Forty-nine patients with active rheumatoid arthritis completed a 24-week, prospective, double-blind, randomized study of dietary supplementation with 2 different dosages of fish oil and 1 dosage of olive oil. Clinical evaluations were performed at baseline and every 6 weeks thereafter, and immunologic variables were measured at baseline and after 24 weeks of study. The 3 groups of patients were matched for age, sex, disease severity, and use of disease-modifying antirheumatic drugs (DMARDs). Subjects continued receiving DMARDs and other background medications without change during the study. Twenty patients consumed daily dietary supplements of n3 fatty acids containing <em>27</em> mg/kg eicosapentaenoic acid (EPA) and 18 mg/kg docosahexaenoic acid (DHA) (low dose), 17 patients ingested 54 mg/kg EPA and 36 mg/kg DHA (high dose), and 12 patients ingested olive oil capsules containing 6.8 gm of oleic acid. Significant improvements from baseline in the number of tender joints were noted in the low-dose group at week 24 (P = 0.05) and in the high-dose group at week 18 (P = 0.04) and 24 (P = 0.02). Significant decreases from baseline in the number of swollen joints were noted in the low-dose group at weeks 12 (P = 0.003), 18 (P = 0.002), and 24 (P = 0.001) and in the high-dose group at weeks 12 (P = 0.0001), 18 (P = 0.008), and 24 (P = 0.02). A total of 5 of 45 clinical measures were significantly changed from baseline in the olive oil group, 8 of 45 in the low-dose fish oil group, and 21 of 45 in the high-dose fish oil group during the study (P = 0.0002). Neutrophil leukotriene B4 production decreased by 19% from baseline in the low-dose fish oil group (P = 0.0003) and 20% in the high-dose group (P = 0.03), while macrophage <em>interleukin</em>-1 production decreased by 38.5% in the olive oil group (P not significant), 40.6% in the low-dose group (P = 0.06), and 54.7% in the high-dose group (P = 0.0005). Tritiated thymidine incorporation in peripheral blood mononuclear cells after stimulation with concanavalin A increased significantly in all 3 groups after 24 weeks, compared with baseline values. We conclude that the clinical benefits of dietary supplementation with omega-3 fatty acids are more commonly observed in patients consuming higher dosages of fish oil for time intervals that are longer than those previously studied. Dietary supplementation with olive oil is also associated with certain changes in immune function, which require further investigation.

The importance of a collagen-binding adhesin in the pathogenesis of septic arthritis has been examined by comparing the virulence of two sets of Staphylococcus aureus mutants in an animal model. Collagen adhesin-negative mutant PH100 was constructed by replacing the chromosomal collagen adhesin gene (cna) in a clinical strain, Phillips, with an inactivated copy of the gene. Collagen adhesin-positive mutant S. aureus CYL574 was generated by introducing the cna gene into CYL316, a strain that normally lacks the cna gene. Biochemical, immunological, and functional analyses of the generated mutants and their respective parent strains showed that binding of 125I-labeled collagen, expression of an immunoreactive collagen adhesin, and bacterial adherence to cartilage were directly correlated with the presence of a functional cna gene. Greater than 70% of the mice injected with the Cna+ strains developed clinical signs of arthritis, whereas less than <em>27</em>% of the animals injected with Cna- strains showed symptoms of disease. Furthermore, mice injected with the Cna+ strain Phillips had remarkably elevated levels of immunoglobulin G1 and <em>interleukin</em>-6 compared with mice injected with the Cna- mutant PH100. Taken together, these results demonstrate that collagen adhesin plays an important role in the pathogenesis of septic arthritis induced by S. aureus.

BACKGROUND

Inflammatory markers are increased in chronic obstructive pulmonary disease (COPD) and are hypothesised to play an important part in muscle dysfunction and exercise intolerance.

METHODS

The Health Aging and Body Composition (Health ABC) study is a prospective observational cohort of well functioning individuals aged 70-79 years. A cross sectional analysis of the baseline data was conducted to examine the association between inflammatory markers and ventilatory limitation, muscle strength, and exercise capacity. These associations were compared in participants with and without obstructive lung disease (OLD).

