A 57-year-old man presented with jugular swelling. A leukocytosis of 50,000 WBC/muL (95% neutrophils) was found. PET/CT demonstrated increased fluorine-18-fluorodeoxyglucose uptake in the cervical/retrosternal mass, in the bone marrow, and in the enlarged spleen. Bone marrow biopsy confirmed myeloid hypercellularity with a left shift, but there were no signs of dysplasia and no evidence of tumor infiltration. Pathology of the thyroidectomy specimen confirmed an anaplastic thyroid carcinoma. Serum granulocyte-colony stimulating factor was elevated to 38.8 pg/mL (normal range,<0.6 pg/mL); granulocyte/macrophage-colony stimulating factor was normal (<2 pg/mL).

OBJECTIVE: To search for novel autoantibodies in patients with rheumatoid arthritis (RA) in an effort to better understand the processes of joint destruction in this disease. METHODS: Using a modified SEREX technique and complementary DNA derived from RA synovium, serpin E2 was identified as a novel autoantigen and was analyzed by immunohistochemistry. Levels of anti-serpin E2 autoantibodies in serum and synovial fluid from patients with RA, osteoarthritis (OA), psoriatic arthritis, and ankylosing spondylitis, and/or from healthy individuals were assessed by enzyme-linked immunosorbent assay. Since serpin E2 is an inhibitor of serine proteases, we studied the inhibitory activity of serpin E2 toward its target, urokinase plasminogen activator (uPA), in vitro in the presence of isolated anti-serpin E2 autoantibodies and in vivo using the uPA activity assay. RESULTS: We identified autoantibodies against serpin E2 by the SEREX technique. Serpin E2 was overexpressed in RA synovial tissues as compared with OA synovial tissues. Significantly higher levels of anti-serpin E2 autoantibodies were present in samples of synovial fluid (28%) and serum (22%) from RA patients as compared with OA patients (0 and 6%, respectively) or with healthy individuals (6% of sera). Most importantly, anti-serpin E2 autoantibodies isolated from RA sera reversed the inhibitory activity of serpin E2 by 70%. Furthermore, the levels of anti-serpin E2 autoantibodies correlated with the uPA activity in vivo. CONCLUSION: This study characterizes a functional property of a novel autoantibody in RA. Since anti-serpin E2 autoantibodies interfere with the inhibitory activity of serpin E2 toward serine proteases, they might facilitate the joint destruction in RA.

BACKGROUND: In spite of all accumulated scientific knowledge on the benefits of physical activity (PA) for health, high rates of sedentary lifestyle are still observed worldwide. The aim of this study was to systematically review articles on temporal trends of PA and fitness, with emphasis on differences between children/ adolescents and adults. METHODS: An electronic search at the Medline/PubMed database was carried out using the following combination of keywords: temporal trends or trends or surveillance or monitoring and PA or exercise or physical fitness or motor activity or sedentary or fitness. RESULTS: By using this strategy, 23,088 manuscripts were detected. After examination, 41 articles fulfilled all inclusion criteria, and were, therefore, included. The data currently available in the literature for adults shows that leisure-time activity levels tend to be increasing over time, while occupational-related PA is decreasing over time. Youth PA seems to be decreasing over time, including a lower level of activity in physical education classes. As a consequence, fitness levels are also declining. CONCLUSION: PA surveillance must be strongly encouraged in all settings and age groups. Special attention must be paid to low and middle-income countries, where PA surveillance is virtually inexistent.

BACKGROUND: The purpose of the study was to evaluate the impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET)/computed tomography (CT) during follow-up of patients with Hodgkin's lymphoma. PATIENTS AND METHODS: Patients in complete remission or an unconfirmed complete remission after first-line therapy who received FDG-PET/CT during their follow-up were analyzed retrospectively. Confirmatory biopsy was mandatory in case of recurrence. RESULTS: Overall, 134 patients were analyzed. Forty-two (31.3%) patients had a recurrence. The positive predictive value of FDG-PET/CT was 0.98. Single-factor analysis identified morphological residual mass [P = 0.0005, hazard ratio (HR) 3.4, 95% confidence interval (CI) 1.7-6.6] and symptoms (P < 0.0001, HR 4.9, 95% CI 2.4-9.9) as significant risk factors for relapse. By multivariate analysis, morphological residual mass was the only significant risk factor for early follow-up (<24 months)(P = 0.0019, HR 7.6, 95% CI 2.1-27.3). Advanced stage (P = 0.0426, HR 3.6, 95% CI 1.1-12.3) and the presence of symptoms (P = 0.0009, HR = 14.6, 95% CI 3.0-69.7) were found to be significant risk factors for later follow-up (>24 months). CONCLUSIONS: Asymptomatic patients without morphological residues and an early stage of disease do not need a routine FDG-PET/CT for follow-up. Asymptomatic patients with morphological residues should receive routine follow-up FDG-PET/CT for the first 24 months. Only patients with advanced initial stage do need a routine follow-up FDG-PET/CT beyond 24 months.

