Novel methods for in vitro modeling of pancreatic cancer reveal important aspects for successful primary cell culture.

BACKGROUND: Pancreatic cancer remains a fatal disease. Experimental systems are needed for personalized treatment strategies, drug testing and to further understand tumor biology. Cell cultures can serve as an excellent preclinical platform, but their generation remains challenging. METHODS: Tumor cells from surgically removed pancreatic ductal adenocarcinoma (PDAC) specimens were cultured under novel protocols. Cellular growth and composition were analyzed and culture conditions were continuously optimized. Characterization of cell cultures and primary tumors was performed via hematoxylin and eosin (HE) and immunofluorescence (IF) staining. RESULTS: Protocols for two- and three-dimensional PDAC primary cell cultures could successfully be established. Primary cell culture depended on dissociation techniques, growth factor supplementation and extracellular matrix components containing Matrigel being crucial for the transformation to three-dimensional PDAC organoids. The generated cultures showed to be highly resemblant to established PDAC primary cell cultures. HE and IF staining for cell culture and corresponding primary tumor characterization could successfully be performed. CONCLUSIONS: The work presented herein shows novel and effective methods to successfully establish primary PDAC cell cultures in a distinct time frame. Factors contributing to cell growth and differentiation could be identified with important implications for further primary cell culture protocols. The established protocols might serve as novel tools in personalized tumor therapy.

In-depth characterization of polyolefin plastomers/elastomers (ethylene/1-octene copolymers) through hyphenated chromatographic techniques.

The chemical composition distribution (CCD) of three single site made ethylene/1-octene copolymers was investigated through offline-hyphenation of solvent gradient interaction chromatography (SGIC) with 1H NMR. Thus, a clear, non-linear correlation between SGIC elution time and chemical composition was found under the specific measurement conditions applied here. The application of 1H NMR as detection allowed to determine the CCD with unprecedented accuracy. 2D-LC of the copolymers revealed the correlation between CCD and molar mass distribution (MMD) in a quantitative manner. Furthermore, this approach allowed a comparison between the response behavior of an evaporative light scattering detector (ELSD, semi-quantitative, commonly applied in SGIC) and that of an infrared (IR) detector (quantitative, commonly applied in SEC). As a result, it could be shown that ELSD results are close to IR results for the system investigated here, in other words, the often-criticized semi-quantitative response behavior of the ELSD is affecting results in an acceptable manner.

High performance liquid chromatography of polyolefin plastomers/elastomers (ethylene/1-octene copolymers) - Comparison of different solvent systems.

A series of ethylene/1-octene copolymers with different chemical composition was separated in six binary mobile phases using solvent gradients and a column packed with porous graphite Hypercarb™. It was found that the elution volumes of the samples were to a larger extent influenced by the choice of desorption promoting solvent (desorli: 1,2-dichlorobenzene vs. 1,2,4-trichlorobenzene) than by the choice of adsorption promoting solvent (2-ethyl-1-hexanol, 1-decanol, n-decane). Elution volumes increased with decreasing number of chlorine atoms in the desorlis as well as with increasing polarity of the adsorlis. The resolution of HPLC systems depended pronouncedly on the choice of solvent pair: While in the majority of the tested HPLC systems, the chromatograms of the polymer samples indicate a shoulder, in n-decane→TCB the samples eluted without indication of a shoulder. In addition to the influence of different solvents on the samples elution behavior, the response of the employed detector, an evaporative light scattering detector (ELSD), was investigated. Its response was found to depend pronouncedly on the nature of the used solvents. Overall, the solvent pair 1-decanol→TCB appears to be the optimal compromise between the considered parameters and thus the best choice for HPLC of ethylene/1-octene copolymers.

BedMachine v3: Complete Bed Topography and Ocean Bathymetry Mapping of Greenland From Multibeam Echo Sounding Combined With Mass Conservation.