RESULTS

Of the 3075 participants enrolled in the Health ABC cohort, OLD was identified by spirometric testing in 268 participants and 2005 participants had normal spirometric results. Of the participants with OLD, 35%, 38%, and <em>27</em>% participants had mild, moderate, and severe OLD, respectively. Participants with OLD had lower quadriceps strength (102.5 Nm v 108.9 Nm, p = 0.02), lower maximum inspiratory pressure (64.7 cm H(2)O v 74.2 cm H(2)O, p<0.0001), higher systemic <em>interleukin</em> (IL)-6 levels (2.6 pg/ml v 2.2 pg/ml, p<0.0001), and higher C-reactive protein (CRP) levels (3.5 mg/l v 2.5 mg/l, p<0.0001) than those with normal spirometry. In participants with OLD and those with normal spirometry, forced expiratory volume in 1 second (FEV(1)) was associated with IL-6 (adjusted regression coefficients (beta) = -5.3 (95% CI -9.1 to-1.5) and -3.1 (95% CI -4.3 to -1.9), respectively). IL-6 and TNF were also associated with quadriceps strength among participants with OLD and those with normal spirometry (beta = -6.4 (95% CI -12.8 to -0.03) and -3.4 (95% CI -5.4 to -1.3), respectively, for IL-6 and beta = -10.1 (95% CI -18.7 to -1.5) and -3.8 (95% CI -7 to -0.6), respectively, for TNF). IL-6, quadriceps strength, and maximum inspiratory pressures were independent predictors of reduced exercise capacity in both groups.

CONCLUSIONS

In well functioning elderly subjects with or without OLD, IL-6 is associated with reduced FEV(1), quadriceps strength, and exercise capacity.

<b>Objective:</b> To analyze the clinical characteristics of 2019 novel coronavirus (2019-nCoV) pneumonia and to investigate the correlation between serum inflammatory cytokines and severity of the disease. <b>Methods:</b> 29 patients with 2019-ncov admitted to the isolation ward of Tongji hospital affiliated to Tongji medical college of Huazhong University of Science and Technology in January 2020 were selected as the study subjects. Clinical data were collected and the general information, clinical symptoms, blood test and CT imaging characteristics were analyzed. According to the relevant diagnostic criteria, the patients were divided into three groups: mild (15 cases), severe (9 cases) and critical (5 cases). The expression levels of inflammatory cytokines and other markers in the serum of each group were detected, and the changes of these indicators of the three groups were compared and analyzed, as well as their relationship with the clinical classification of the disease. <b>Results:</b> (1) The main symptoms of 2019-nCoV pneumonia was fever (28/29) with or without respiratory and other systemic symptoms. Two patients died with underlying disease and co-bacterial infection, respectively. (2) The blood test of the patients showed normal or decreased white blood cell count (23/29), decreased lymphocyte count (20/29), increased hypersensitive C reactive protein (hs-CRP) (<em>27</em>/29), and normal procalcitonin. In most patients,serum lactate dehydrogenase (LDH) was significantly increased (20/29), while albumin was decreased(15/29). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Tbil), serum creatinine (Scr) and other items showed no significant changes. (3) CT findings of typical cases were single or multiple patchy ground glass shadows accompanied by septal thickening. When the disease progresses, the lesion increases and the scope expands, and the ground glass shadow coexists with the solid shadow or the stripe shadow. (4) There were statistically significant differences in the expression levels of <em>interleukin</em>-2 receptor (IL-2R) and IL-6 in the serum of the three groups (P<0.05), among which the critical group was higher than the severe group and the severe group was higher than the mildgroup. However, there were no statistically significant differences in serum levels of tumor necrosis factor-alpha (TNF-α), IL-1, IL-8, IL-10, hs-CRP, lymphocyte count and LDH among the three groups (P>0.05). <b>Conclusion:</b> The clinical characteristics of 2019-nCoV pneumonia are similar to those of common viral pneumonia. High resolution CT is of great value in the differential diagnosis of this disease. The increased expression of IL-2R and IL-6 in serum is expected to predict the severity of the 2019-nCoV pneumonia and the prognosis of patients.

It has been more than 15 years since the identification of individual <em>interleukin</em>-<em>27</em> (IL-<em>27</em>) and IL-<em>27</em> receptor components. The last decade has seen the description of the signaling pathways engaged by IL-<em>27</em>, and an appreciation has emerged that this cytokine can modulate the intensity and duration of many classes of T cell responses. Here we provide an overview of the immunobiology of IL-<em>27</em> and review advances in understanding the functions of individual IL-<em>27</em> and IL-<em>27</em> receptor subunits and the role of IL-<em>27</em> in dictating the balance between protective and pathological immunity. Additionally, this cytokine has been proposed as a therapy to modify inflammatory conditions or to promote antitumor responses, and situations where experimental and clinical data sets implicate IL-<em>27</em> in the outcome of disease are highlighted.

BACKGROUND

The aim of this study was to quantify the number of T-helper (TH)-17 cells present in rheumatoid arthritis (RA) synovial fluid (SF) and to determine the level of <em>interleukin</em> (IL)-17 cytokine in RA, osteoarthritis (OA) and normal synovial tissue, as well as to examine SF macrophages for the presence of IL-23, IL-<em>27</em> and interferon (IFN)-gamma.

