[S100A4, a link between metastasis and inflammation].

Chronic inflammation is acknowledged to be a hallmark of neoplasia - both in cancer initiation and metastasis progression. Here we summarise data suggesting that S100A4 is а trigger of the cascade events that establish an inflammatory milieu and provide a potent flame for primary tumour growth and especially for its metastatic dissemination. The S100A4 protein belongs to the S100 superfamily of small Ca^(2+)-binding proteins. Well established function of S100A4 is associated with induction and promotion of tumour metastasis. However, this protein is also involved in the pathogenesis of major human non-communicable diseases (NCD), such as autoimmune diseases, fibrosis, and other disorders. Therefore, we suggest that S100A4 is a common pro-inflammatory factor involved in the pathogenesis of diverse NCD including cancer.

A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4.

S100A4 is implicated in metastasis and chronic inflammation, but its function remains uncertain. Here we establish an S100A4-dependent link between inflammation and metastatic tumor progression. We found that the acute-phase response proteins serum amyloid A (SAA) 1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-κB signaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cell expressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrix metalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulate their own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, they strongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of human and mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins and cytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 or SAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massive infiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samples from colorectal carcinoma patients significantly correlated with reduced overall survival. These data show that SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a link between inflammation and tumor progression.

[Preoperative portal vein embolization: dynamics of portal pressure].

The pressure dynamics was studied in a portal vein (PV) in patients, suffering focal hepatic pathology, to whom portal vein embolization (PVE) was performed as a stage of preparation to radical hepatic resection. In 236 patients the immediate measurement of pressure in a PV was performed intraoperatively before and after PVE, in 26 - catheter for control portography and monitoring of pressure in a PV was left in its trunk for 24 h postoperatively. There was noted a pressure rising in a PV immediately after its embolization by 86.7%, positive correlation was established between PVE volume and pressure gradient in a PV before and after it. While doing monitoring during 24 h there was observed the pressure rising in a PV during 3 h after its embolization with subsequent lowering down to initial. Application of PVE as a preparation procedure for performance of extended hepatic resection, together with enhancement of residual liver minimizes sharp postresectional pressure rising in PV, what constitutes essential factor of the hepatocytes damage of residual hepatic part in immediate postoperative period.

Stem cell quiescence acts as a tumour suppressor in squamous tumours.

In some organs, adult stem cells are uniquely poised to serve as cancer cells of origin. It is unclear, however, whether tumorigenesis is influenced by the activation state of the adult stem cell. Hair follicle stem cells (HFSCs) act as cancer cells of origin for cutaneous squamous cell carcinoma and undergo defined cycles of quiescence and activation. The data presented here show that HFSCs are unable to initiate tumours during the quiescent phase of the hair cycle, indicating that the mechanisms that keep HFSCs dormant are dominant over the gain of oncogenes (such as Ras) or the loss of tumour suppressors (such as p53). Furthermore, Pten activity is necessary for quiescence-based tumour suppression, as its deletion alleviates tumour suppression without affecting proliferation. These data demonstrate that stem cell quiescence is a form of tumour suppression in HFSCs, and that Pten plays a role in maintaining quiescence in the presence of tumorigenic stimuli.

[Results of preoperative embolization of portal vein in patients with biliary hepatic tumors].

The results of preoperative embolization of portal vein (EPV) in 90 patients, operated on for biliary hepatic tumors, were analyzed. In 47 patients Klatskin tumor was revealed, in 29--peripheral cholangiocarcinoma, in 14--tumor of a gallbladder. In all the patients a radical major hepatic resection was planned, a checking hepatic volume (CHHV) did not exceed 40% of a noninvolved parenchyma. The EPV volume have corresponded generally to the planned resection volume. After performance of EPV a pressure in a portal vein have risen by 75%, and later it have had lowered step by step during 24 h. The CHHV index have raised from (354 +/- 72) up to (462 +/- 118) cm3, or from (33 +/- 7) up to (45 +/- 11)%, permitting to perform radical hepatic resection in 79 (87.8%) patients. Thus, application of EPV in patients, suffering biliary hepatic tumors, have permitted to increase the CHHV index after radical resection, and to raise resectability of such tumors.

Glutathione reductase levels in patients with unstable angina.