Greenland's bed topography is a primary control on ice flow, grounding line migration, calving dynamics, and subglacial drainage. Moreover, fjord bathymetry regulates the penetration of warm Atlantic water (AW) that rapidly melts and undercuts Greenland's marine-terminating glaciers. Here we present a new compilation of Greenland bed topography that assimilates seafloor bathymetry and ice thickness data through a mass conservation approach. A new 150 m horizontal resolution bed topography/bathymetric map of Greenland is constructed with seamless transitions at the ice/ocean interface, yielding major improvements over previous data sets, particularly in the marine-terminating sectors of northwest and southeast Greenland. Our map reveals that the total sea level potential of the Greenland ice sheet is 7.42 ± 0.05 m, which is 7 cm greater than previous estimates. Furthermore, it explains recent calving front response of numerous outlet glaciers and reveals new pathways by which AW can access glaciers with marine-based basins, thereby highlighting sectors of Greenland that are most vulnerable to future oceanic forcing.

Scanning electron microscopy-energy dispersive X-ray spectrometry (SEM-EDX) and aerosol time-of-flight mass spectrometry (ATOFMS) single particle analysis of metallurgy plant emissions.

The chemical composition of single particles deposited on industrial filters located in three different chimneys of an iron-manganese (Fe-Mn) alloy manufacturing plant have been compared using aerosol time-of-flight mass spectrometry (ATOFMS) and scanning electron microscopy-energy dispersive X-ray spectrometry (SEM-EDX). Very similar types of particles were observed using both analytical techniques. Calcium-containing particles dominated in the firing area of the sintering unit, Mn and/or Al-bearing particles were observed at the cooling area of the sintering unit, while Mn-containing particles were dominant at the smelting unit. SEM-EDX analysis of particles collected downstream of the industrial filters showed that the composition of the particles emitted from the chimneys is very similar to those collected on the filters. ATOFMS analysis of ore samples was also performed to identify particulate emissions that could be generated by wind erosion and manual activities. Specific particle types have been identified for each emission source (chimneys and ore piles) and can be used as tracers for source apportionment of ambient PM measured in the vicinity of the industrial site.

MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial.

OBJECTIVES: To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA). METHODS: Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety. RESULTS: Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters. CONCLUSIONS: MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01023256.

Management of combined anterior or posterior cruciate ligament and posterolateral corner injuries: a systematic review.

BACKGROUND: Combined injuries to the posterolateral corner and cruciate ligaments are uncommon. The heterogeneity of injury patterns in many studies complicates the assessment of outcomes. OBJECTIVE: To assess the prognosis and functional outcomes after surgery for combined injuries to the posterolateral corner and to the anterior cruciate ligament (ACL) or posterior cruciate ligament (PCL). MATERIAL AND METHODS: We systematically reviewed the literature for articles reporting outcomes 1 year or more after surgery for combined injuries to the posterolateral corner and ACL (n=4) or PCL (n=9). Patients with bicruciate injuries were not studied. RESULTS: Overall, 65% of patients were IKDC A or B after surgery. The mean Lysholm score improved from 67 to 90. Mean time to surgery was 4.43 months in the group with ACL tears and 18.4 months in the group with PCL tears, and mean follow-up was 34.4 and 40.7 months in these two groups, respectively. In the groups with ACL and PCL tears, the proportions of patients classified as IKDC A or B at last follow-up were 81.6% and 81.0%, respectively, whereas 88% and 99% of patients, respectively, were IKDC grade C or D before surgery. The mean Lysholm score improved from 77 to 92 in the group with ACL tears and from 65 to 89 in the group with PCL tears. Improvements in laxity ranged from 28% to 79% in the group with PCL tears. DISCUSSION: Most of the articles selected for our review provided level III or IV evidence. Functional outcomes were satisfactory but less good than those reported after surgical reconstruction of isolated cruciate ligament tears. Full reconstruction seems the best strategy in patients with combined ACL/posterolateral corner injuries. Outcomes were also good but more variable in the group with PCL/posterolateral corner injuries. The time to surgery, which reflected the time to diagnosis, was shorter in patients with ACL than with PCL tears in addition to the posterolateral corner injury. LEVEL OF EVIDENCE: Level III (systematic literature review).

Surgical management of combined anterior or posterior cruciate ligament and posterolateral corner tears: for what functional results?

