Variant proteins stimulate more IgM+ GC B-cells revealing a mechanism of cross-reactive recognition by antibody memory

This is the final version. Available from eLife Sciences Publications via the DOI in this recordVaccines induce memory B-cells that provide high affinity secondary antibody responses to identical antigens. Memory B-cells can also re-instigate affinity maturation, but how this happens against antigenic variants is poorly understood despite its potential impact on driving broadly protective immunity against pathogens such as Influenza and Dengue. We immunised mice sequentially with identical or variant Dengue-virus envelope proteins and analysed antibody and germinal-centre (GC) responses. Variant protein boosts induced GCs with a higher proportion of IgM+ B cells. The most variant protein re-stimulated GCs with the highest proportion of IgM+ cells with the most diverse, least mutated V-genes and with a slower but efficient serum antibody response. Recombinant antibodies from GC B-cells showed a higher affinity for the variant antigen than antibodies from a primary response, confirming a memory origin. This reveals a new process of antibody memory, that IgM memory cells with fewer mutations participate in secondary responses to variant antigens, demonstrating how the hierarchical structure of B-cell memory is used and indicating the potential and limits of cross-reactive antibody based immunity.Funder: Wellcome Trust; Grant reference number 100115/Z/12/

P05-11. Yeast mannan genetics controls the molecular specificity of anti-carbohydrate antibodies cross-reactive to the HIV envelope

Immunologically self carbohydrates protect the human immunodeficiency virus type -1 (HIV-1) surface glycoprotein, gp120 from antibody recognition. However, one broadly neutralising antibody, 2G12, can protect against primary viral challenge by direct recognition of these "self" glycans on gp120

Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3-5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial.

BACKGROUND: Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. PATIENTS AND METHODS: Eligible patients were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). RESULTS: A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9-74.6] and 2-year overall survival was 76.0% (90% CI 68.5-82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9-58.0). CONCLUSIONS: This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19)

Favourable outcomes for high-risk diffuse large B-cell lymphoma (IPI 3–5) treated with front-line R-CODOX-M/R-IVAC chemotherapy: results of a phase 2 UK NCRI trial

Background: Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. / Patients and methods: Eligible patients were aged 18–65 years with stage II–IV untreated DLBCL and an International Prognostic Index (IPI) score of 3–5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). / Results: A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9–74.6] and 2-year overall survival was 76.0% (90% CI 68.5–82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9–58.0). / Conclusions: This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. / Trial Registration: ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19)

Stereotactic body radiotherapy in the treatment of Pancreatic Adenocarcinoma in elderly patients

Background: Treatment of pancreatic adenocarcinoma in the elderly is often complicated by comorbidities that preclude surgery, chemotherapy and/or conventional external beam radiation therapy (EBRT). Stereotactic body radiotherapy (SBRT) has thus garnered interest in this setting.Methods: A retrospective review of 26 patients of age ≥ 80 with pancreatic adenocarcinoma treated with definitive SBRT+/-chemotherapy from 2007-2011 was performed. Twenty-seven percent of patients were stage I, 38% were stage II, 27% were stage III and 8% were stage IV. Patients most commonly received 24 Gy/1 fraction or 30-36 Gy/3 fractions. Kaplan-Meier was used to estimate overall survival (OS), local control (LC), cause specific survival (CSS) and freedom-from-metastatic disease (FFMD).Results: The median age was 86 (range 80-91), and median follow-up was 11.6 months (3.5-24.6). The median planning target volume was 21.48 cm3 (6.1-85.09). Median OS was 7.6 months with 6/12 month OS rates of 65.4%/34.6%, respectively. Median LC was 11.5 months, 6-month and 12-month actuarial LC rates were 60.1% and 41.2%, respectively. There were no independent predictors for LC, but there was a trend for improved LC with prescription dose greater than 20 Gy (p = 0.063). Median CSS was 6.3 months, and 6-month and 12-month actuarial CSS were 53.8% and 23.1%, respectively. Median FFMD was 8.4 months, and 6-month and 12-month actuarial rates were 62.0% and 41.4%, respectively. Nine patients (47%) had local failures, 11 (58%) had distant metastasis, and 7 (37%) had both. There were no acute or late grade 3+ toxicities.Conclusions: Definitive SBRT is feasible, safe and effective in elderly patients who have unresectable disease, have comorbidities precluding surgery or decline surgery. © 2013 Kim et al.; licensee BioMed Central Ltd

The influence of 'significant others' on persistent back pain and work participation: a qualitative exploration of illness perceptions

