Anthrazykline und Herceptin® als neue Therapieoption beim metastasierten Mammakarzinom

Single-agent treatment with the humanized monoclonal antibody trastuzumab (herceptin) has shown remarkable activity in patients with metastatic breast cancer overexpressing the HER-2/neu proto-oncogen. Further significant advances could be achieved with the combined use of herceptin and paclitaxel or doxorubicin/cyclophosphamide. However, cardiotoxicity remains a significant and thus far unresolved problem of the herceptin-doxo-rubicin combination. Thus, several studies have recently been initiated to identify equally effective but less toxic first-line regimens. Epirubicin, the taxanes paclitaxel and docetaxel, Navelbine(R), cisplatin, and Caelyx(R), a liposomal encapsulated formulation of doxorubicin, were selected for combination with herceptin in these studies because the appeared the most promising agents

Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis

The incidence of brain metastasis is increasing, however, little is known about molecular mechanism responsible for lung cancer-derived brain metastasis and their development in the brain. In the present study, brain pathology was examined in an experimental model system of brain metastasis as well as in human brain with lung cancer metastasis. In an experimental model, after 3–6 weeks of intracardiac inoculation of human lung cancer-derived (HARA-B) cells in nude mice, wide range of brain metastases were observed. The brain sections showed significant increase in glial fibrillary acidic protein (GFAP)-positive astrocytes around metastatic lesions. To elucidate the role of astrocytes in lung cancer proliferation, the interaction between primary cultured mouse astrocytes and HARA-B cells was analyzed in vitro. Co-cultures and insert-cultures demonstrated that astrocytes were activated by tumor cell-oriented factors; macrophage migration inhibitory factor (MIF), interleukin-8 (IL-8) and plasminogen activator inhibitor-1 (PAI-1). Activated astrocytes produced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β), which in turn promoted tumor cell proliferation. Semi-quantitative immunocytochemistry showed that increased expression of receptors for IL-6 and its subunits gp130 on HARA-B cells. Receptors for TNF-α and IL-1β were also detected on HARA-B cells but down-regulated after co-culture with astrocytes. Insert-culture with astrocytes also stimulated the proliferation of other lung cancer-derived cell lines (PC-9, QG56, and EBC-1). These results suggest that tumor cells and astrocytes stimulate each other and these mutual relationships may be important to understand how lung cancer cells metastasize and develop in the brain

Neutrophilic airways inflammation in lung cancer: the role of exhaled LTB-4 and IL-8

Background: Recent advances in lung cancer biology presuppose its inflammatory origin. In this regard, LTB-4 and IL-8 are recognized to play a crucial role in neutrophil recruitment into airways during lung cancer.Notwithstanding the intriguing hypothesis, the exact role of neutrophilic inflammation in tumour biology remains complex and not completely known.The aim of this study was to give our contribution in this field by investigating LTB-4 and IL-8 in the breath condensate of NSCLC patients and verifying their role in cancer development and progression.Method: We enrolled 50 NSCLC patients and 35 controls. LTB-4 and IL-8 concentrations were measured in the breath condensate and the blood of all the subjects under study using EIA kits. Thirty NSCLC patients and ten controls underwent induced sputum collection and analysis.Results: LTB-4 and IL-8 resulted higher in breath condensate and the blood of NSCLC patients compared to controls. Significantly higher concentrations were found as the cancer stages progressed. A positive correlation was observed between exhaled IL-8 and LTB-4 and the percentage of neutrophils in the induced sputum.Conclusion: The high concentrations of exhaled LTB-4 and IL-8 showed the presence of a neutrophilic inflammation in the airways of NSCLC patients and gave a further support to the inflammatory signalling in lung cancer. These exhaled proteins could represent a suitable non-invasive marker in the diagnosis and monitoring of lung cancer. © 2011 Carpagnano et al; licensee BioMed Central Ltd

Prophylactic Medication for the Prevention of Endoscopic Recurrence in Crohn's Disease: a Prospective Study Based on Clinical Risk Stratification