INTRODUCTION: Management of combined anterior or posterior cruciate ligament and posterolateral corner tears is still poorly codified. The aim of this study was to evaluate functional outcome after complete surgical treatment. MATERIALS AND METHODS: This retrospective multicenter study included 53 patients. Mean age was 29.8 yrs. (15-49). The anterior and posterior cruciate ligaments were involved in respectively 48 and 5 cases. Mean time to surgery was 25.6 months (0-184), and in 10 cases less than 21 days. Nine patients were sedentary workers and 29 non-sedentary (13 laborers). All ligament injuries were treated surgically. Mean follow-up was 49 months (12-146). Last follow-up assessment used IKDC, Lysholm and KOOS scores. RESULTS: At last follow-up, IKDC score graded 14 patients A, 25 B, 8 C and 6 D, versus 0 A, 4 B, 25 C, 22 D and 2 ungraded preoperatively. Mean subjective IKDC and Lysholm scores were respectively 72.8 (11.5-100) and 77.5 (37-100). Mean KOOS scores (pain, symptoms, daily life, sports, quality of life) were respectively 78 (3-100), 70 (25-100), 88 (47-100), 53 (0-100) and 50 (0-100). Posterolateral laxity was corrected in all but two cases. All sedentary workers and 86.7% of non-sedentary workers could return to work. The job had to be changed in 10% of cases overall, but in 25% of cases for laborers. DISCUSSION: The present results are comparable with those of the literature. The strategy of combined surgical treatment showed functional efficacy, usually associated with return to work except for some laborers. There was a non-significant trend in favor of acute-phase ligament reconstruction. LEVEL OF EVIDENCE: IV (retrospective series).

A retrospective evaluation of doxorubicin-based chemotherapy for dogs with right atrial masses and pericardial effusion.

OBJECTIVE: To report the outcome of doxorubicin-based chemotherapy as the sole treatment for dogs with echocardiographically identified right atrial masses and pericardial effusion. METHODS: A retrospective study of case records of dogs with right atrial masses treated with doxorubicin. Dogs were excluded from the study if they had any type of surgery performed such as pericardiectomy or right atrial mass resection, or if their chemotherapy protocol did not include doxorubicin. The data collected included signalment, history, physical examination findings, diagnostic test results and long-term survival. RESULTS: Dogs with right atrial masses and pericardial effusion that received doxorubicin-based chemotherapy alone had a median survival of 139 · 5 days (range 2 to 302 days). Chemotherapy side effects were frequent but mild. CLINICAL SIGNIFICANCE: Doxorubicin-based chemotherapy alone appears to be a viable treatment option for dogs with echocardiographically identified right atrial masses and pericardial effusion.

Application of the evaporative light scattering detector to analytical problems in polymer science.

Over the last two decades the evaporative light scattering detector (ELSD) has found more and more use in liquid chromatography (LC) of synthetic polymers. The reason behind this is that it can be used for a significantly wider variety of analyte/solvent combinations. Although in many of the applications the ELSD has been used in a qualitative manner, it can also be used quantitatively. For quantitative interpretation of analyses it is, in the case of synthetic polymers, essential to know how parameters, which characterize a polymer sample (i.e., molar mass and chemical composition), as well as parameters, which are a consequence of the LC separation (i.e., composition and flow rate of the mobile phase, its composition), influence the response of the ELSD. This review gives a tabulated overview over applications of ELS detectors in polymer analysis. The influence of parameters arising from either the polymer side or the chromatographic separation is discussed in detail and, in addition, the influence of the ELS detector's running conditions, i.e. type and flow rate of gas and temperature of nebulizer and evaporator), will be reviewed. This information will prove valuable whenever the calibration of an ELSD for the quantitative analysis of synthetic polymers is attempted.

Anterior knee laxity measurement using stress radiographs and the GNRB(®) system versus intraoperative navigation.