Background Individual illness perceptions have been highlighted as important influences on clinical outcomes for back pain. However, the illness perceptions of 'significant others' (spouse/partner/close family member) are rarely explored, particularly in relation to persistent back pain and work participation. The aim of this study was to initiate qualitative research in this area in order to further understand these wider influences on outcome. Methods Semi-structured interviews based on the chronic pain version of the Illness Perceptions Questionnaire-Revised were conducted with a convenience sample of UK disability benefit claimants, along with their significant others (n=5 dyads). Data were analysed using template analysis. Results Significant others shared, and perhaps further reinforced, claimants' unhelpful illness beliefs including fear of pain/re-injury associated with certain types of work and activity, and pessimism about the likelihood of return to work. In some cases, significant others appeared more resigned to the permanence and negative inevitable consequences of the claimant's back pain condition on work participation, and were more sceptical about the availability of suitable work and sympathy from employers. In their pursuit of authenticity, claimants were keen to stress their desire to work whilst emphasising how the severity and physical limitations of their condition prevented them from doing so. In this vein, and seemingly based on their perceptions of what makes a 'good' significant other, significant others acted as a 'witness to pain', supporting claimants' self-limiting behaviour and statements of incapacity, often responding with empathy and assistance. The beliefs and responses of significant others may also have been influenced by their own experience of chronic illness, thus participants lives were often intertwined and defined by illness. Conclusions The findings from this exploratory study reveal how others and wider social circumstances might contribute both to the propensity of persistent back pain and to its consequences. This is an area that has received little attention to date, and wider support of these findings may usefully inform the design of future intervention programmes aimed at restoring work participation

An improved microtiter assay for evaluating anti-HIV-1 neutralizing antibodies from sera or plasma

BACKGROUND: The anti-HIV-1 neutralizing antibody assay is widely used in AIDS vaccine research and other experimental and clinical studies. The vital dye staining method applied in the detection of anti-HIV-1 neutralizing antibody has been used in many laboratories. However, the unknown factor(s) in sera or plasma affected cell growth and caused protection when the tested sera or plasma was continuously maintained in cell culture. In addition, the poor solubility of neutral red in medium (such as RPMI-1640) also limited the use of this assay. METHODS: In this study, human T cell line C8166 was used as host cells, and 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) instead of neutral red was used as vital dye. In order to avoid the effect of the unknown factor(s), the tested sera or plasma was removed by a washout procedure after initial 3–6 h culture in the assay. RESULT: This new assay eliminated the effect of the tested sera or plasma on cell growth, improved the reliability of detection of anti-HIV-1 neutralizing antibody, and showed excellent agreement with the p24 antigen method. CONCLUSION: The results suggest that the improved assay is relatively simple, highly duplicable, cost-effective, and well reliable for evaluating anti-HIV-1 neutralizing antibodies from sera or plasma

Effects of exposure to facial expression variation in face learning and recognition.

Facial expression is a major source of image variation in face images. Linking numerous expressions to the same face can be a huge challenge for face learning and recognition. It remains largely unknown what level of exposure to this image variation is critical for expression-invariant face recognition. We examined this issue in a recognition memory task, where the number of facial expressions of each face being exposed during a training session was manipulated. Faces were either trained with multiple expressions or a single expression, and they were later tested in either the same or different expressions. We found that recognition performance after learning three emotional expressions had no improvement over learning a single emotional expression (Experiments 1 and 2). However, learning three emotional expressions improved recognition compared to learning a single neutral expression (Experiment 3). These findings reveal both the limitation and the benefit of multiple exposures to variations of emotional expression in achieving expression-invariant face recognition. The transfer of expression training to a new type of expression is likely to depend on a relatively extensive level of training and a certain degree of variation across the types of expressions

Erythroderma: A clinical study of 97 cases

BACKGROUND: Erythroderma is a rare skin disorder that may be caused by a variety of underlying dermatoses, infections, systemic diseases and drugs. METHODS: We reviewed the clinical, laboratory and biopsy material of 97 patients diagnosed with erythroderma who were treated in our department over a 6-year period (1996 through 2002). RESULTS: The male-female ratio was 1.85:1. The mean age at diagnosis was 46.2 years. The most common causative factors were dermatoses (59.7%), followed by drug reactions (21.6%), malignancies (11.3%) and idiopathic causes (7.2%). Carbamazepine was the most common drug (57.1%). The best clinicopathologic correlation was found in cutaneous T-cell lymphoma and pityriasis rubra pilaris related erythroderma. Apart from scaling and erythema that were present in all patients, pruritus was the most common finding (97.5%), followed by fever (33.6%), lymphadenopathy (21.3%), edema (14.4%) and hyperkeratosis (7.2%). CONCLUSION: This study outlines that underlying etiologic factors of erythroderma may show geographic variations. Our series had a high percentage of erythroderma secondary to preexisting dermatoses and a low percentage of idiopathic cases. There was no HIV-infected patient among our series based on multiple serum antibody tests. The clinical features of erythroderma were identical, irrespective of the etiology. The onset of the disease was usually insidious except in drug-induced erythroderma, where it was acute. The group associated with the best prognosis was that related to drugs