METHODS

Peripheral blood (PB) mononuclear cells from normal and RA donors and mononuclear cells from RA SF were examined either without stimulation or after pretreatment with IL-23 followed by stimulation with phorbol myristate acetate (PMA) plus ionomycin (P/I). The abundance of TH-17 cells in RA SF was determined by flow cytometry. IL-17 levels were quantified in synovial tissue from RA, OA and normal individuals by ELISA and IL-23 was identified in SFs by ELISA. RA SF and control in vitro differentiated macrophages were either untreated or treated with the toll-like receptor (TLR) 2 ligand peptidoglycan, and then IL-23, IL-<em>27</em> and IFN-gamma mRNA levels were quantified by real-time polymerase chain reaction (RT-PCR).

RESULTS

Treatment with P/I alone or combined with IL-23 significantly increased the number of TH-17 cells in normal, RA PB and RA SF. With or without P/I plus IL-23, the percentage of TH-17 cells was higher in RA SF compared with normal and RA PB. IL-17 levels were comparable in OA and normal synovial tissues, and these values were significantly increased in RA synovial tissue. Although IL-17 was readily detected in RA SFs, IL-23 was rarely identified in RA SF. However, IL-23 mRNA was significantly increased in RA SF macrophages compared with control macrophages, with or without TLR2 ligation. IL-<em>27</em> mRNA was also significantly higher in RA SF compared with control macrophages, but there was no difference in IL-<em>27</em> levels between RA and control macrophages after TLR2 ligation. IFN-gamma mRNA was also detectable in RA SF macrophages but not control macrophages and the increase of IFN-gamma mRNA following TLR2 ligation was greater in RA SF macrophages compared with control macrophages.

CONCLUSIONS

These observations support a role for TH-17 cells in RA. Our observations do not strongly support a role for IL-23 in the generation of TH-17 cells in the RA joint, however, they suggest strategies that enhance IL-<em>27</em> or IFN-gamma might modulate the presence of TH-17 cells in RA.

BACKGROUND

Fluorodeoxyglucose positron-emission tomography (FDG PET) imaging of atherosclerosis has been used to quantify plaque inflammation and to measure the effect of plaque-stabilizing drugs. We explored how atherosclerotic plaque inflammation varies across arterial territories and how it relates to arterial calcification. We also tested the hypotheses that the degree of local arterial inflammation measured by PET is correlated with the extent of systemic inflammation and presence of risk factors for vascular disease.

RESULTS

Forty-one subjects underwent vascular PET/computed tomography imaging with FDG. All had either vascular disease or multiple risk factors. Forty subjects underwent carotid imaging, <em>27</em> subjects underwent aortic, 24 subjects iliac, and 13 subjects femoral imaging. Thirty-three subjects had a panel of biomarkers analyzed. We found strong associations between FDG uptake in neighboring arteries (left versus right carotid, r=0.91, P<0.001; ascending aorta versus aortic arch, r=0.88, P<0.001). Calcification and inflammation rarely overlapped within arteries (carotid artery FDG uptake versus calcium score, r=-0.42, P=0.03). Carotid artery FDG uptake was greater in those with a history of coronary artery disease (target-to-

BACKGROUND

<0.01) and in males versus females (target-to-

BACKGROUND

<0.05). Similar findings were also noted in the aorta and iliac arteries. Subjects with the highest levels of FDG uptake also had the greatest concentrations of inflammatory biomarkers (descending aorta target-to-

BACKGROUND

=0.53, P=0.01; carotid target-to-

BACKGROUND

=0.50, P=0.01). Nonsignificant positive trends were seen between FDG uptake and levels of interleukin-18, fibrinogen, and C-reactive protein. Finally, we found that the atheroprotective biomarker adiponectin was negatively correlated with the degree of arterial inflammation in the descending aorta (r=-0.49, P=0.03).

CONCLUSIONS

This study shows that FDG PET imaging can increase our knowledge of how atherosclerotic plaque inflammation relates to calcification, serum biomarkers, and vascular risk factors. Plaque inflammation and calcification rarely overlap, supporting the theory that calcification represents a late, burnt-out stage of atherosclerosis. Inflammation in one arterial territory is associated with inflammation elsewhere, and the degree of local arterial inflammation is reflected in the blood levels of several circulating biomarkers. We suggest that FDG PET imaging could be used as a surrogate marker of both atherosclerotic disease activity and drug effectiveness. Prospective, event-driven studies are now underway to determine the role of this technique in clinical risk prediction.

