Relationship between sedimentation sign and morphological grade in symptomatic lumbar spinal stenosis.

PURPOSE: We aimed to study the relationship between two morphological parameters recently described on MRI images in relation to lumbar spinal stenosis (LSS): the first is the sedimentation sign (SedS) and the second is the morphological grading of lumbar stenosis. MATERIALS AND METHODS: MRIs from a total of 137 patients were studied. From those, 110 were issued from a prospective database of symptomatic LSS patients, of whom 73 were treated surgically and 37 conservatively based on symptom severity. A third group consisting of 27 subjects complaining of low back pain (LBP) served as control. Severity of stenosis was judged at disc level using the four A to D grade morphological classification. The presence of a SedS was judged at pedicle level, above or below the site of maximal stenosis. RESULTS: A positive SedS was observed in 58, 69 and 76% of patients demonstrating B, C and D morphology, respectively, but in none with grade A morphology. The SedS was positive in 67 and 35% of the surgically and conservatively treated patients, respectively, and in 8% of the LBP group. C and D morphological grades were present in 97 and 35% of patients in the surgically and conservatively treated group, respectively, and in 18% of the LBP group. Presence of a positive SedS carried an increased risk of being submitted to surgery in the symptomatic LSS group (OR 3.5). This risk was even higher in the LSS patients demonstrating grade C or D morphology (OR 65). DISCUSSION AND CONCLUSION: One-third of surgically treated LSS patients do not present a SedS. This sign appears to be a lesser predictor of treatment modality in our setting of symptomatic LSS patients compared to the severity of stenosis judged by the morphological grade.

Precision therapy to target apoptosis in prostate cancer.

Androgen-independent prostate cancer shows limited response to existing systemic therapies. Recent advances in prostate-selective targeting of small molecule inhibitors and bacterial toxins have created opportunities to design a new generation of therapies for advanced prostate cancer. Yet prioritizing targets for these therapies remain challenging, since multiple mechanisms contribute to the pathophysiology of androgen-independent prostate cancer. This review explores the possibility of targeting the apoptosis regulatory network as most direct approach to efficient treatment of advanced androgen-independent prostate cancer.

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells.

Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44(+)/CD24(-) cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44(+) CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

Decision-making in lumbar spinal stenosis: A survey on the influence of the morphology of the dural sac.

Surgical decision-making in lumbar spinal stenosis involves assessment of clinical parameters and the severity of the radiological stenosis. We suspected that surgeons based surgical decisions more on dural sac cross-sectional area (DSCA) than on the morphology of the dural sac. We carried out a survey among members of three European spine societies. The axial T2-weighted MR images from ten patients with varying degrees of DSCA and morphological grades according to the recently described morphological classification of lumbar spinal stenosis, with DSCA values disclosed in half the assessed images, were used for evaluation. We provided a clinical scenario to accompany the images, which were shown to 142 responding physicians, mainly orthopaedic surgeons but also some neurosurgeons and others directly involved in treating patients with spinal disorders. As the primary outcome we used the number of respondents who would proceed to surgery for a given DSCA or morphological grade. Substantial agreement among the respondents was observed, with severe or extreme stenosis as defined by the morphological grade leading to surgery. This decision was not dependent on the number of years in practice, medical density or specialty. Disclosing the DSCA did not alter operative decision-making. In all, 40 respondents (29%) had prior knowledge of the morphological grading system, but their responses showed no difference from those who had not. This study suggests that the participants were less influenced by DSCA than by the morphological appearance of the dural sac. Classifying lumbar spinal stenosis according to morphology rather than surface measurements appears to be consistent with current clinical practice.

Disc degeneration: current surgical options.