BACKGROUND: Anterior knee laxity measurement serves both to diagnose and to evaluate the severity of anterior cruciate ligament (ACL) damage. HYPOTHESIS: We tested the hypothesis that anterior laxity measurements of ACL-deficient knees obtained using the GNRB(®) system and stress radiographs differed from each other and from intraoperative navigation measurement taken as the reference standard. MATERIAL AND METHODS: Twenty-one patients with chronic ACL deficiency underwent arthroscopic ACL reconstruction. Anterior knee laxity was measured preoperatively using the GNRB(®) system without anaesthesia and anterior-drawer stress radiographs under anaesthesia then intraoperatively using a non-image-based navigation system. RESULTS: The three measurements differed significantly (P=0.05). A systematic measurement error of -3.7 mm occurred for both preoperative measurements versus the reference standard. No significant difference was found between the two preoperative measurements. DISCUSSION: The GNRB(®) system should be preferred over stress radiographs, as reliability is similar but no radiation exposure is required. Both preoperative measurement methods underestimate anterior laxity as measured intraoperatively using the navigation system. This systematic bias may be relevant to treatment decision-making. LEVEL OF EVIDENCE: II, development of a diagnostic criterion in consecutive patients versus a validated reference standard.

Simultaneous bilateral total knee arthroplasty. A multicenter feasibility study.

INTRODUCTION: The value and risk of simultaneous total knee arthroplasty (TKA) in patients with bilateral knee arthritis is a subject of debate. HYPOTHESES: The risk of complications following simultaneous bilateral TKA will be increased compared to the rates published in the literature for unilateral TKA, and the clinical and functional outcomes will be poorer in this particular group. MATERIALS AND METHODS: One hundred and twenty-three patients who underwent simultaneous bilateral TKA between 2005 and 2011 in five specialized, high volume centers were evaluated. The files were analyzed retrospectively after a mean 33 months of follow-up. RESULTS: The mean hospital stay was 11 days. Mean blood loss was 4.1g/dL. A postoperative transfusion was performed in 68 patients (55%), with a mean 3.1 units of blood. The mean global IKS score increased from 90 to 150 points. Eighty patients would agree to undergo simultaneous bilateral TKA again (65%), and 70 would recommend this procedure to others (57%). DISCUSSION: The hypothesis was not confirmed: the risk of complications was not increased compared to the generally accepted risk of a unilateral procedure. The risk of complications in this study was very similar to that published in the literature for the same therapeutic strategy. Therefore, there is no solid medical evidence to prevent recommending this strategy. The results of the participating centers suggest that this therapeutic approach should be continued in selected indications. LEVEL OF EVIDENCE: IV, retrospective study.

Forces applied with a hoof tester to cadaver feet vary widely between users.

Hoof testers are commonly used in equine practice. In this study, we determined the intraoperator and interoperator reliability of force application with hoof testers for different groups: experienced veterinarians, novices and farriers. For this purpose, we have developed and validated an instrumented hoof tester. Forces varied significantly between the different regions of the foot for experienced operators applying the highest forces to the heels, then the frog, then the toe, and the lowest forces to the quarters. Novices applied significantly more force to the toe versus the frog. Intraoperator reliability varied significantly between regions and operators. Novices had the narrowest width of limits of agreement for the frog and heel, but the widest for the toe and the quarters, whereas farriers had the narrowest width of agreement for the toe and quarter. Force application differed significantly between groups for the frog and heel regions, but not the toe and quarters. Veterinarians applied higher forces to the frog compared with farriers and novices, and higher forces to the heel compared with novices. This study showed that hoof tester forces vary widely within and between operators, and standardisation of hoof tester use is needed to make this diagnostic test more reliable.

Immediate passive motion versus immobilization after endoscopic supraspinatus tendon repair: a prospective randomized study.