Experimental evidence suggests that free-radical damage and antioxidant defense may play an important role in the pathogenesis of coronary heart disease. We have examined the association between plasmatic glutathione reductase (GR) levels and the prognosis of patients with unstable angina. We have evaluated 37 patients, under the age of 75, diagnosed with unstable angina and 19 healthy volunteers. The patients were divided into two groups: the first group--10 patients with unstable angina with readmission in the following 6 months--and the second group--27 patients with unstable angina and favourable evolution. GR was measured in dynamics during hospitalization period. After discharge, the patients were monitored and the following data were recorded: months of follow-up, death due to cardiovascular cause and onset of major cardiovascular events. In patients with unstable angina there was a statistically significant higher increase of GR on admission to the values of the control group (p < 0.0001). Subsequently, plasmatic levels begin to decline, so that at discharge, the GR is similar to the control group. Plasmatic levels of GR were statistically significantly lower in patients with unstable angina without cardiovascular event than in patients with readmission in the following months (p < 0.05). In conclusion, patients who experienced unstable angina and without cardiovascular events during follow-up had lower GR plasmatic levels and that GR activity was an independent predictor of cardiovascular events during follow-up.

[Antibacterial therapy in surgical treatment of chronic hepatic abscess].

The results of surgical treatment of 58 patients for chronic hepatic abscess were presented. In patients of the main group hepatic resection was performed and in a control one--sanation and drainage of the abscess cavity. Antibacterial therapy was conducted in patients of both groups before and after operative treatment. The peculiarities and common efficacy of antibacterial therapy depending on the operative treatment kind were noted.

Study of endothelin-1 in acute ischemic stroke.

Endothelins (ETs) are potent vasoconstrictor and may play a role in the pathophysiology of several cardiovascular diseases. Endothelin-mediated vasoconstriction may enhance ischemic neuronal damage. The study aimed to find out whether the plasma ET-1 levels may serve as marker of early ischemic stroke. Plasma ET-1 levels were tested in 20 patients with acute ischemic stroke, mean age 63.7 +/- 5.03 years, 12 men and 8 women, within 24 hours of stroke onset as compared to 10 sex- and age-matched control subjects; only the patients with normal CT-scan at admission were included in the study. Plasma ET-1 was measured by ELISA. The results were statistically analyzed by Student test and a p < 0.05 (95% CI) was considered statistically significant. ET-1 levels in patients with hemiplegia and normal CT-scan at admission were significantly higher as compared to control group (0.0910 +/- 0.0256 pg/mL vs. 0.0490 +/- 0.0185 pg/mL, p < 0.0001) (95% CI). Ischemic stroke is associated with acute and marked increased levels of ET-1 in plasma. This may reflect enhanced production by damaged endothelial cells within the infarcted lesion. ET-1 may be used as additional marker of cerebral ischemia in selected cases to distinguish between the onset of an ischemic stroke and other non-vascular diseases presenting similar symptoms.

The metastasis associated protein S100A4: a potential novel link to inflammation and consequent aggressive behaviour of rheumatoid arthritis synovial fibroblasts.

The metastasis-associated protein S100A4 belongs to the large family of S100 calcium-binding proteins that appear to play regulatory roles in diverse biological activities. Moreover, a prognostic role of S100A4 has been suggested for patients with several types of cancer. Cancer promoting properties for S100A4 have been demonstrated, particularly through its regulation of cell motility, proliferation and apoptosis, as well as by stimulation of angiogenesis and remodelling of the extracellular matrix. Increased expression of S100A4 mRNA has been detected in proliferating synovial fibroblasts in rheumatoid arthritis. Furthermore, strong upregulation of the S100A4 protein in rheumatoid arthritis synovial tissue compared with osteoarthritis and control tissues has been demonstrated recently, especially at sites of joint invasion. Several immune and vascular cells were also identified to be producing S100A4 within the synovium. The local upregulation of S100A4 was accompanied by high plasma and synovial fluid concentrations of the S100A4 protein existing in the bioactive oligomeric form in patients with rheumatoid arthritis. Consistent with data from cancer studies, the extracellular S100A4 oligomer appears to be involved in regulation of several matrix-degrading enzymes and modulation of the transcriptional activation function of the tumour suppressor protein p53 in rheumatoid arthritis synovial fibroblasts. Taken together, one can speculate that increased S100A4 protein in circulation and locally at sites of inflammation, particularly at sites of joint destruction, might be linked to the process of aggressive fibroblast behaviour contributing to the pathogenesis of chronic autoinflammatory diseases such as rheumatoid arthritis.

