The relationship between the local and systemic inflammatory responses and survival in patients undergoing resection for localized renal cancer

To examine the relationship between the systemic inflammatory response (C-reactive protein, CRP), tumour interleukin-6 receptor and cyclooxygenase (COX)-2 expression, tumour T-lymphocytic (CD4+, CD8+) infiltration and cancer survival in patients undergoing resection for renal cell carcinoma (RCC), as both the local and systemic inflammatory responses appear to predict the outcome in these patients. <b>PATIENTS AND METHODS:</b> The study included 60 patients undergoing nephrectomy for localized RCC. Pre-operative circulating CRP levels were measured and tumour interleukin-6 receptor and COX-2 expression, tumour CD4+ and CD8+ T lymphocytes were assessed using immunohistochemical analysis. <b>RESULTS:</b> The median follow-up was 78 months, with 14 patients relapsing from their disease and nine cancer-specific deaths. On univariate and multivariate survival analysis, tumour stage and grade and CRP levels were identified as significant factors associated with relapse-free and cancer-specific survival. There was a significant direct relationship between Fuhrman grade and CD4+ T-lymphocytic infiltrate (P > 0.05). An increase in tumour expression of interleukin-6 receptor was weakly associated with an increase in tumour CD8+ T-lymphocytic infiltration (P = 0.057). An increase in tumour CD4+ T-lymphocytic infiltration was associated with an increase in CD8+ T-lymphocytic infiltration (P > 0.01). <b>CONCLUSIONS:</b> The present results suggest that tumour-based factors such as interleukin-6 receptor and COX-2 expression or T-lymphocytic subset infiltration are subordinate to systemic factors such as CRP level in determining survival in patients with localized RCC

Metabolism within the tumor microenvironment and its implication on cancer progression: an ongoing therapeutic target

Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages and tumor-infiltrating T cells, surround tumor cells in the so-called tumor microenvironment. Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the tumor microenvironment and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that tumor microenvironment is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with combined therapies including anti-tumor agents with those targeting stromal cell metabolism, anti-angiogenic drugs and/or immunotherapy are being developed as promising therapeutics.Mª Carmen Ocaña is recipient of a predoctoral FPU grant from the Spanish Ministry of Education, Culture and Sport. Supported by grants BIO2014-56092-R (MINECO and FEDER), P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript

Metabolic and morphological alterations induced by proteolysis-inducing factor from Walker tumour-bearing rats in C2C12 myotubes

BACKGROUND: Patients with advanced cancer suffer from cachexia, which is characterised by a marked weight loss, and is invariably associated with the presence of tumoral and humoral factors which are mainly responsible for the depletion of fat stores and muscular tissue. METHODS: In this work, we used cytotoxicity and enzymatic assays and morphological analysis to examine the effects of a proteolysis-inducing factor (PIF)-like molecule purified from ascitic fluid of Walker tumour-bearing rats (WF), which has been suggested to be responsible for muscle atrophy, on cultured C2C12 muscle cells. RESULTS: WF decreased the viability of C2C12 myotubes, especially at concentrations of 20-25 mug.mL-1. There was an increase in the content of the pro-oxidant malondialdehyde, and a decrease in antioxidant enzyme activity. Myotubes protein synthesis decreased and protein degradation increased together with an enhanced in the chymotrypsin-like enzyme activity, a measure of functional proteasome activity, after treatment with WF. Morphological alterations such as cell retraction and the presence of numerous cells in suspension were observed, particularly at high WF concentrations. CONCLUSION: These results indicate that WF has similar effects to those of proteolysis-inducing factor, but is less potent than the latter. Further studies are required to determine the precise role of WF in this experimental model. © 2008 Yano et al; licensee BioMed Central Ltd