Background To prevent recurrence after ileocolonic resection [ICR] in Crohn's disease [CD], postoperative prophylaxis based on risk stratification is recommended in international guidelines. This study aimed to evaluate postoperative CD recurrence after implementation of a clinical management algorithm and to determine the predictive value of clinical and histological risk factors [RFs]. Methods In this multicentre, prospective cohort study, CD patients [>= 16 years] scheduled for ICR were included. The algorithm advised no postoperative medication for low-risk patients, and treatment with prophylaxis [immunosuppressant/biological] for high-risk patients [>= 1 RF: active smoking, penetrating disease, prior ICR]. Clinical and histological RFs [active inflammation, granulomas, plexitis in resection margins] for endoscopic recurrence [Rutgeerts' score >= i2b at 6 months] were assessed using logistic regression and ROC curves based on predicted probabilities. Results In total, 213 CD patients after ICR were included [age 34.5 years; 65% women] (93 [44%] low-risk; 120 [56%] high-risk: 45 [38%] smoking; 51 [43%] penetrating disease; 51 [43%] prior ICR). Adherence to the algorithm was 82% in low-risk [no prophylaxis] and 51% in high-risk patients [prophylaxis]. Endoscopic recurrence was higher in patients treated without prophylaxis than with prophylaxis in both low [45% vs 16%, p = 0.012] and high-risk patients [49% vs 26%, p = 0.019]. Clinical risk stratification including the prescription of prophylaxis corresponded to an area under the curve [AUC] of 0.70 (95% confidence interval [CI] 0.61-0.79). Clinical RFs combined with histological RFs increased the AUC to 0.73 [95% CI 0.64-0.81]. Conclusion Adherence to this management algorithm is 65%. Prophylactic medication after ICR prevents endoscopic recurrence in low- and high-risk patients. Clinical risk stratification has an acceptable predictive value, but further refinement is needed.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Nebulisation of synthetic lamellar lipids mitigates radiation-induced lung injury in a large animal model

Item originally deposited in University of Edinburgh, Edinburgh Research Explorer Repository at: https://www.research.ed.ac.uk/portal/en/publications/nebulisation-of-synthetic-lamellar-lipids-mitigates-radiationinduced-lung-injury-in-a-large-animal-model(ab917c99-7e7f-4fa1-8d1e-40511ca9abd3).htmlMethods to protect against radiation-induced lung injury (RILI) will facilitate the development of more effective radio-therapeutic protocols for lung cancer and may provide the means to protect the wider population in the event of a deliberate or accidental nuclear or radiological event. We hypothesised that supplementing lipid membranes through nebulization of synthetic lamellar lipids would mitigate RILI. Following pre-treatment with either nebulised lamellar lipids or saline, anaesthetised sheep were prescribed fractionated radiotherapy (30 Gray (Gy) total dose in five 6 Gy fractions at 3–4 days intervals) to a defined unilateral lung volume. Gross pathology in radio-exposed lung 37 days after the first radiation treatment was consistent between treatment groups and consisted of deep red congestion evident on the pleural surface and firmness on palpation. Consistent histopathological features in radio-exposed lung were subpleural, periarteriolar and peribronchial intra-alveolar oedema, alveolar fibrosis, interstitial pneumonia and type II pneumocyte hyperplasia. The synthetic lamellar lipids abrogated radiation-induced alveolar fibrosis and reduced alpha-smooth muscle actin (ASMA) expression in radio-exposed lung compared to saline treated sheep. Administration of synthetic lamellar lipids was also associated with an increased number of cells expressing dendritic cell-lysosomal associated membrane protein throughout the lung.This work was supported by Grant MRC/CIC3/025 awarded to D.C., J.L., J.M., G.M. & J.P. The authors wish to acknowledge the assistance of Dryden Animal Services in the conduct of this work, and the assistance of Dr Helen Brown in relation to experimental design and statistical analysis. The authors are grateful to Lamellar Biomedical Ltd., Strathclyde Business Park, Bellshill, Scotland, United Kingdom, for the supply of LAMELLASOME™ used in this research.8pubpubArticle no: 1331

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 x10(-8)), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD

ANTIOXIDANTS, CYTOKINES AND MARKERS OF OXIDATIVE STRESS IN LUNG CANCER: associations with adverse events, response and survival

