Etiotropic Therapy

Introduction: 1,7% of the population of Latvia in 2008 was HCV RNA positive, thus approximately 38 thousands required the CHC antiviral therapy. The objective of the study was to evaluate some biochemical and immunogenetic parameters allowing predicting the efficacy of the etiotropic therapy for CHC patients. Material and methods: Medical records of 213 CHC patients were analyzed. HCV RNA, anti-HCV, concentration of HA, GGT activity were detected and immunogenetic investigations were performed. Results and discussion: Evaluation of GGT activity showed increase in 46,81% of non-responders and in only 21,57% responders. HA level in responders was significantly lower than in non-responders. Correlation between the incidence of HLA class II gene alleles in CHC patients and the type of CHC therapy was found. The results of the study confirmed the hypothesis that some biochemical and immunogenetic parameters characterizing the condition of the macro organism had an essential role in the efficacy of the CHC therapy. Conclusions: The non-efficacy of the CHC etiotropic therapy was associated with increased GGT and HA levels upon the start of the therapy. The efficacy of PEG IFN+RBV combination therapy in comparison with the efficacy of Realdiron therapy was associated with different MHC HLA class II gene alleles.

Chondroitin Sulfate Is a Crucial Determinant for Skeletal Muscle Development/Regeneration and Improvement of Muscular Dystrophies

Skeletal muscle formation and regeneration require myoblast fusion to form multinucleated myotubes or myofibers, yet their molecular regulation remains incompletely understood. We show here that the levels of extra- and/or pericellular chondroitin sulfate (CS) chains in differentiating C2C12 myoblast culture are dramatically diminished at the stage of extensive syncytial myotube formation. Forced down-regulation of CS, but not of hyaluronan, levels enhanced myogenic differentiation in vitro. This characteristic CS reduction seems to occur through a cell-autonomous mechanism that involves HYAL1, a known catabolic enzyme for hyaluronan and CS. In vivo injection of a bacterial CS-degrading enzyme boosted myofiber regeneration in a mouse cardiotoxin-induced injury model and ameliorated dystrophic pathology in mdx muscles. Our data suggest that the control of CS abundance is a promising new therapeutic approach for the treatment of skeletal muscle injury and progressive muscular dystrophies.

Modeling of hyaluronan clearance with application to estimation of lymph flow

One of the important factors in blood pressure regulation is the maintenance of the level of blood volume, which depends on several factors including the rate of lymph flow. Lymph flow can be measured directly using cannulation of lymphatic vessels, which is not clinically feasible, or indirectly by the tracer appearance rate, which is the rate at which macromolecules appear into the blood from the peritoneal cavity. However, indirect lymph flow measurements do not always provide consistent results. Through its contribution to osmotic pressure and resistance to flow, the macromolecule hyaluronan takes part in the regulation of tissue hydration and the maintenance of water and protein homeostasis. It arrives in blood plasma through lymph flow. Lymphatic hyaluronic acid (HA, hyaluronan) concentration is several times higher than that in plasma, suggesting that the lymphatic route may account for the majority of HA found in plasma. Furthermore, circulating levels of HA reflect the dynamic state between delivery to—and removal from—the bloodstream. To develop an accurate estimation of the fluid volume distribution and dynamics, the rate of lymph flow needs to be taken into account and hyaluronan could be used as a marker in estimating this flow. To examine the HA distribution and system fluid dynamics, a six-compartment model, which could reflect both the steady-state relationships and qualitative characteristics of the dynamics, was developed. This was then applied to estimate fluid shifts from the interstitial space via the lymphatic system to the plasma during different physiological stresses (orthostatic stress and the stress of ultrafiltration during dialysis). Sensitivity analysis shows that during ultrafiltration, lymph flow is a key parameter influencing the total HA level, thus suggesting that the model may find applications in addressing the problem of estimating lymph flow. Since the fluid balance between interstitium and plasma is maintained by lymph flow and microvasculature filtration, our novel method of flow estimation may provide an important tool for understanding fluid dynamics during perturbations of the cardiovascular system. Since the fluid balance between interstitium and plasma is maintained by lymph flow and microvasculature filtration, our novel method of flow estimation may provide an important tool for understanding fluid dynamics during perturbations of the cardiovascular system.