A first pilot study of <em>interleukin</em>-1 blockade in ST-segment elevation acute myocardial infarction showed improved remodeling. In the present second pilot study, we enrolled 30 patients with clinically stable ST-segment elevation acute myocardial infarction randomized to anakinra, recombinant <em>interleukin</em>-1 receptor antagonist, 100 mg/day for 14 days or placebo in a double-blind fashion. The primary end point was the difference in the interval change in left ventricular (LV) end-systolic volume index between the 2 groups within 10 to 14 weeks. The secondary end points included changes in the LV end-diastolic volume index, LV ejection fraction, and C-reactive protein levels. No significant changes in end-systolic volume index, LV end-diastolic volume index, or LV ejection fraction were seen in the placebo group. Compared to placebo, treatment with anakinra led to no measurable differences in these parameters. Anakinra significantly blunted the increase in C-reactive protein between admission and 72 hours (+0.8 mg/dl, interquartile range -6.4 to +4.2, vs +21.1 mg/dl, interquartile range +8.7 to +36.6, p = 0.002), which correlated with the changes in LV end-diastolic volume index and LV end-systolic volume index at 10 to 14 weeks (R = +0.83, p = 0.002, and R = +0.55, p = 0.077, respectively). One patient in the placebo group (7%) died. One patient (7%) in the anakinra group developed recurrent acute myocardial infarction. More patients were diagnosed with new-onset heart failure in the placebo group (4, <em>27</em>%) than in the anakinra group (1, 7%; p = 0.13). When the data were pooled with those from the first Virginia Commonwealth University-Anakinra Remodeling Trial (n = 40), this difference reached statistical significance (30% vs 5%, p = 0.035). In conclusion, <em>interleukin</em>-1 blockade with anakinra blunted the acute inflammatory response associated with ST-segment elevation acute myocardial infarction. Although it failed to show a statistically significant effect on LV end-systolic volume index, LV end-diastolic volume index, or LV ejection fraction in this cohort of clinically stable patients with near-normal LV dimensions and function, anakinra led to a numerically lower incidence of heart failure.

OBJECTIVE

We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer.

METHODS

A nested case-control design was used to select patients enrolled onto the MA.<em>27</em> phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip.

RESULTS

The GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression.

CONCLUSIONS

This GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events.

Pancreatic cancer is characterized by an extremely poor prognosis. For the development of more effective immunotherapies, the systemic and local immunological escape mechanisms need to be further elaborated. These mechanisms may include the secretion of immunosuppressive cytokines, the local hindrance of tumor-infiltrating lymphocytes (TILs), or the loss of the signal transducing CD3 zeta-chain of TILs. In this study, we have analyzed these parameters in 116 patients suffering from pancreatic ductal adenocarcinoma. Mean concentrations of <em>interleukin</em> (IL)-10 and transforming growth factor-beta1/2 were considerably higher than in control sera (P < 0.0001). Disseminated tumor cells were found in 16 of 39 cases. In 28 of 33 surgical specimens, TILs did not reach tumor cells in significant numbers, being "trapped" in the peritumoral tissues. We suggest this as a simple but highly effective tumor escape mechanism. In cases of a TIL/tumor cell contact, CD3 zeta was mostly lost. Overall, <em>27</em> of 33 surgical specimens, 9 of 19 peritumoral lymph nodes, and 13 of 25 peritoneal lavage specimens showed significant loss of CD3 zeta (P < 0.02). Elevated concentrations of IL-10/TGF-beta1/2 were, in all but one of three cases, correlated with a CD3 zeta loss in corresponding specimens. Patients with disseminated tumor cells also showed a CD3 zeta loss in all but two corresponding tumor specimens. These results present strong evidence for an active systemic immunosuppression in pancreatic cancer, as shown by elevated IL-10 and TGF-beta1/2 serum levels as well as the presence of disseminated tumor cells. Killing of tumor cells by potentially cytotoxic TILs is obviously suppressed by the prevention of a direct TIL/tumor cell contact and the inactivation of TILs, as shown by a severe loss of CD3 zeta. In addition to active immunization strategies, successful immunotherapies have to focus on restoring in vivo T-cell function to improve the almost always fatal prognosis of pancreatic cancer.

BACKGROUND

Early clinical studies suggested that the anti-interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis.

METHODS

In two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician's global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to a 100% reduction in PASI score (PASI 100).

RESULTS

At week 12, the PASI 75 response rates were higher with brodalumab at the 210-mg and 140-mg doses than with placebo (86% and 67%, respectively, vs. 8% [AMAGINE-2] and 85% and 69%, respectively, vs. 6% [AMAGINE-3]; P<0.001); the rates of sPGA scores of 0 or 1 were also higher with brodalumab (P<0.001). The week 12 PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (44% vs. 22% [AMAGINE-2] and 37% vs. 19% [AMAGINE-3], P<0.001). The PASI 100 response rates with 140 mg of brodalumab were 26% in AMAGINE-2 (P=0.08 for the comparison with ustekinumab) and 27% in AMAGINE-3 (P=0.007). Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo. Mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo. Through week 52, the rates of serious infectious episodes were 1.0 (AMAGINE-2) and 1.3 (AMAGINE-3) per 100 patient-years of exposure to brodalumab.

CONCLUSIONS

Brodalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis. (Funded by Amgen; AMAGINE-2 and AMAGINE-3 ClinicalTrials.gov numbers, NCT01708603 and NCT01708629.).