Väitöskirjatutkimuksessa todettiin, että keuhkosyöpään liittyy lisääntynyt vapaiden radikaalien ja tiettyjen sytokiinien tuotanto. Tutkimuksen mukaan myös säde- ja solunsalpaajahoito lisäävät elimistön oksidatiivista kuormitusta. Tiettyjen antioksidanttien, sytokiinien ja oksidatiivisen kuormituksen merkkiaineiden tasot ennustivat elossaoloaikaa keuhkosyöpäpotilailla. Keuhkosyöpä on merkittävä maailmanlaajuinen terveysongelma. Yli 1,3 miljoonaa ihmistä sairastuu siihen vuosittain. Suomessa keuhkosyöpä on miesten toiseksi yleisin ja naisten neljänneksi yleisin syöpämuoto. Vapaita radikaaleja syntyy muun muassa soluhengityksen aikana, ja niiden on todettu olevan osallisena useiden sairauksien, mukaan lukien syövän, synnyssä. Aiemmat tutkimukset ovat osoittaneet, että keuhkosyöpäpotilailla vapaiden radikaalien tuotanto on lisääntynyt. Myös sädehoidossa syntyy vapaita radikaaleja, jotka voivat vaurioittaa lipidejä, proteiineja ja DNA:ta. Lisäksi monien solunsalpaajien vaikutukset välittyvät vapaiden radikaalien kautta. Huolimatta siitä, että tutkimustieto vapaiden radikaalien osuudesta syövässä on lisääntynyt, on antioksidantteja, sytokiineja ja oksidatiivisen kuormituksen merkkiaineita keuhkosyövän hoitojen aikana tutkittu vähän. Väitöskirjatutkimukseen osallistui 65 keuhkosyöpäpotilasta sekä 66 kontrollihenkilöä, joilla ei ollut syöpää. Osallistujilta määritettiin useita antioksidantteja ja sytokiineja, kokonaisantioksidanttikapasiteetti sekä oksidatiivisen ja nitrosatiivisen kuormituksen merkkiaineita verestä ja bronkoalveolaarinesteestä. Väitöskirjatutkimuksen tavoitteena oli arvioida keuhkosyövän sekä säde- ja solunsalpaajahoidon paikallisia ja systeemisiä vaikutuksia mainittuihin merkkiaineisiin. Lisäksi työn tavoitteena oli tutkia oksidatiivisen kuormituksen merkkiaineiden yhteyttä muihin taustatekijöihin sekä niiden soveltuvuutta syövän hoitojen yhteydessä ilmenevien sivuvaikutusten, hoitovasteen ja elossaolon ennustamiseen. Väitöskirjatutkimuksessa todettiin, että keuhkosyöpään liittyy lisääntynyt vapaiden radikaalien ja tiettyjen sytokiinien tuotanto. Tutkimus osoittaa myös keuhkojen tähystyksessä saatavan bronkoalveolaarinesteen tarkoituksenmukaisuuden mitattaessa paikallisesti antioksidantteja ja sytokiineja keuhkosyöpäpotilailla. Tutkimuksen mukaan sekä sädehoito että solunsalpaajahoito lisäävät vapaiden radikaalien tuotantoa, sillä tiettyjen antioksidanttien tasot laskivat hoidon aikana samalla kun oksidatiivisen kuormituksen merkkiaineiden tasot nousivat. Vaikuttaa kuitenkin siltä, että elimistön omat puolustusmekanismit pystyvät melko hyvin torjumaan keuhkosyövän hoitojen aikaista oksidatiivista kuormitusta. Tutkimuksen mukaan korkeammat lipidiperoksidaation merkkiaineen, uloshengitetyn pentaanin, tasot ennustivat pitempää elossaoloaikaa. Tulosten perusteella myös seerumin ja bronkoalveolaarinesteen interleukiini-8, seerumin verisuonikasvutekijä (VEGF) sekä plasman ja bronkoalveolaarinesteen tiolit saattavat olla hyödyllisiä merkkiaineita ennustettaessa keuhkosyöpäpotilaiden elossaoloaikaa. Laajempia tutkimuksia tarvitaan kuitenkin selvittämään oksidatiivisen vaurion merkkiaineiden mahdollisia yhteyksiä hoitojen yhteydessä ilmeneviin sivuvaikutuksiin sekä hoitovasteeseen.Lung cancer represents a major health concern with over 1.3 million cases diagnosed worldwide each year. A growing body of evidence has indicated that lung cancer, among other cancers, is associated with increased production of reactive oxygen species (ROS). Also ionizing radiation induces the formation of ROS, which can damage lipids, proteins and DNA. In addition, many chemotherapeutic agents seem to be associated with the generation of free radicals and increased lipid peroxidation. Despite accumulating data on ROS in cancer, there are few studies examining antioxidants, cytokines and markers of oxidative stress during cancer treatments. To evaluate oxidative stress in lung cancer, we examined the levels of a number of antioxidants, various cytokines, total peroxyl radical trapping antioxidant potential (TRAP) and a number of parameters of oxidative and nitrosative stress in 65 lung cancer patients and 66 non-cancer controls. Our aim was to assess the local and systemic effects of lung cancer and its treatment by radiotherapy and chemotherapy on these markers. The markers were also evaluated in relation to various clinicopathological parameters, and possible associations between these markers and adverse events, response to treatment and overall survival of the patients were investigated. The findings here would indicate that lung cancer is associated with increased oxidative stress and production of certain cytokines. It was also demonstrated that bronchoalveolar lavage (BAL) fluid can be a useful medium for analyzing local cytokine and oxidative stress marker status in lung cancer patients. The involvement of radiotherapy and chemotherapy produces free radicals, as evidenced by a decrease in the levels of various antioxidants and elevation of certain markers of oxidative stress during these treatments. However, it appears that the body´s own antioxidant defense system is fairly sufficient to counteract the increase in ROS during lung cancer treatments. Higher exhaled pentane levels, as a marker of lipid peroxidation, seemed to predict better survival. In addition, these data imply that serum and BAL fluid IL-8 and serum VEGF may be useful prognostic factors in lung cancer patients. A further interesting future research topic is the association between plasma and BAL thiols and survival of patients. However, additional studies are called for to explore the possible associations between oxidative stress markers and adverse events and response to treatment