Chronic low back pain attributed to lumbar disc degeneration poses a serious challenge to physicians. Surgery may be indicated in selected cases following failure of appropriate conservative treatment. For decades, the only surgical option has been spinal fusion, but its results have been inconsistent. Some prospective trials show superiority over usual conservative measures while others fail to demonstrate its advantages. In an effort to improve results of fusion and to decrease the incidence of adjacent segment degeneration, total disc replacement techniques have been introduced and studied extensively. Short-term results have shown superiority over some fusion techniques. Mid-term results however tend to show that this approach yields results equivalent to those of spinal fusion. Nucleus replacement has gained some popularity initially, but evidence on its efficacy is scarce. Dynamic stabilisation, a technique involving less rigid implants than in spinal fusion and performed without the need for bone grafting, represents another surgical option. Evidence again is lacking on its superiority over other surgical strategies and conservative measures. Insertion of interspinous devices posteriorly, aiming at redistributing loads and relieving pain, has been used as an adjunct to disc removal surgery for disc herniation. To date however, there is no clear evidence on their efficacy. Minimally invasive intradiscal thermocoagulation techniques have also been tried, but evidence of their effectiveness is questioned. Surgery using novel biological solutions may be the future of discogenic pain treatment. Collaboration between clinicians and basic scientists in this multidisciplinary field will undoubtedly shape the future of treating symptomatic disc degeneration.

Biodistribution analysis of cisplatin in liposomal form in animals with cisplatin-resistant and cisplatin-sensitive carcinoma.

AIM: To analyze the relation between pharmacokinetics of cisplatin in liposomal form and antitumor efficacy toward cisplatin-resistant and cisplatin-sensitive variants of Guerin carcinoma. METHODS: Concentration of platinum was measured by atomic absorption spectrophotometry (C115M1 "Selmi", Ukraine). Elimination constant was calculated based on the dynamics of cisplatin concentration in time period between 1 h to 24 h using nonlinear regression analysis. Area under curve (AUC24) was calculated by the trapezium method. RESULTS: It was shown that for liposomal form of cisplatin (LCp) AUC24 in tumor practically didn't depend on the level of the tumor sensitivity, while in animals with the resistant variant (CpRGC), AUC24 for free cisplatin (FCp) decreased by 70% less (p < 0.001) as compared to the sensitive tumor strain (CpSGC). Significant decrease of elimination constant of LCp compared to FCp in blood serum of rats bearing either CpRGC or CpSGC tumors favors cisplatin accumulation in tumor tissues with low vascularization level. The dynamics of cisplatin concentration in CpRGC variant was characterized by 90% higher level in 24 h after administration of LCp as compared to FCp (p < 0.05). This fact may explain increased antitumor efficacy of LCp compared to FCp toward CpRGC variant. In the study of kidney function, AUC24 index for LCp was by 68.6% (p < 0.01) and 50.7% (p < 0.05) lower than AUC24 index for FCp in rats with CpRGC and CpSGC variants, respectively. No significant differences have been found in biodistribution of cisplatin in both pharmaceutical forms in liver and lung in CpRGC- or CpSGC-bearing rats. CONCLUSION: The results suggest that cisplatin in liposomal form possesses higher specificity of antitumor action than free cisplatin.

The use of nanoferromagnetics to increase the cytotoxic effect of antitumor drugs.

AIM: To investigate the influence of ferromagnetic nanoparticles on antitumor effect of doxorubicin and mitochondria oxidative phosphorylation. METHODS: The study was carried out on the mice-hybrids (C57Bl/6xDBA/2) with intraperitoneally (i/p) transplantated Ehrlich ascitic carcinoma. Single i/p injection of doxorubicin (Dox), stabilized ferromagnetic nanoparticles (Fe3O4; 20-40 nm; FM) or their combination were performed 7 days after tumor transplantation. The cytotoxic effect of agents, morphology and cell cycle of tumor cells were studied 24, 48 and 72 h after Dox administration. RESULTS: The investigations showed that ferromagnetic nanoparticles increased the cytotoxic effect of doxorubicin on Ehrlich ascsmall i, Ukrainiantic carcinoma mainly 48 h after agents' administration. The largest number of apoptotic cells was observed in group of animals in which doxorubicin was administered before ferromagnetic nanoparticles. Moreover, the ferromagnetic nanoparticles at concentration 1.45 microg Fe/ml and, particularly, 7.25 microg Fe/ml decreased mitochondria oxygen consumption in phosphorylation state that may negatively influence their living capability. CONCLUSIONS: Obtained data point out the perspective of use of certain sized FM nanoparticles to increase the cytotoixc effect of antitumor drugs.

[Ultrastructural organization of carcinoma Lewis (3LL) cells during cisplatin resistance formation].