Patients with metastatic renal cell cancer and metastatic melanoma treated with high-dose <em>interleukin</em>-2-based immunotherapy were prospectively evaluated for the development of vitiligo. All patients seen in the Surgery Branch, NCI Immunotherapy Clinic, who had been followed for at least 1 year were evaluated. Of 104 patients with metastatic renal cancer none developed vitiligo, though vitiligo was seen in 11 of 74 (15%) patients with metastatic melanoma (p2 = 0.0001). No vitiligo was seen in <em>27</em> patients who did not respond to immunotherapy, although vitiligo was seen in 11 of 43 (26%) melanoma patients who had an objective response to IL-2-based immunotherapy (p2 = 0.0002). These findings provide further evidence that the presence of a growing melanoma can sensitize patients to melanocyte-differentiation antigens and that the immune response against these antigens is associated with cancer regression in patients undergoing immunotherapy.

Increased <em>interleukin</em>-6 (IL-6) production is implicated in the pathogenesis of hepatocellular carcinoma (HCC) in animal models. Although previous studies showed that HCC patients had higher serum IL-6 level at the time of diagnosis, it is unclear if the cytokine contributes to the development of HCC or is just a reaction to cancer. To address this question, we performed a nested case-control study. Consecutive chronic hepatitis B patients were recruited from 1997 to 2000 and followed till 2008. Profiling of <em>27</em> cytokines, chemokines and growth factors was performed at baseline, date of peak alanine aminotransferase (ALT) level and the last visit. Thirty-seven patients developed HCC at a median follow-up of 62 months (interquartile range: 41-110). Serum IL-6 was higher in patients with HCC than controls both during peak ALT and at the last visit (both p = 0.02). Patients with IL-6 above 7 pg/ml during peak ALT had increased risk of HCC or death (adjusted hazard ratio 3.0; 95% confidence interval 1.2, 7.8; p = 0.02). The sensitivity, specificity, positive and negative predictive values of this cutoff to predict future HCC development were 70%, 73%, 72% and 71%, respectively. Combination of IL-6 and AFP improved the sensitivity in diagnosing HCC or predicting future HCC development. In conclusion, high serum IL-6 level predates the development of HCC in chronic hepatitis B patients, and has moderate accuracy in predicting future cancer. This may assist clinicians in selecting high-risk patients for HCC surveillance program.

<em>Interleukin</em>-<em>27</em> (IL-<em>27</em>) is a cytokine with strikingly diverse influences on the immune response. Although it was initially linked with the development of Th1 responses, it is now recognized as a potent antagonist of different classes of inflammation through its ability to directly modify CD4(+) and CD8(+) T cell effector functions, to induce IL-10, and to promote specialized T regulatory cell responses. Although this aspect of IL-<em>27</em> biology has provided insights into how the immune system prevents hyperactivity in the setting of infectious and autoimmune inflammation, in vaccination and cancer models the stimulatory effects of IL-<em>27</em> on CD8(+) T cell function appear prominent. Additionally, associations between IL-<em>27</em> and antibody-mediated disease have led to an interest in defining the impact of IL-<em>27</em> on innate immunity and humoral responses in different disease states. The maturation of this literature has been accompanied by attempts to translate these findings from experimental models into human diseases and by efforts to define where IL-<em>27</em> might represent a viable therapeutic target.

BACKGROUND

Chronic heart failure is associated with inflammation and neurohormonal imbalance. The 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, exert anti-inflammatory and vascular protective effects. We hypothesized that short-term statin therapy may have beneficial effects in patients with nonischemic heart failure.

RESULTS

Sixty-three patients with symptomatic, nonischemic, dilated cardiomyopathy were randomly divided into 2 groups. One group received simvastatin (n=24), and the other group received placebo (n=<em>27</em>). The initial dose of simvastatin was 5 mg/d, which was increased to 10 mg/d after 4 weeks. After 14 weeks, patients receiving simvastatin exhibited a modest reduction in serum cholesterol level compared with patients receiving placebo (130+/-13 versus 148+/-18, P<0.05). Patients treated with simvastatin had a lower New York Heart Association functional class compared with patients receiving placebo (2.04+/-0.06 versus 2.32+/-0.05, P<0.01). This corresponded to improved left ventricular ejection fraction in the simvastatin group (34+/-3 to 41+/-4%, P<0.05) but not in the placebo group. Furthermore, plasma concentrations of tumor necrosis factor-alpha, <em>interleukin</em>-6, and brain natriuretic peptide were significantly lower in the simvastatin group compared with the placebo group.

CONCLUSIONS

Short-term statin therapy improves cardiac function, neurohormonal imbalance, and symptoms associated with idiopathic dilated cardiomyopathy. These findings suggest that statins may have therapeutic benefits in patients with heart failure irrespective of serum cholesterol levels or atherosclerotic heart disease.