ANTIOXIDANTS, CYTOKINES AND MARKERS OF OXIDATIVE STRESS IN LUNG CANCER: associations with adverse events, response and survival

Väitöskirjatutkimuksessa todettiin, että keuhkosyöpään liittyy lisääntynyt vapaiden radikaalien ja tiettyjen sytokiinien tuotanto. Tutkimuksen mukaan myös säde- ja solunsalpaajahoito lisäävät elimistön oksidatiivista kuormitusta. Tiettyjen antioksidanttien, sytokiinien ja oksidatiivisen kuormituksen merkkiaineiden tasot ennustivat elossaoloaikaa keuhkosyöpäpotilailla. Keuhkosyöpä on merkittävä maailmanlaajuinen terveysongelma. Yli 1,3 miljoonaa ihmistä sairastuu siihen vuosittain. Suomessa keuhkosyöpä on miesten toiseksi yleisin ja naisten neljänneksi yleisin syöpämuoto. Vapaita radikaaleja syntyy muun muassa soluhengityksen aikana, ja niiden on todettu olevan osallisena useiden sairauksien, mukaan lukien syövän, synnyssä. Aiemmat tutkimukset ovat osoittaneet, että keuhkosyöpäpotilailla vapaiden radikaalien tuotanto on lisääntynyt. Myös sädehoidossa syntyy vapaita radikaaleja, jotka voivat vaurioittaa lipidejä, proteiineja ja DNA:ta. Lisäksi monien solunsalpaajien vaikutukset välittyvät vapaiden radikaalien kautta. Huolimatta siitä, että tutkimustieto vapaiden radikaalien osuudesta syövässä on lisääntynyt, on antioksidantteja, sytokiineja ja oksidatiivisen kuormituksen merkkiaineita keuhkosyövän hoitojen aikana tutkittu vähän. Väitöskirjatutkimukseen osallistui 65 keuhkosyöpäpotilasta sekä 66 kontrollihenkilöä, joilla ei ollut syöpää. Osallistujilta määritettiin useita antioksidantteja ja sytokiineja, kokonaisantioksidanttikapasiteetti sekä oksidatiivisen ja nitrosatiivisen kuormituksen merkkiaineita verestä ja bronkoalveolaarinesteestä. Väitöskirjatutkimuksen tavoitteena oli arvioida keuhkosyövän sekä säde- ja solunsalpaajahoidon paikallisia ja systeemisiä vaikutuksia mainittuihin merkkiaineisiin. Lisäksi työn tavoitteena oli tutkia oksidatiivisen kuormituksen merkkiaineiden yhteyttä muihin taustatekijöihin sekä niiden soveltuvuutta syövän hoitojen yhteydessä ilmenevien sivuvaikutusten, hoitovasteen ja elossaolon ennustamiseen. Väitöskirjatutkimuksessa todettiin, että keuhkosyöpään liittyy lisääntynyt vapaiden radikaalien ja tiettyjen sytokiinien tuotanto. Tutkimus osoittaa myös keuhkojen tähystyksessä saatavan bronkoalveolaarinesteen tarkoituksenmukaisuuden mitattaessa paikallisesti antioksidantteja ja sytokiineja keuhkosyöpäpotilailla. Tutkimuksen mukaan sekä sädehoito että solunsalpaajahoito lisäävät vapaiden radikaalien tuotantoa, sillä tiettyjen antioksidanttien tasot laskivat hoidon aikana samalla kun oksidatiivisen kuormituksen merkkiaineiden tasot nousivat. Vaikuttaa kuitenkin siltä, että elimistön omat puolustusmekanismit pystyvät melko hyvin torjumaan keuhkosyövän hoitojen aikaista oksidatiivista kuormitusta. Tutkimuksen mukaan korkeammat lipidiperoksidaation merkkiaineen, uloshengitetyn pentaanin, tasot ennustivat pitempää elossaoloaikaa. Tulosten