The electron-microscopic analysis of the morphological status of 3LL (Lewis) carcinoma tumour cells in the process of cisplatin resistant phenotype formation has been performed. It was shown that selection of tumour cells forming cell clones characterized by more complicated nuclear and cytoplasm organization took place. The tumour cells had the diffused nuclear chromatin; nuclear envelope had the numerous pores with expanded diaphragms. The prominent nucleoli consisted of the active centres surrounded by considerable areas of the condensed nucleolar chromatin. Cell cytoplasm contained the well-developed Goldgi complex and the numerous well-structured myelinoid formations in the form of dense-wrapped concentric membrane structures. The obtained data can morphologically confirm the hypothesis of Gately D.P. and Howel S.B., 1993, thain the process of resistant phenotype formation the tumour cells can create the cellular mechanisms to remove the drug from the cell and to correct the damages of the cellular nucleus and cytoplasm.

Alkylphosphonate modified aluminum oxide surfaces.

The surface properties of aluminum, such as chemical composition, roughness, friction, adhesion, and wear, can play an important role in the performance of micro-/nano-electromechanical systems, e.g., digital micromirror devices. Aluminum substrates chemically reacted with octadecylphosphonic acid (ODP/Al), decylphosphonic acid (DP/Al), and octylphosphonic acid (OP/Al) have been investigated and characterized by X-ray photoelectron spectroscopy (XPS), contact angle measurements, and atomic force microscopy (AFM). XPS analysis confirmed the presence of alkylphosphonate molecules on ODP/Al, DP/Al, and OP/Al. No phosphonates were found on bare Al as a control. The sessile drop static contact angle of pure water on ODP/Al and DP/Al was typically more than 115 degrees and on OP/Al typically less than 105 degrees indicating that all phosphonic acid reacted Al samples were highly hydrophobic. The root-mean-square surface roughness for ODP/Al, DP/Al, OP/Al, and bare Al was less than 15 nm as determined by AFM. The surface energy for ODP/Al and DP/Al was determined to be approximately 21 and 22 mJ/m2, respectively, by the Zisman plot method, compared to 25 mJ/m2 for OP/Al. ODP/Al and OP/Al were studied by friction force microscopy, a derivative of AFM, to better understand their micro-/nano-tribological properties. ODP/Al gave the lowest coefficient of friction values while bare Al gave the highest. The adhesion forces for ODP/Al and OP/Al were comparable.

The role of expression of the components of proteome in the formation of molecular profile of human ovarian carcinoma A2780 cells sensitive and resistant to cisplatin.

AIM: To study the expression of proteins that characterize drug resistance, proliferation and apoptosis of human ovarian carcinoma cells. METHODS: The study was carried out on human ovarian carcinoma A2780 cells and on the A2780/DDP8 subline resistant to cisplatin. Expression of the surface and intracellular antigens (p53, Bcl-2, CD95, antigen of proliferating cells, metallothioneins, drug resistance proteins (P-glycoprotein (P-gp), glutathione-S-transferase), molecules of adhesion (E-cadherin, alpha- and beta-catenins) was studied by immunocytochemical method. RESULTS: It has been shown that the formation of the resistance to cisplatin in A2780/DDP8 cells is accompanied by the increase of expression of glutathione-S-transferase and Bcl-2, by the decrease of expression of CD95-antigene and proliferation potential of the cells, by appearance of EGF receptors and elevation of expression level of E-cadherin, alpha- and beta-catenins, proving the enhancement of adhesive properties of tumor cells. CONCLUSION: Antiapoptotic program seems to be the leading mechanism of the development of the resistance to cisplatin in A2780/DDP8 cells and is realized via high expression of Bcl-2. During the development of drug resistance of A2780/DDP cells, the program of glutathione detoxification is functionally replacing the decrease of the content of metallothioneins.

Olivomycin induces tumor cell apoptosis and suppresses p53-induced transcription.

Olivomycin (DNA-binding antibiotic) in nanomolar concentrations induces apoptosis of human tumor cells and inhibits p53-dependent transcription of the reporter gene (basal and induced by antitumor drugs). Olivomycin aglycon induces no cytotoxicity and does not block transcription.