Advances in cytokine biology have helped us understand the complex communication that takes place between antigen-presenting cells and cells of the adaptive immune system, such as T cells, which collectively mediate an appropriate immune response to a plethora of pathogens while maintaining tolerance to self-antigens. The <em>interleukin</em>-12 (IL-12) cytokine family remains one of the most important and includes IL-12, IL-23, IL-<em>27</em>, and the recently identified IL-35. All four are heterodimeric cytokines, composed of an alpha chain (p19, p28, or p35) and a beta chain (p40 or Ebi3), and signal through unique pairings of five receptor chains (IL-12Rbeta1, IL-12Rbeta2, IL-23R, gp130, and WSX-1). Despite the interrelationship between the cytokines themselves and their receptors, their source, activity, and kinetics of expression are quite different. Studies using genetically deficient mice have greatly enhanced our understanding of the biology of these cytokines. However, interpretation of these data has been complicated by the recent realization that p40(-/-), p35(-/-), and Ebi3(-/-) mice all lack more than one cytokine (IL-12/IL-23, IL-12/IL-35, and IL-<em>27</em>/IL-35, respectively). In this review, we compare and contrast the biology of this expanded IL-12 family and re-evaluate data derived from the analysis of these dual cytokine-deficient mice. We also discuss how the opposing characteristics of the IL-12 family siblings may help to promote a balanced immune response.

The beta-chemokine RANTES was measured in plasma in 43 patients with breast cancer and in 23 patients with cervical cancer, and the RANTES content in primary tumors, tumor metastatic to lymph nodes, and clinically normal skin or pelvic mucosa was measured. In addition, plasma levels were determined in all of the patients for the platelet-derived chemokine beta-thromboglobulin (beta-TG) and for IFN-gamma, <em>interleukin</em> (IL)-2, IL-4, IL-5, and IL-10, along with serum IgE levels and blood eosinophils. Plasma RANTES levels were found to be higher in order of stages IV, III, II, and I of each cancer except for stage I. A marked increase in plasma RANTES level >> 10,000 pg/ml) was found in <em>27</em>% of patients with progressive malignancy but in none of those in clinical remission. The platelet RANTES content was correspondingly decreased in those patients with increased plasma RANTES levels. Beta-TG showed a pattern similar to RANTES both in plasma and platelets, but with much less dramatic differences between patients with different stages of disease. Other allergic parameters, IgE, eosinophils and plasma IFN-gamma, IL-2, -5, and -10, were not elevated in the cancer patients. The RANTES content was markedly elevated in the primary tumor and metastatic lesions (lymph node or skin) from all of the patients with breast or cervical cancer, irrespective of the plasma RANTES level. In addition, in patients with progressive breast or cervical cancer, but not in patients thought to be cured of these tumors, the RANTES content was markedly increased in clinically normal tissue taken from near the operative site several months postoperatively, as well as in intact skin or mucosa taken perioperatively near the excised tumor. This study suggests an as-yet-undefined but important role played by RANTES in carcinogenesis, as well as the possibility that a RANTES assay in tissue surrounding a tumor or postoperative tumor site may help predict prognosis in these patients.

OBJECTIVE

Contrast-induced nephropathy (CIN) is at present the third leading cause of hospital-acquired acute kidney injury (AKI). Traditionally, it is diagnosed by measuring the increase of the serum creatinine concentration. However, in patients with acute changes in their glomerular filtration rate, serum creatinine is an insensitive marker. This clinical study was designed to investigate whether human urinary interleukin-18 (IL-18) and neutrophil gelatinase-associated lipocalin (NGAL) are early predictive markers for AKI after coronary angiography and their correlation with later cardiac events.

METHODS

Patients undergoing coronary angiography using low-osmolar contrast medium were enrolled and then followed up for at least 17 months. Urine samples were collected before and 24 h after coronary angiography and IL-18 and NGAL levels measured by using an ELISA kit.

RESULTS

CIN was diagnosed in 13 of 150 (8.7%) patients (CIN group); 27 patients without CIN served as control group. At 24 h after the procedure, the urinary IL-18 and NGAL levels were significantly increased in the CIN group, but not in the control group (p < 0.05). The predictable time of AKI onset determined by IL-18 was 24 h earlier than determined by serum creatinine (p < 0.01). Receiver operating characteristic curve analysis showed that both IL-18 and NGAL showed a good performance in early diagnosis of CIN as compared with serum creatinine (p < 0.05). We also found that IL-18 is an independent predictive marker for later major cardiac events: relative risk = 2.09 (p < 0.01).

CONCLUSIONS

We conclude that urinary IL-18 or NGAL could be early biomarkers of CIN and that urinary IL-18 is well associated with the later cardiac outcomes in patients after coronary angiography.

OBJECTIVE

Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin-2) is a glycoprotein with bacteriostatic properties. Growing evidence suggests that NGAL may also be involved in cell survival, inflammation, and matrix degradation. We therefore aimed to investigate the role of NGAL in heart failure (HF).