Tumor macroenvironment and metabolism

In this review we introduce the concept of the tumor macroenvironment and explore it in the context of metabolism. Tumor cells interact with the tumor microenvironment including immune cells. Blood and lymph vessels are the critical components that deliver nutrients to the tumor and also connect the tumor to the macroenvironment. Several factors are then released from the tumor itself but potentially also from the tumor microenvironment, influencing the metabolism of distant tissues and organs. Amino acids, and distinct lipid and lipoprotein species can be essential for further tumor growth. The role of glucose in tumor metabolism has been studied extensively. Cancer-associated cachexia is the most important tumor-associated systemic syndrome and not only affects the quality of life of patients with various malignancies but is estimated to be the cause of death in 15%–20% of all cancer patients. On the other hand, systemic metabolic diseases such as obesity and diabetes are known to influence tumor development. Furthermore, the clinical implications of the tumor macroenvironment are explored in the context of the patient’s outcome with special consideration for pediatric tumors. Finally, ways to target the tumor macroenvironment that will provide new approaches for therapeutic concepts are described

Cyclooxygenase activity and tumor progression

Invasive growth of malignant tumors is associated with local and systemic inflammation, which may promote progression and metastases. Inflammation is also responsible for appearing manifestations of advanced cancer as fatigue, anorexia and wasting with eicosanoids, proinflammatory cytokines and nitric oxide as mediators. The aim of the present work was to extend information on the significance of cyclooxygenase activity in local and systemic progression of tumor disease. Methods: Murine tumor models (MCG-101, K1735-M2), human carcinomas xenontransplanted to nude mice, tumor cell cultures and tissue samples from human colorectal adenocarcinomas were used. Inhibitors of cyclooxygenase and nitric oxide synthase, antibodies against IL-6 and recombinant IL-12 were used to evaluate effects on tumor growth, inflammation (SAP, CRP, ESR) and host wasting (anorexia, body composition). Expression of proteins was evaluated by immunohistochemistry, western blot and RT-PCR. Signal molecules were quantified by RIA, ELISA and immunoelectrophoresis. Eicosanoids and polyamines were fractionated by HPLC. Cell proliferation was estimated by mitotic counting and flow cytometry. Results: Inhibition of prostaglandin synthesis (indomethacin) reduced tumor growth, attenuated host wasting and prolonged survival in MCG-101 bearing mice with high tumor production of PGE2. By contrast, no such effects were seen in K1735-M2 bearing mice with insignificant PGE2 production. Indomethacin also reduced growth of human tumors on nude mice. There was no clear-cut correlation between overall COX-2 expression in tumors and sensitivity to indomethacin treatment, although COX-2 expression was significantly correlated to tumor PGE2 production; factors that predicted reduced survival in colon carcinoma. IL-6 deficient mice showed reduced tumor growth and wasting. Indomethacin reduced plasma PGE2 levels and wasting in all groups of cytokine knockout mice, but only IL-12 knockouts showed concomitant reduction in tumor growth. Recombinant IL-12 reduced tumor growth in wild type mice, but not so in IFN- deficient mice. Cytokine knockout tumor-bearing mice experienced anorexia to the same extent as wild types. Our results suggested subtype EP receptors to explain effects by PGE2 exposure to tumor and stroma cells. Systemic inflammation was related to tumor cell proliferation evaluated by p15, TGFb3 and Bcl-2 in tumor tissue. Indomethacin treatment increased tumor tissue expression of IL-6, TNF-, GM-CSF, TGF, cNOS decreased expression of b-FGF, angiogenin, vWF and blood vessel density, whereas EGF, VEGF, PDGF A, B, IL-1, transferrin receptors were unchanged. Cell cycle was prolonged in vivo but not in vitro by indomethacin. NSAID inhibition of tumor growth and host-wasting was not simply related to COX specificity. NOS-inhibitors reduced tumor growth in both MCG-101 and K1735-M2 tumors expressing high amounts of cNOS and iNOS. Synergism between COX- and NOS-inhibition was not observed. NOS inhibition attenuated host wasting to the same extent as indomethacin in MCG-101 bearing mice. Conclusion: Results in the present study demonstrate that cyclooxygenase activity is central in tumor progression with well-recognized host stigmata of systemic inflammation both in experimental and clinical cancer. Such effects are connected to classic tumor growth factors, cytokines and nitric oxide, where redundancy among cytokines was pronounced in development of host deteriorations (cachexia)