S100A4 is expressed at site of invasion in rheumatoid arthritis synovium and modulates production of matrix metalloproteinases.

The metastasis-associated protein S100A4 promotes the progression of cancer by regulating the remodelling of the extracellular matrix. The expression of S100A4 in vivo is shown and the functional role of S100A4 in the pathogenesis of osteoarthritis and rheumatoid arthritisis is explored. The expression of S100A4 in rheumatoid arthritis, osteoarthritis and normal synovial tissues was determined by immunohistochemistry. The expression of matrix metalloproteinase (MMP) mRNA was measured in rheumatoid arthritis and osteoarthritis synovial fibroblasts treated and untreated with S100A4 oligomer by real-time polymerase chain reaction. Levels of released MMPs were confirmed by ELISA in cell culture supernatants. S100A4 protein was expressed in rheumatoid arthritis and osteoarthritis synovial tissues, in contrast with normal synovium. S100A4 up regulated MMP-3 mRNA in rheumatoid arthritis synovial fluid, with a peak after 6 h. This resulted in release of MMP-3 protein. MMP-1, MMP-9 and MMP-13 mRNA were also up regulated in synovial fluid, but with different kinetics. MMP-14 mRNA showed no change. Thus, S100A4 protein is expressed in synovial tissues of patients with rheumatoid arthritis and osteoarthritis in contrast with healthy people. It induces the expression and release of MMP-3 and other MMPs from synovial fluid. The data suggest that S100A4-producing cells could be involved in the pathogenesis of osteoarthritis and rheumatoid arthritis, including pannus formation and joint destruction.

The association of meniscal pathologic changes with cartilage loss in symptomatic knee osteoarthritis.

OBJECTIVE: To explore the role of meniscal tears and meniscal malposition as risk factors for subsequent cartilage loss in subjects with symptomatic osteoarthritis (OA). METHODS: Study subjects were patients with symptomatic knee OA from the Boston Osteoarthritis of the Knee Study. Baseline assessments included knee magnetic resonance imaging (MRI) with followup MRI at 15 and 30 months. Cartilage and meniscal damage were scored on MRI in the medial and lateral tibiofemoral joints using the semiquantitative whole-organ magnetic resonance imaging score. Tibiofemoral cartilage was scored on MR images of all 5 plates of each tibiofemoral joint, and the meniscal position was measured using eFilm Workstation software. A proportional odds logistic regression model with generalized estimating equations was used to assess the effect of each predictor (meniscal position factor and meniscal damage as dichotomous predictors in each model) on cartilage loss in each of the 5 plates within a compartment. Models were adjusted for age, body mass index (BMI), tibial width, and sex. RESULTS: We assessed 257 subjects whose mean +/- SD age was 66.6 +/- 9.2 years and BMI was 31.5 +/- 5.7 kg/m2; 42% of subjects were female, and 77% of knees had a Kellgren/Lawrence radiographic severity grade > or = 2. In the medial tibiofemoral joint, each measure of meniscal malposition was associated with an increased risk of cartilage loss. There was also a strong association between meniscal damage and cartilage loss. Since meniscal coverage and meniscal height diminished with subluxation, less coverage and reduced height also increased the risk of cartilage loss. CONCLUSION: This study highlights the importance of an intact and functioning meniscus in patients with symptomatic knee OA, since the findings demonstrate that loss of this function has important consequences for cartilage loss.

High signal in knee osteophytes is not associated with knee pain.