RESULTS

Our main findings were (i) patients with acute post-myocardial infarction (MI) HF (n = 236) and chronic HF (n = 150) had elevated serum levels of NGAL (determined by enzyme immunoassay), significantly correlated with clinical and neurohormonal deterioration, (ii) in patients with HF following acute MI, elevated NGAL levels of at baseline were associated with adverse outcomes (median of <em>27</em> months follow-up), (iii) in a rat model of post-MI HF, NGAL/lipocalin-2 gene expression was increased in the non-ischaemic part of the left ventricle primarily located to cardiomyocytes, (iv) strong NGAL immunostaining was found in cardiomyocytes within the failing myocardium both in experimental and clinical HF, (v) <em>interleukin</em>-1beta and agonists for toll-like receptors 2 and 4, representing components of the innate immune system, were potent inducers of NGAL/lipocalin-2 in isolated neonatal cardiomyocytes.

CONCLUSIONS

Our demonstration of enhanced systemic and myocardial NGAL expression in clinical and experimental HF further support a role for innate immune responses in the pathogenesis of HF.

Although much promising data that <em>interleukin</em> (IL)-12 could be a powerful therapeutic agent against cancer were reported in animal models, its excessive toxicity has become a problem for its clinical application. IL-<em>27</em> is a novel IL-12 family member that plays a role in the early regulation of T helper cell 1 initiation, including induction of T-bet and IL-12 receptor beta 2 expression. In the present study, we have evaluated the antitumor activity of IL-<em>27</em> against a murine tumor model of colon carcinoma C26. C26 cells, which were transduced with the single-chain IL-<em>27</em> cDNA and became secreting IL-<em>27</em> (C26-IL-<em>27</em>), exhibited minimal tumor growth in vivo, and all of the mice inoculated with these cells survived healthily with complete tumor remission. Inoculation of mice with C26-IL-<em>27</em> induced enhanced IFN-gamma production and cytotoxic T-lymphocyte activity against C26 tumor in spleen cells. Recovered mice from the inoculation showed a tumor-specific protective immunity to the following challenge with parental C26 tumor. The antitumor activity of IL-<em>27</em> was almost diminished in nude mice, and depletion of CD8(+) T cells and neutralization of IFN-gamma in immunocompetent mice reduced greatly the antitumor activity. Moreover, the antitumor activity was abolished in T-bet-deficient mice, whereas it was observed unexpectedly in mice deficient of signal transducer and activator of transcription (STAT) 4. These results suggest that IL-<em>27</em> has potent abilities to induce tumor-specific antitumor activity and protective immunity and that the antitumor activity is mediated mainly through CD8(+) T cells, IFN-gamma, and T-bet but not through STAT4.

The purpose of the study was to identify a comprehensive prognostic system of pretreatment clinical parameters in 425 patients (pts) with metastatic renal-cell carcinoma treated with different subcutaneous (s.c.) recombinant cytokine-based home therapies in consecutive trials. Treatment consisted of (A) s.c. interferon-alpha 2a (INF-alpha), s.c. <em>interleukin</em>-2 (IL-2) (n=102 pts), (B) s.c. IFN-alpha 2a, s.c. IL-2, and i.v. 5-fluorouracil (5-FU) (n=235 pts) or (C) s.c. IFN-alpha 2a, s.c. IL-2, and i.v. 5-FU combined with p.o. 13-cis-retinoic acid (13cRA) (n=88 pts). Kaplan-Meier survival analysis, log-rank statistics, and Cox regression analysis were employed to identify risk factors and to create a multiple risk factor model. The following pretreatment risk factors were identified by univariate analysis: (1) three and more metastatic sites, (2) presence of liver, lymph node or bone metastases, (3) neutrophil count>> or = 6500 cells microl(-1), (4) serum lactate dehydrogenase level (LDH)>> or = 220 U l(-1), and (5) serum C-reactive protein level (CRP)>> or = 11 mg l(-1). Cox regression analysis with forward stepwise variable selection identified neutrophil count as the major prognostic factor (hazard ratio=1.9, P<0.001), while serum levels of LDH and CRP, time between diagnosis of tumour and onset of metastatic disease, number of metastatic sites, and bone metastases were significant but somewhat less important prognostic variables within the multiple risk factor model (hazard ratio < or = 1.5). Patients were assigned to one of the three risk groups according to cumulative risk defined as the sum of simplified risk s.c.ores for six pretreatment variables. Low-, intermediate-, and high-risk patients achieved a median overall survival of 32+ months (95% CI 24, 43; 5-year survival of <em>27</em>%), 18+ months (95% CI 15, 20; 5-year survival of 11%), and 8+ months (95% CI 6, 10; 5-year survival of 5%), respectively. These prognostic categories are helpful both in individual patient care and in the assessment of patients entering prospective clinical trials.

OBJECTIVE

Bone metastases occur in approximately 80% of patients with advanced prostate cancer. Pain is common in these patients. The purpose of this study was to evaluate the effect of an intravenous bisphosphonate, pamidronate disodium, on pain control in metastatic prostate cancer patients.