BACKGROUND: To document changes in physical activity of Brazilian adults by comparing two surveys carried out five years apart. METHODS: Two population-based cross-sectional surveys were carried out in the city of Pelotas, Brazil, in 2002 and 2007. Their multi-stage sampling strategies were virtually identical. The first study included 3,182 and the second 2,986 adults aged 20 years or older. The short version of the International Physical Activity Questionnaire (IPAQ) was used in both surveys, and individuals were classified as insufficiently active if reporting less than 150 minutes per week, according to a score combining moderate and vigorous-intensity physical activity. RESULTS: Prevalence of insufficient physical activity increased from 41.1%(95%CI 37.4; 44.9) in 2002 to 52.0%(95%CI 49.1; 53.8) in 2007. A 70% increase in prevalence of insufficient physical activity (p=0.008) was observed among poor individuals, whereas there was no significant change in the better-off. In contrast to the direct association between insufficient physical activity and socioeconomic level found in 2002, the 2007 survey showed no association. In the 2007 multivariable analysis, insufficient physical activity was directly associated with age and inversely with schooling. CONCLUSION: Effective interventions for the promotion of physical activity are urgently required in order to overcome the decline in physical activity levels in this population, particularly among the poor.

The aim of the present study was to evaluate public awareness of the association between four behavioral factors (sedentary lifestyle, smoking, alcohol abuse, and inadequate diet) and eight diseases (diabetes, hypertension, AIDS, osteoporosis, lung cancer, depression, liver cirrhosis, and acute myocardial infarction). We conducted a population-based cross-sectional study including 2,096 individuals 10 years or older. A random clustered sampling strategy was used. For each behavioral factor, a knowledge score was constructed, ranging from zero to eight points. The highest mean score was observed for inadequate diet (5.3), followed by smoking (5.1), sedentary lifestyle (4.7), and alcohol abuse (4.5). Overall, higher knowledge scores were observed among people with high socioeconomic status and more schooling, and in intermediate age groups. Government health promotion strategies are needed to raise public awareness of risk factors for chronic diseases.

Immunotherapeutic targeting of G250/Carbonic anhydrase IX (CA-IX) represents a promising strategy for treatment of renal cell carcinoma (RCC). The well characterized human-mouse chimeric G250 (cG250) antibody has been shown in human studies to specifically enrich in CA-IX positive tumors and was chosen as a carrier for site specific delivery of TNF in form of our IgG-TNF-fusion protein (cG250-TNF) to RCC xenografts. Genetically engineered TNF constructs were designed as CH2/CH3 truncated cG250-TNF fusion proteins and eucariotic expression was optimized under serum-free conditions. In-vitro characterization of cG250-TNF comprised biochemical analysis and bioactivity assays, alone and in combination with Interferon-gamma (IFNgamma). Biodistribution data on radiolabeled [(125)J] cG250-TNF and antitumor activity of cG250-TNF, alone and in combination with IFNgamma, were measured on RCC xenografts in BALB/c nu/nu mice. Combined administration of cG250-TNF and IFNgamma caused synergistic biological effects that represent key mechanisms displaying antitumor responses. Biodistribution studies demonstrated specific accumulation and retention of cG250-TNF at CA-IX-positive RCC resulting in growth inhibition of RCC and improved progression free survival and overall survival. Antitumor activity induced by targeted TNF-based constructs could be enhanced by coadministration of low doses of nontargeted IFNgamma without significant increase in side effects. Administration of cG250-TNF and IFNgamma resulted in significant synergistic tumoricidal activity. Considering the poor outcome of renal cancer patients with advanced disease, cG250-TNF-based immunotherapeutic approaches warrant clinical evaluation.(c) 2009 UICC.