Medication in temporomandibular disorders and bruxism

The aim of this thesis was to explore aspects of pharmaceutical intervention in temporomandibular disorders (TMDs) and bruxism. Sleep bruxism is a movement disorder that signals disturbed sleep and constitutes a significant health problem due to TMDs, headache and tooth wear. In Study I, medication was reviewed in patients referred for specialist treatment for TMDs. Female patients with myofascial pain used significantly more psychoactive medication, including antidepressants, tranquilizers, sedatives and hypnotics, compared with matched controls. These findings support other research demonstrating an overrepresentation of the diagnoses depression, anxiety, stress and sleep problems among TMD patients. Study II compared the effect of oral glucosamine sulfate on osteoarthritis in the temporomandibular joints with that of placebo. Glucosamine sulfate appeared to improve signs and symptoms over time, but it was not significantly superior to placebo. In Study III, the dopamine agonist, pramipexole, was investigated in severe sleep bruxism confirmed by polysomnographic/electromyographic monitoring. The severity of sleep bruxism was not reduced compared with control conditions, indicating that the involvement of the dopamine system in bruxism is less likely. In Study IV, the effects of botulinum toxin injections in the masticatory muscles, compared with placebo injections, were evaluated in subjects with cerebral palsy and bruxism. No significant differences between active and control injections in terms of subjective or objective oral functions could be observed at group level. In conclusion, the results were negative with respect to the evaluated pharmacologic remedies for TMDs and bruxism. There is a relative lack of controlled studies in this area. Considering the pronounced negative impact on quality of life that has been reported for these conditions, it should be an important task continuously to evaluate putative pharmacologic therapies in TMDs and bruxism

Sambandet mellan blodets viskositet och infarktens tillväxt vid ischemisk stroke - En pilotstudie