METHODS

Two multicenter, double-blind, randomized, placebo-controlled trials were conducted in patients with bone pain due to metastatic prostate cancer, with disease progression after first-line hormonal therapy. Intravenous pamidronate disodium (90 mg) or placebo was administered every 3 weeks for <em>27</em> weeks. Efficacy was measured via self-reported pain score (Brief Pain Inventory), analgesic use, the proportion of patients with a skeletal-related event (SRE; defined as pathologic fracture, radiation or surgery to bone, spinal cord compression, or hypercalcemia), and a pilot quantitative measurement of mobility. Laboratory evaluations included serum prostate-specific antigen, <em>interleukin</em>-6, bone alkaline phosphatase, and urinary bone resorption markers.

RESULTS

Results of the two trials were pooled. There were no sustained significant differences between the pamidronate and placebo groups in self-reported pain measurements, analgesic use, proportion of patients with an SRE, or mobility at week 9 or <em>27</em>. Urinary bone resorption markers were suppressed in the pamidronate group compared with placebo.

CONCLUSIONS

Pamidronate disodium failed to demonstrate a significant overall treatment benefit compared with placebo in palliation of bone pain or reduction of SREs. Evaluation of more potent bisphosphonates in patients with prostate cancer is warranted.

The unique clinicopathologic features of Hodgkin lymphoma (HL) are due to the multiple cytokines produced by its neoplastic cells, the Hodgkin and Reed-Sternberg (HRS) cells. Cytokine signaling is mediated through the signal transducer and activator of transcription (STAT) family of transcription factors. Immunoblotting and immunohistochemistry were used to examine cell lines and tissue sections derived from patients with HL and non-Hodgkin lymphoma (NHL) for expression of activated STAT proteins. Constitutive phosphorylation of STAT6 and STAT3 was common in HL. STAT6 was constitutively phosphorylated in 5 of 5 HL cell lines and in HRS cells from 25 of 32 (78%) classical HL cases. STAT3 was constitutively phosphorylated in 4 of 5 HL cell lines and in HRS cells from <em>27</em> of 31 (87%) classical HL cases. Only 4 of 24 NHL cases demonstrated constitutive STAT6 activation, whereas STAT3 activation was observed in 6 of 13 (46%) cases of B-cell NHL and 8 of 11 (73%) cases of T-cell NHL. Constitutive STAT5 phosphorylation was not a common feature of HL or NHL. STAT6 mediates signaling by <em>interleukin</em> 13 (IL-13), a cytokine frequently expressed by HRS cells. Antibody-mediated neutralization of IL-13 resulted in significant decreases in both cellular proliferation and levels of phosphorylated STAT6 of HL cell lines. In conclusion, constitutive STAT6 phosphorylation is a common and distinctive feature of HRS cells in classical HL, whereas STAT3 activation was regularly present in both HL and NHL. These results suggest that IL-13 signaling is largely responsible for the constitutive STAT6 activation observed in HRS cells and further implicate IL-13 as an important growth factor in classical HL.

OBJECTIVE

gamma9delta2 T lymphocytes have been shown to be directly cytotoxic against renal carcinoma cells. Lymphocytes T gammadelta can be selectively expanded in vivo with BrHPP (IPH1101, Phosphostim) and interleukin 2 (IL-2). A phase I Study was conducted in patients with metastatic renal cell carcinoma (mRCC) to determine the maximum-tolerated dose and safety of Innacell gammadelta, an autologous cell-therapy product based on gamma9delta2 T lymphocytes, in patients with mRCC.

METHODS

A 1-h intravenous infusion of gamma9delta2 T lymphocytes was administered alone during treatment cycle 1 and combined with a low dose of subcutaneous interleukin-2 (IL-2, 2 MIU/m2 from Day 1 to Day 7) in the two subsequent cycles (at 3-week intervals). The dose of gamma9delta2 T lymphocytes was escalated from 1 up to 8 x 10(9) cells.

RESULTS

Ten patients underwent a total of 27 treatment cycles. Immunomonitoring data demonstrate that gamma9delta2 T lymphocytes are initially cleared from the blood to reappear at the end of IL-2 administration. Dose-limiting toxicity occurred in one patient at the dose of 8 x 10(9) cells (disseminated intravascular coagulation). Other treatment-related adverse events (AEs) included mainly gastrointestinal disorders and flu-like symptoms (fatigue, pyrexia, rigors). Hypotension and tachycardia also occurred, especially with co-administered IL-2. Six patients showed stabilized disease. Time to progression was 25.7 weeks.

CONCLUSIONS

The data collected in ten patients with mRCC indicate that repeated infusions of Innacell gammadelta at different dose levels (up to 8 x 10(9) total cells), either alone or with IL-2 is well tolerated. These results are in favor of the therapeutic value of cell therapy with Innacell gammadelta for the treatment of cancers.