INTRODUCTION: Rehabilitation programs after rotator cuff repair should allow recovery of shoulder function without preventing tendon healing. The aim of this randomized prospective study was to compare the clinical results after two types of postoperative management: immediate passive motion versus immobilization. PATIENTS AND METHODS: We followed 100 patients, mean age 55 years old, who underwent arthroscopic repair of a non-retracted supraspinatus tear. Patients were randomized to receive postoperative management of immediate passive motion or strict immobilization for 6 weeks. A clinical evaluation was performed in 92 patients, and CT arthrography in 82. Mean follow-up was 15 months. RESULTS: The mean preoperative Constant score improved significantly from 46.1 points to 73.9 at the final follow-up. The rate of intact cuffs was 58.5%. Functional results were statistically better after immediate passive motion with a mean passive external rotation of 58.7° at the final follow-up versus 49.1° after immobilization (P=0.011), a passive anterior elevation of 172.4° versus 163.3° (P=0.094) respectively, a Constant score of 77.6 points versus 69.7 (P=0.045) respectively, and a lower rate of adhesive capsulitis and complex regional pain syndrome. Results for healing seemed to be slightly better with immobilization, but this was not statistically significant: the cuff had a normal appearance in 35.9% of cases after immobilization compared to 25.6% after passive motion, an image of intratendinous addition was found in 25.6% versus 30.2%, punctiform leaks in 23.1% versus 20.9%, and recurrent tears in 15.4% versus 23.3% respectively. DISCUSSION: The rehabilitation program that results in better tendon healing by preventing postoperative stiffness has not yet been identified. Our results suggest that early passive motion should be authorized: the functional results were better with no significant difference in healing.

Magnetism, f-electron localization and superconductivity in 122-type heavy-fermion metals.

Both CeCu2Si2 and YbRh2Si2 crystallize in the tetragonal ThCr2Si2 crystal structure. Recent neutron-scattering results on normal-state CeCu2Si2 reveal a slowing down of the quasielastic response which complies with the scaling expected for a quantum critical point (QCP) of itinerant, i.e., three-dimensional spin-density-wave (SDW), type. This interpretation is in full agreement with the non-Fermi-liquid behavior observed in transport and thermodynamic measurements. The momentum dependence of the magnetic excitation spectrum reveals two branches of an overdamped dispersive mode whose coupling to the heavy charge carriers is strongly retarded. These overdamped spin fluctuations are considered to be the driving force for superconductivity in CeCu2Si2 (Tc = 600 mK). The weak antiferromagnet YbRh2Si2 (TN = 70 mK) exhibits a magnetic-field-induced QCP at BN = 0.06 T (B⊥c). There is no indication of superconductivity down to T = 10 mK. The magnetic QCP appears to concur with a breakdown of the Kondo effect. Doping-induced variations of the average unit-cell volume result in a detachment of the magnetic and electronic instabilities. A comparison of the properties of these isostructural compounds suggests that 3D SDW QCPs are favorable for unconventional superconductivity. The question whether a Kondo-breakdown QCP may also give rise to superconductivity, however, remains to be clarified.

The role of mitogen-activated protein kinase-activated protein kinase 2 in the p38/TNF-alpha pathway of systemic and cutaneous inflammation.

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a downstream molecule of p38, involved in the production of TNF-alpha, a key cytokine, and an established drug target for many inflammatory diseases. We investigated the role of MK2 in skin inflammation to determine its drug target potential. MK2 deficiency significantly decreased plasma TNF-alpha levels after systemic endotoxin application. Deficient mice showed decreased skin edema formation in chronic 2-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritative dermatitis and in subacute 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity. Surprisingly, MK2 deficiency did not inhibit edema formation in subacute 2,4-dinitrochlorobenzene (DNCB)-induced contact allergy and even increased TNF-alpha and IL-1beta levels as well as granulocyte infiltration in diseased ears. Ear inflammation in this model, however, was inhibited by TNF-alpha neutralization as it was in the subacute DNFB model. MK2 deficiency also did not show anti-inflammatory effects in acute DNFB-induced contact hypersensitivity, whereas the p38 inhibitor, SB203580, ameliorated skin inflammation supporting a pathophysiological role of p38. When evaluating possible mechanisms, we found that TNF-alpha production in MK2-deficient spleen cells was strongly diminished after TLR stimulation but less affected after T-cell receptor stimulation. Our data suggest that MK2, in contrast to its downstream effector molecule, TNF-alpha, has a rather elusive role in T-cell-dependent cutaneous inflammation.

Superconductivity versus quantum criticality: what can we learn from heavy fermions?