OBJECTIVE: Our understanding of the local source of pain in osteoarthritis (OA) remains unclear. We undertook this study to determine if the presence of high-signal osteophytes on magnetic resonance imaging (MRI) was associated with pain presence, location or severity. METHODS: Subjects were chosen from the Boston Osteoarthritis of the Knee Study, a natural history study of symptomatic knee OA. Assessments included knee MRI, pain assessments and information on weight and height. Osteophyte signal was defined as areas of increased signal intensity in the osteophyte on fat-suppressed T2 weighted images, and graded in the joint margins where osteophyte size is graded. All patients were evaluated with the frequent knee symptoms question for pain presence, the Western Ontario McMasters Osteoarthritis Index (WOMAC) for pain severity, and location of self-reported pain was recorded as present or absent based on locations identified on a standardized diagram. The osteophyte signal measures anywhere within one given knee were summed, creating an osteophyte signal aggregate. Logistic regression was conducted with quartile of osteophyte signal aggregate as the independent predictor and frequent knee symptom question as the dependent outcome. Association between quartile of osteophyte signal aggregate and pain severity on WOMAC was assessed using a linear regression. Logistic regression was used to evaluate the association between compartment-specific high-signal osteophytes aggregates (independent variable) and compartment-specific knee pain (dependent variable). Analyses were adjusted for gender, body mass index (BMI), and age. RESULTS: Two hundred and seventeen subjects were included in this analysis. They were predominantly male and 75% of subjects had radiographic tibio-femoral (TF) OA, and the remainder had patello-femoral (PF) radiographic OA. We did not find any association of high-signal osteophytes with presence of pain, pain severity or self-reported pain location. CONCLUSION: High-signal osteophytes detected on MRI are not associated with the presence of pain, pain severity or the self-reported location of pain.

The metastasis associated protein S100A4: role in tumour progression and metastasis.

The metastasis associated protein S100A4 is a small calcium binding protein that is associated with metastatic tumors and appears to be a molecular marker for clinical prognosis. Below we discuss its biochemical properties and possible cellular functions in metastasis including cell motility, invasion, apoptosis, angiogenesis and differentiation.

[Activator of metastasis in cancer cells, Mst1/S100A4 protein binds to tumor suppressor protein p53]. / Aktivator metastazirovaniia opukholevykh kletok, belok Mts1/S100A4, sviazyvaetsia s supressorom opukholevogo rosta, belkom p53.

This study for the first time demonstrates a physical and functional interaction between the Ca(2+)-binding protein Mts1/S100A4 and tumor suppressor p53 protein. Using different in vitro and in vivo approaches, we have found that Mts1 can bind to the C-terminal regulatory domain of p53. The Mts1 binding to p53 promotes activation of the reporter gene transcription in vivo. A modulation of the p53 target gene (p21/WAF, bax, mdm-2, and thrombospondin-1) expression was observed upon Mts1 induction in the cells expressing the wild-type p53. These results suggest that the ability of Mts1 to enhance p53-dependent apoptosis of tumor cells leads to the decrease/disappearance of the tumor cells expressing the wild-type p53. Thus, Mts1 promotes selection of more aggressive, metastatic phenotype during tumor progression.

Femoral neck and intertrochanteric fractures: radiographic indicators of fracture healing.

Serial hip radiographs from 280 patients with proximal femoral fractures were analyzed retrospectively by 3 radiologists to evaluate conventional radiographic healing patterns. Patients with hemiarthroplasty or insufficient follow-up were excluded. In the remaining 41 patients, the fracture line and callus was assessed. Intertrochanteric fractures demonstrated increasing callus and sclerosis at the fracture site. No such association was seen in femoral neck fractures. Traditional indicators of fracture healing cannot be readily applied at the hip. Radiographic features relate more to fracture type and fixation method.

Does osteoporosis classification using heel BMD agree across manufacturers?

The lack of standardization in bone mineral density (BMD) measurements is known. Several studies have been carried out to cross-calibrate the axial dual X-ray absorptiometry (DXA) devices. Recently, a number of peripheral DXA (pDXA) densitometers have been introduced. In this study we evaluated the agreement between two heel DXA devices on BMD and T-scores. A total of 99 females aged 21-78 years (ca. 16 per decade) had their non-dominant heel BMD measured using the PIXI (Lunar Inc.) and the Apollo (Norland Medical) pDXA scanners. The mean BMD values were 0.492 and 0.607 g/cm(2) and the mean T-scores using manufacturers' specified reference data were -0.07 and -0.25 for the PIXI and Apollo, respectively. Both the BMD and T-score intermachine relationships were highly correlated but showed significant nonidentity slopes and non-zero offsets. The diagnostic comparison on T-scores resulted in 86% agreement between the instruments (weighted kappa score of 0.550). Normalizing the reference peaks and SDs using this study's young adult population BMD results removed the systematic T-score disagreement. We found that PIXI and Apollo are highly correlated. Differences in BMD values are mainly due to different region of interest (ROI) definitions and additional T-score disagreement reflects the difference in normative databases.