Total proteolytic activity and levels of the main proteinase inhibitors in blood plasma of mice bearing Lewis lung carcinoma upon development of resistance to cisplatin.

UNLABELLED: The aim of the study was to evaluate the total proteolytic activity (TPA) and the content of alpha-1-proteinase inhibitor (alpha1PI) and alpha-2-macroblobulin (alpha2M) in the blood plasma of mice with Lewis lung carcinoma (LLC) upon the development of resistance to cisplatin. METHODS: Experimental LLC model with different sensitivity to cisplatin was obtained by sequential subcutaneous transplantation of LLC cells from cisplatin-treated animals. TPA, alpha1PI and alpha2M levels were evaluated by standard biochemical methods. RESULTS: It has been shown that the development of LLC resistance to cisplatin is accompanied by the increase of TPA activity and the level of the main proteinase inhibitor - alpha1PI. Despite the high level of alpha1PI in the resistant variant of LLC compared to parental tumor, the increase of TPA/alpha1PI ratio indicated the deficiency of that inhibitor in the blood of mice bearing cisplatin-resistant tumors, that promotes metastasis. The growth of both resistant to cisplatin LLC and sensitive variant was accompanied with the reduction of the alpha2M concentration. CONCLUSIONS: Upon the development of resistance to cisplatin in vivo the shift in the balance between proteinases and their inhibitors toward activation of TPA simultaneously with the increased metastasis is taking place.

Age-related effects of methionine-enriched diet on plasma homocysteine concentration and methylation of hepatic DNA in rats.

In the present study we determined the age-related effect of methionine-enriched diet, a model of hyperhomocysteinemia, on the level of plasma homocysteine and hepatic global DNA methylation in rats. Feeding methionine diet to middle-aged rats for only 14 days resulted in a significant increase in plasma homocysteine level and DNA hypomethylation. In contrast, feeding the methionine-containing diet for 2 weeks to juvenile or post-pubertal animals did not alter the level of plasma homocysteine or hepatic DNA methylation. Supplementation of the methionine-enriched diet with vitamins B6, B12 and folic acid prevented both hepatic DNA hypomethylation and an increase of plasma homocysteine concentration in the middle-aged rats. These findings indicate that the elevated level of plasma homocysteine may be indicative of much broader and deeper alterations in intracellular methylation dysfunction, and suggest that dietary enrichment with B-vitamins is essential for the metabolism of homocysteine, especially in adult animals.

Hydrogen loading and UV-irradiation induced etch rate changes in phosphorus-doped fibers.

We show strong changes in chemical etching of phosphorus-doped fiber cores due to hydrogen loading and subsequent UV-irradiation using an atomic force microscope. The etch rate of the fiber core in a low concentration hydrofluoric acid solution (HF) is decreasing after hydrogen loading by as much as 30%. In contrast, UV-irradiation of the hydrogenated fiber increases the core etch rate to values of 27% above the etch rate of the pristine fiber. The UV-induced change in etch rate does not depend on pulse fluence, but only on total dose. We attribute the changes in etch rate to a hydrogen- and radiation-induced modification of color center population.

The SEIRA spectroscopy data of nucleic acids and phospholipids from sensitive- and drug-resistant rat tumours.

It is known that tumour progression towards drug resistance is one of the main factors resulting in the failure of cancer treatment. As tumour progression is based on the genetic instability, the study of the structure of nucleic acid from tumour cells is of great importance both for basic knowledge and for biomedical application. We applied surface enhanced infrared absorption spectroscopy (SEIRA) of nucleic acids on gold substrate and essentially increased the sensitivity of IR spectroscopy. We observed numerous changes in infrared spectra of DNA from sensitive and resistant cells that reflect drastic changes in molecular structure of DNA from tumour cells. The DNA from resistant cancer cells could be characterised as rigid structure, the structure of DNA from sensitive cancer strain seems to be flexible and after application of anticancer drugs drastically changes and approaches to the structure of helix forms. The molecular structure of lipids from resistant and sensitive cancers after application of anti-tumour drugs is also modified. Thus, we observed a disordering in the lipid chain packing from resistant cells after application of cisplatin and, in some cases, formation of phospholipid-Pt complex.