perusteella myös seerumin ja bronkoalveolaarinesteen interleukiini-8, seerumin verisuonikasvutekijä (VEGF) sekä plasman ja bronkoalveolaarinesteen tiolit saattavat olla hyödyllisiä merkkiaineita ennustettaessa keuhkosyöpäpotilaiden elossaoloaikaa. Laajempia tutkimuksia tarvitaan kuitenkin selvittämään oksidatiivisen vaurion merkkiaineiden mahdollisia yhteyksiä hoitojen yhteydessä ilmeneviin sivuvaikutuksiin sekä hoitovasteeseen.Lung cancer represents a major health concern with over 1.3 million cases diagnosed worldwide each year. A growing body of evidence has indicated that lung cancer, among other cancers, is associated with increased production of reactive oxygen species (ROS). Also ionizing radiation induces the formation of ROS, which can damage lipids, proteins and DNA. In addition, many chemotherapeutic agents seem to be associated with the generation of free radicals and increased lipid peroxidation. Despite accumulating data on ROS in cancer, there are few studies examining antioxidants, cytokines and markers of oxidative stress during cancer treatments. To evaluate oxidative stress in lung cancer, we examined the levels of a number of antioxidants, various cytokines, total peroxyl radical trapping antioxidant potential (TRAP) and a number of parameters of oxidative and nitrosative stress in 65 lung cancer patients and 66 non-cancer controls. Our aim was to assess the local and systemic effects of lung cancer and its treatment by radiotherapy and chemotherapy on these markers. The markers were also evaluated in relation to various clinicopathological parameters, and possible associations between these markers and adverse events, response to treatment and overall survival of the patients were investigated. The findings here would indicate that lung cancer is associated with increased oxidative stress and production of certain cytokines. It was also demonstrated that bronchoalveolar lavage (BAL) fluid can be a useful medium for analyzing local cytokine and oxidative stress marker status in lung cancer patients. The involvement of radiotherapy and chemotherapy produces free radicals, as evidenced by a decrease in the levels of various antioxidants and elevation of certain markers of oxidative stress during these treatments. However, it appears that the body´s own antioxidant defense system is fairly sufficient to counteract the increase in ROS during lung cancer treatments. Higher exhaled pentane levels, as a marker of lipid peroxidation, seemed to predict better survival. In addition, these data imply that serum and BAL fluid IL-8 and serum VEGF may be useful prognostic factors in lung cancer patients. A further interesting future research topic is the association between plasma and BAL thiols and survival of patients. However, additional studies are called for to explore the possible associations between oxidative stress markers and adverse events and response to treatment