När en blodpropp täpper till ett av hjärnans blodkärl får inte hjärnan längre något syre eller någon näring. Detta gör att nervcellerna inte kan fungera som de skall och om inte blodflödet inom några minuter återställs i det tilltäppta kärlet kommer hjärncellerna att dö. Då uppstår irreversibel hjärnskada. Detta kallas för ischemisk stroke eller slaganfall. Patienten får då vanligen olika grad av bestående symptom från nervsystemet så som exempelvis förlamning, känselstörning och svårt att hitta ord. Ett specifikt område i hjärnan kan dock försörjas med blod från flera blodkärl. Det extra blodflödet räcker då sällan för att förhindra hjärnskada men kan göra att hjärncellerna överlever under en lägre tid (minuter till timmar) och om blodproppen släpper innan hjärncellerna dör kan de i viss mån återhämta sig. Viskositet är ett mått på hur trögflytande en vätska är. Högre viskositet i blodet leder till sämre blodflöde. Syftet med den här studien var att undersöka om högre blodviskositet är associerat med en större tillväxt av det skadade området i hjärnan vid ischemisk stroke. Vi hade som hypotes att högre blodviskositet skulle leda till ett sämre blodflöde via de extra blodkärlen och därmed vara associerat med en större infarkttillväxt i akutskedet. Patientens blodviskositet mättes genom ett blodprov som togs när patienten kom till sjukhuset. Hjärnskadans tillväxt kartlades genom att jämföra röntgenbilder på patientens hjärna vid ankomsten till sjukhuset och cirka ett dygn senare. Hjärnskadans tillväxtvolym jämfördes sedan med blodviskositeten för att se om det fanns ett samband mellan hur hög blodviskositeten var och hur mycket hjärnskadan tillväxte. 2 Resultaten kan tolkas som en indikation på att det finns en association mellan högre blodviskositet och större tillväxt av det skadade området i hjärnan vid ischemisk stroke men för få patienter ingick i studien för att man skall kunna dra några säkra slutsatser. Fortsatta studier med fler patienter behöver därför genomföras inom området. Om blodviskositeten visar sig ha en inverkan på hur mycket det skadade området i hjärnan tillväxer skulle framtida studier kunna undersöka om man kan minska tillväxten av skadan, och därmed minska den totala hjärnskadan, genom att med läkemedel påverka blodviskositeten hos en patient som insjuknat i ischemisk stroke.Background: Ischemic stroke is caused by focal hypoperfusion in the brain due to an obstructed cerebral vessel. Viscosity is the internal friction in a fluid and determinates its resistance to flow. Higher whole blood viscosity (WBV) has previously been associated with increased risk of ischemic stroke as well as reduced blood flow and tissue perfusion. However, the impact of elevated WBV on infarct growth remains unclear. Aim: The aim of the study was to explore the association between WBV and infarct growth in patients with acute ischemic stroke. Method: Forty-three patients with ischemic stroke were included in the study. The blood viscosity was measured in a whole blood sample, obtained on arrival to hospital, at a temperature of 37 °C and a shear rate of 20 s–1 after adjusting it to 40% hematocrit. The infarct growth was calculated as the difference in infarct volume between an initial brain computer tomography and a follow up magnetic resonance imaging examination. The relationship between WBV and infarct growth was analyzed using simple linear regression. Findings: A non-significant linear regression equation was found with a constant of –22.53 (95% CI: –64.41-19.36, p=0.28) and a slope of 5.86 (95% CI: –2.38-14.10, p=0.16). The correlation coefficient (R) for the linear model was 0.22 (p=0.16) and the coefficient of determination (R2) was 0.05. A post-hoc power analysis showed that the study was under dimensioned with a power of 0.30. To obtain a power of 0.80 in a sample with the same effect size as in this study an estimate of 158 patients would be needed to include. 2 Interpretation: A linear relationship between WBV and infarct growth cannot be proven in acute ischemic stroke because of the low statistical significance of the results in this study. However, due to the limited statistical power, nor can it be ruled out. Further studies with lager sample size will be needed for any definite conclusions to be made. The results in this paper can thus be used as a support while designing future studies in the field

Real-Time Estimation of Aerodynamic Parameters

Extensive testing is performed when a new aircraft is developed. Flight testing is costly and time consuming but there are aspects of the process that can be made more efficient. A program that estimates aerodynamic parameters during flight could be used as a tool when deciding to continue or abort a flight from a safety or data collecting perspective. The algorithm of such a program must function in real time, which for this application would mean a maximum delay of a couple of seconds, and it must handle telemetric data, which might have missing samples in the data stream. Here, a conceptual program for real-time estimation of aerodynamic parameters is developed. Two estimation methods and four methods for handling of missing data are compared. The comparisons are performed using both simulated data and real flight test data. The first estimation method uses the least squares algorithm in the frequency domain and is based on the chirp z-transform. The second estimation method is created by adding boundary terms in the frequency domain differentiation and instrumental variables to the first method. The added boundary terms result in better estimates at the beginning of the excitation and the instrumental variables result in a smaller bias when the noise levels are high. The second method is therefore chosen in the algorithm of the conceptual program as it is judged to have a better performance than the first. The sequential property of the transform ensures functionality in real-time and the program has a maximum delay of just above one second. The four compared methods for handling missing data are to discard the missing data, hold the previous value, use linear interpolation or regard the missing samples as variations in the sample time. The linear interpolation method performs best on analytical data and is compared to the variable sample time method using simulated data. The results of the comparison using simulated data varies depending on the other implementation choices but neither method is found to give unbiased results. In the conceptual program, the variable sample time method is chosen as it gives a lower variance and is preferable from an implementational point of view.