[Use of WOBE-MUGOS E for prevention and correction of experimental doxorubicin side-effects]. / Ispol'zovanie VOBE-MUGOS E dlia profilaktiki i korrektsii pobochnykh reaktsii doksorubitsina gidrokhlorida v éksperimente.

Examined in treating rats with Guerin's carcinoma with doxorubicin was the possibility that the polyenzymic drug preparation wobe-mugos E had hepatoprotective, cardioprotective and myeloprotective effects. In intramuscular administration wobe-mugos E has not been found to stimulate the tumour growth, it exhibited a manifest hepatoprotective and myeloprotective actions with respect to adverse reactions of doxorubicin but failed to diminish cardiotoxicity of the latter. The protective effect of the above polyenzymic drug was of a dose-dependent character.

Tumor necrosis factor alpha induces BID cleavage and bypasses antiapoptotic signals in prostate cancer LNCaP cells.

Survival of cancer cells in response to therapy, immune response, or metastasis depends on interactions between pro- and antiapoptotic signals. Two major proapoptotic pathways have been described: (a) a death receptor pathway; and (b) a mitochondrial pathway. We reported previously that Akt and the epidermal growth factor (EGF) receptor send separate, redundant survival signals that act to inhibit the mitochondrial proapoptotic pathway in prostate cancer LNCaP cells. However, it was unclear at what level the pro- and antiapoptotic signals interact in these cells, and it was also unclear whether these signals would inhibit the death receptor pathway. We found that EGF can protect LNCaP cells from apoptosis induced by LY294002 but not from tumor necrosis factor a (TNF-alpha)-induced apoptosis. Furthermore, TNF-alpha induced apoptosis under conditions in which Akt was active. Treatment with TNF-alpha resulted in activation of caspase 8 and cleavage of BID, which in turn induced cytochrome c release and caspase 9-dependent activation of effector caspases. Thus, proapoptotic signals induced by both TNF-alpha and LY294002 converge on mitochondria and trigger cytochrome c release. Because EGF can inhibit cytochrome c release induced by LY294002 but not cytochrome c release induced by TNF-alpha, we suggest that the EGF survival mechanism operates on the mitochondrial pathway at a site upstream of cytochrome c release. The ability of TNF-alpha to bypass survival signals from activated EGF receptor and Akt in prostate cancer cells makes death receptor signaling a promising avenue for therapeutic intervention.

[Lyposomal form of doxorubicin hydrochloride lypodox in the treatment of lymphogranulomatosis and non-Hodgkin's lymphomas]. / Liposomal'naia forma doksorubitsina gidrokhlorida--"lipodoks"--v lechenii limfogranulomatoza i nekhodzhkinskikh limfom.

The article focuses on the possibility of our employing the drug preparation lypodox, a lyposomal form of doxorubicini hydrochloridum, of the Byolek firm, in treating of Hodgkin's disease and non-Hodgkin's lymphomas. A comparative analysis was performed of efficacy and ill effects of lyposomal and free forms of doxorubicini hydrochloridum. It has been shown that by clinical effectiveness the drug preparation lypodox, doxorubicini hydrochloridum in a lyposomal form, is superior to doxorubicini hydrochloridum in a free form in resistant and aggressive forms of Hodgkin's disease and non-Hodgkin's lymphomas. Side reactions developing in the wake of lypodox administration do not threaten the life and health of patients; these do not preclude us from employing the drug in a clinical setting.

[Dynamics of fluid volumes of body sectors in patients after laparoscopic surgery]. / Dinamika ob"emov zhidkostnykh sektorov organizma u bol'nykh, perenesshikh laparoskopicheskie operatsii.

An investigation of the state of volumes of the organism's fluid sectors (general, extra- and intracellular fluid) by a noninvasive method of double-frequency impedancemetry has revealed the influence of preoperative preparing the patients and restriction of the water regimen after operation upon the development of moderate dehydration of the extracellular sector. During the operation lasting about an hour the intravenous administration of 400 ml of crystalloid solutions maintains the volumes of fluid sectors within the due values. These solutions injected in greater volumes result in accumulation of the extra- and intracellular fluid. The antiperistaltic purgation of the intestine before the operation reduces the concentration of calcium in blood by 1 mmol/l at an average.