Two quantum critical point (QCP) scenarios are being discussed for different classes of antiferromagnetic (AF) heavy-fermion (HF) systems. In the itinerant one, where AF order is of the spin-density wave (SDW) type, the heavy 'composite' charge carriers keep their integrity at the QCP. The second one implies a breakdown of the Kondo effect and a disintegration of the composite fermions at the AF QCP. We discuss two isostructural compounds as exemplary materials for these two different scenarios: CeCu(2)Si(2) exhibits a three-dimensional (3D) SDW QCP and superconductivity, presumably mediated by SDW fluctuations, as strongly suggested by recent inelastic neutron scattering experiments. In Y bRh(2)Si(2), the AF QCP is found to coincide with a Kondo-destroying one. However, in the latter compound these two QCPs can be detached by varying the average unit-cell volume, e.g. through the application of chemical pressure, as realized by partial substitution of either Ir or Co for Rh. A comparison of CeCu(2)Si(2) and Y bRh(2)Si(2) indicates that the apparent differences in quantum critical behaviour go along with disparate behaviour concerning the (non-) existence of superconductivity (SC). No sign of SC could be detected in Y bRh(2)Si(2) down to mK temperatures. A potential correlation between the specific nature of the QCP and the occurrence of SC, however, requires detailed studies on further quantum critical HF superconductors, e.g. on ß-Y bAlB(4), UBe(13), CeCoIn(5) and CeRhIn(5).

Serum serotonin concentrations in dogs with degenerative mitral valve disease.

BACKGROUND: Increased serotonin (5HT) signaling has been implicated in valvular disease of humans and animals, including canine degenerative mitral valve disease (DMVD). High circulating 5HT concentration is a potential source of increased signaling, and serum 5HT concentrations have not been previously reported in dogs with DMVD. HYPOTHESIS: Dogs with DMVD and small breed dogs predisposed to DMVD have higher serum 5HT concentrations than large breed controls. ANIMALS: Fifty dogs affected with DMVD, 34 dogs predisposed to DMVD but without cardiac murmur or echocardiographic evidence of DMVD, and 36 healthy large breed control dogs. METHODS: Prospective analysis. Serum 5HT concentration was measured by an ELISA test. RESULTS: Median serum 5HT concentration was significantly higher in dogs with DMVD and in dogs predisposed to DMVD as compared with controls (DMVD, 765.5 ng/mL [interquartile range, 561.3-944.4]; predisposed, 774.9 ng/mL [528.3-1,026]; control, 509.8 ng/mL [320.8-708.8]; P= .0001). Subgroup analysis of predisposed dogs indicated significantly higher serum 5HT concentrations in Cavalier King Charles Spaniel (CKCS) dogs than in other breeds (CKCS, 855.0 ng/mL [635.8-1,088]; non-CKCS, 554.2 ng/mL [380.6-648.4]; P= .0023). Age, platelet count, and platelet morphology were not correlated with 5HT concentration in any group. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with DMVD had significantly higher serum 5HT concentrations when compared with large breed control dogs. Healthy CKCS dogs had significantly higher serum 5HT concentrations than other healthy dogs predisposed to DMVD. Additional investigation into a possible role of 5HT in the pathogenesis of DMVD is warranted.

Cytokines, NF-kappaB, microenvironment, intestinal inflammation and cancer.

Inflammation and cancer have been viewed as closely linked for many years. This link is not merely a loose association but causative. In colorectal cancer (CRC), chronic inflammation as observed in inflammatory bowel (IBD) disease is a key predisposing factor and IBD-associated CRC comprises five percent of all CRCs. Although the molecular mechanisms linking IBD with CRC are not well understood, recent results obtained in preclinical models point to the transcription factor NF-kappaB as a central player. On the one hand, NF-kappaB regulates the expression of various cytokines and modulates the inflammatory processes in IBD. On the other, NF-kappaB stimulates the proliferation of tumor cells and enhances their survival through the regulation of anti-apoptotic genes. Furthermore, it has been clearly established that most carcinogens and tumor promoters activate NF-kappaB, while chemopreventive agents generally suppress this transcription factor. Actually, several lines of evidence suggest that activation of NF-kappaB may cause cancer. These include the finding that NF-kappaB genes can be oncogenes, and that this transcription factor controls apoptosis, cell-cycle progression and proliferation, and possibly also cell differentiation.