Assessment of bone status using speed of sound at multiple anatomical sites.

Studies in vitro and in vivo have shown that quantitative ultrasound (QUS) is a valid tool for the assessment of bone status. Current QUS methods using the transmission technique are limited to one peripheral bone site. A new system, Sunlight Omnisense (Omnisense, Sunlight Medical Ltd., Rehovot, Israel), measures speed of sound (SOS, in m/s) along the surface of the bone based on an axial transmission technique. The Omnisense can measure SOS at several anatomical sites. This study evaluated the SOS at different anatomical sites in a healthy population. A total of 334 adult women from three research centers in the USA and Canada with a mean (+/- SD) age of 48.8 (+/- 17.4) years were enrolled in this study. SOS was measured at the proximal third phalanx, distal one third radius, midshaft tibia, and fifth metatarsal. The mean SOS (+/- SD) values for the phalanx, radius, tibia and metatarsal were 3984 (+/- 221), 4087 (+/- 147), 3893 (+/- 150) and 3690 (+/- 246) m/s, respectively. Each anatomical site SOS was significantly different (p < 0.001) from that of the other sites. SOS at the different anatomical sites was modestly, but significantly, correlated (r = 0.31 to 0.56, p < 0.001). Similar correlation coefficients were obtained for the T scores. The mean T scores for subjects over the age of 60 years were -1.94, -2.01, -0.97 and -1.42 for the phalanx, radius, tibia and metatarsal, respectively. The age of peak SOS and the rate of change thereafter varied with anatomical site, implying that the prevalence of osteopenia and osteoporosis was site-dependent if only one T score cut-off point was used. Comparing individuals, 10% to 17% of patients had T scores that differed by more than a factor of 2 between sites. Weight and age were some of the contributing factors to this heterogeneity. The Omnisense provides an opportunity to assess bone status at different anatomical sites. Whether or not combining measurements from all these anatomical sites will improve osteoporosis management still needs to be determined.

The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor.

The involvement of Mts1(S100A4), a small Ca(2+)-binding protein in tumor progression and metastasis had been demonstrated. However, the mechanism by which mts1(S100A4) promoted metastasis had not been identified. Here we demonstrated that Mts1(S100A4) had significant stimulatory effect on the angiogenesis. We detected high incidence of hemangiomas--benign tumors of vascular origin in aged transgenic mice ubiquitously expressing the mts1(S100A4) gene. Furthermore, the serum level of the Mts1(S100A4) protein increased with ageing. Tumors developed in Mts1-transgenic mice revealed an enhanced vascular density. We showed that an oligomeric, but not a dimeric form of the Mts1(S100A4) protein was capable of enhancing the endothelial cell motility in vitro and stimulate the corneal neovascularization in vivo. An oligomeric fraction of the protein was detected in the conditioned media as well as in human serum. The data obtained allowed us to conclude that mts1(S100A4) might induce tumor progression via stimulation of angiogenesis.

Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction.

A physical and functional interaction between the Ca(2+)-binding protein Mts1 (S100A4) and the tumor suppressor p53 protein is shown here for the first time. We demonstrate that Mts1 binds to the extreme end of the C-terminal regulatory domain of p53 by several in vitro and in vivo approaches: co-immunoprecipitation, affinity chromatography, and far Western blot analysis. The Mts1 protein in vitro inhibits phosphorylation of the full-length p53 and its C-terminal peptide by protein kinase C but not by casein kinase II. The Mts1 binding to p53 interferes with the DNA binding activity of p53 in vitro and reporter gene transactivation in vivo, and this has a regulatory function. A differential modulation of the p53 target gene (p21/WAF, bax, thrombospondin-1, and mdm-2) transcription was observed upon Mts1 induction in tet-inducible cell lines expressing wild type p53. Mts1 cooperates with wild type p53 in apoptosis induction. Our data imply that the ability of Mts1 to enhance p53-dependent apoptosis might accelerate the loss of wild type p53 function in tumors. In this way, Mts1 can contribute to the development of a more aggressive phenotype during tumor progression.