T-cell interaction with a target cell is a key event in the adaptive immune response and primarily driven by T-cell receptor (TCR) recognition of peptide-MHC (pMHC) complexes. TCR avidity for a given pMHC is determined by number of MHC molecules, availability of coreceptors, and TCR affinity for MHC or peptide, respectively, with peptide recognition being the most important factor to confer target specificity. Here we present high-resolution crystal structures of 2 Fab antibodies in complex with the immunodominant NY-ESO-1(157-165) peptide analogue (SLLMWITQV) presented by HLA-A*0201 and compare them with a TCR recognizing the same pMHC. Binding to the central methionine-tryptophan peptide motif and orientation of binding were almost identical for Fabs and TCR. As the MW "peg" dominates the contacts between Fab and peptide, we estimated the contributions of individual amino acids between the Fab and peptide to provide the rational basis for a peptide-focused second-generation, high-affinity antibody library. The final Fab candidate achieved better peptide binding by 2 light-chain mutations, giving a 20-fold affinity improvement to 2-4 nM, exceeding the affinity of the TCR by 1,000-fold. The high-affinity Fab when grafted as recombinant TCR on T cells conferred specific killing of HLA-A*0201/NY-ESO-1(157-165) target cells. In summary, we prove that affinity maturation of antibodies mimicking a TCR is possible and provide a strategy for engineering high-affinity antibodies that can be used in targeting specific pMHC complexes for diagnostic and therapeutic purposes.

The aim of this study was to evaluate public knowledge on the role of physical activity in the prevention and treatment of diabetes and hypertension, and the factors associated with such knowledge. A population-based cross-sectional study was conducted in Pelotas, southern Brazil, including 972 adults aged 20 to 69 years, selected with a clustering protocol. Knowledge on the preventive and curative benefits of physical activity was higher for hypertension (87.2%) than for diabetes (47.2%). Women were more knowledgeable on the role of physical activity in preventing diabetes (PR: 1.16; 95%CI: 1.03-1.31). In terms of treatment, greater knowledge was associated with female gender, current physical activity, obesity, subjects, and higher socioeconomic status. For prevention of hypertension, greater knowledge was observed in individuals with higher socioeconomic status (PR: 1.23; 95%CI: 1.11-1.36). For treatment of hypertension, physically active and obese subjects showed greater knowledge. Subjects were generally more knowledgeable on the curative role of physical activity than on its preventive benefits. Public health efforts should aim to raise public awareness on the preventive effects of physical activity against diabetes, hypertension, and other chronic non-communicable diseases.

Polymorphonuclear neutrophils (PMNs) are potent effectors of inflammation and their attempts to respond to cancer are suggested by their systemic, regional and intratumoral activation. We previously reported on the recruitment of CD11b+ leukocytes due to tumor site-specific enrichment of TNF activity after intravenous administration of a dimeric TNF immunokine with specificity for fibroblast activation protein (FAP). However, TNF-induced chemo-attraction and extravasation of PMNs from blood into the tumor is a multistep process essentially mediated by interleukin 8. With the aim to amplify the TNF-induced and IL-8-mediated chemotactic response, we generated immunocytokines by N-terminal fusion of a human anti-FAP scFv fragment with human IL-8 (IL-8(72)) and its N-terminally truncated form IL-8(3-72). Due to the dramatic difference in chemotaxis induction in vitro, we favored the mature chemokine fused to the anti-FAP scFv for further investigation in vivo. BALB/c nu/nu mice were simultaneously xenografted with FAP-positive or -negative tumors and extended chemo-attraction of PMNs was only detectable in FAP-expressing tissue after intravenous administration of the anti-FAP scFv-IL-8(72) construct. As TNF-activated PMNs are likewise producers and primary targets for IL-8, we investigated the therapeutic efficacy of co-administration of both effectors: Sequential application of scFv-IL-8(72) and dimeric IgG1-TNF fusion proteins significantly enhanced anti-tumor activity when compared either to a single effector treatment regimen or sequential application of non-targeted cytokines, indicating that the tumor-restricted sequential application of IL-8(72) and TNF is a promising approach for cancer therapy.