B-cell Zone Reticular Cell Microenvironments Shape CXCL13 Gradient Formation

Through the formation of concentration gradients, morphogens drive graded responses to extracellular signals, thereby fine-tuning cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13+ follicular reticular cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B-cell trafficking. Consistent with this prediction, imaging analysis show that CXCL13 binds to extracellular matrix components in situ, constraining its diffusion. CXCL13 solubilization requires the protease cathepsin B that cleaves CXCL13 into a stable product. Mice lacking cathepsin B display aberrant follicular architecture, a phenotype associated with effective B cell homing to but not within lymph nodes. Our data thus suggest that reticular cells of the B cell zone generate microenvironments that shape both immobilized and soluble CXCL13 gradient

Establishing a large prospective clinical cohort in people with head and neck cancer as a biomedical resource: head and neck 5000

BACKGROUND: Head and neck cancer is an important cause of ill health. Survival appears to be improving but the reasons for this are unclear. They could include evolving aetiology, modifications in care, improvements in treatment or changes in lifestyle behaviour. Observational studies are required to explore survival trends and identify outcome predictors. METHODS: We are identifying people with a new diagnosis of head and neck cancer. We obtain consent that includes agreement to collect longitudinal data, store samples and record linkage. Prior to treatment we give participants three questionnaires on health and lifestyle, quality of life and sexual history. We collect blood and saliva samples, complete a clinical data capture form and request a formalin fixed tissue sample. At four and twelve months we complete further data capture forms and send participants further quality of life questionnaires. DISCUSSION: This large clinical cohort of people with head and neck cancer brings together clinical data, patient-reported outcomes and biological samples in a single co-ordinated resource for translational and prognostic research

Interventions for adult Eustachian tube dysfunction: A systematic review

BACKGROUND: Eustachian tube dysfunction (ETD) is the inability of the Eustachian tube (ET) to adequately perform at least one of its functions: to protect the middle ear from sources of disease, to ventilate the middle ear, and to help drain secretions away from the middle ear. There are a number of treatment options for ETD, but there is little consensus about management. OBJECTIVES: To determine the clinical effectiveness of interventions for adult ETD and to identify gaps in the evidence to inform future research. DATA SOURCES: Twelve databases were searched up to October 2012 for published and unpublished studies in English (e.g. MEDLINE from 1946, EMBASE from 1974, Biosis Previews from 1969 and Cumulative Index to Nursing and Allied Health Literature from inception). References of included studies, relevant systematic reviews and regulatory agency websites were checked. REVIEW METHODS: A systematic review was undertaken. Controlled studies evaluating prespecified treatments for adult patients diagnosed with ETD were eligible. Uncontrolled studies with at least 10 participants were included for interventions where no controlled studies were found. Outcomes included change in symptoms severity/frequency (primary outcome), quality of life, middle ear function, hearing, clearance of middle ear effusion, early ventilation tube extrusion, additional treatment, adverse events and complications. All aspects of the review process were performed using methods to reduce reviewer error and bias. Owing to heterogeneous data, a quantitative synthesis could not be performed, and results were reported in a narrative synthesis. RESULTS: Nineteen studies were included: three randomised controlled trials (RCTs) and two non-RCTs evaluating pharmacological interventions or mechanical devices for middle ear pressure equalisation; and 13 case series and one retrospective controlled before-and-after study evaluating surgical interventions. None was conducted in the UK. All studies were small (11 to 108 participants). Most non-surgical studies reported including mixed populations of adults and children. All except two studies were at high risk of bias, and subject to multiple limitations. Based on a single RCT, nasal steroids showed no improvement in symptoms or middle ear function for patients with otitis media with effusion and/or negative middle ear pressure. Very short-term improvements in middle ear function were observed in patients receiving directly applied topical decongestants or a combination of antihistamine and ephedrine. Single trials found two pressure equalisation devices were each associated with significant short-term improvements in symptoms, middle ear function and/or hearing. Eustachian tuboplasty (seven case series) and balloon dilatation (three case series) were associated with improved outcomes. Positive results were also reported for myringotomy (two case series), directly applied topical steroids (one case series) and laser point coagulation (one controlled before-and-after study). High rates of co-interventions were documented. Minor complications of surgery and pharmacological treatments but no serious adverse effects were reported. LIMITATIONS: The evidence was limited in quantity and overall was of poor quality. No data were identified on several interventions despite extensive searches. CONCLUSIONS: It is not possible to draw conclusions regarding the effectiveness of any of the interventions for the treatment of adults with an ETD diagnosis, and there is insufficient evidence to recommend a trial of any particular intervention. Further research is needed to address lack of consensus on several issues, including the definition of ETD in adults, its relation to broader middle ear ventilation problems and clear diagnostic criteria. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012003035. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24.

Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10(-34)), rs1867277A (p=5.90×10(-24)), rs944289T (p=6.95×10(-7)), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (P(GG vs GT + TT)=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10(-13)) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (∼11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74)

B cell zone reticular cell microenvironments shape CXCL13 gradient formation

Through the formation of concentration gradients, morphogens drive graded responses to extracellular signals, thereby fine-tuning cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13+ follicular reticular cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B cell trafficking. Consistent with this prediction, imaging analysis show that CXCL13 binds to extracellular matrix components in situ, constraining its diffusion. CXCL13 solubilization requires the protease cathepsin B that cleaves CXCL13 into a stable product. Mice lacking cathepsin B display aberrant follicular architecture, a phenotype associated with effective B cell homing to but not within lymph nodes. Our data thus suggest that reticular cells of the B cell zone generate microenvironments that shape both immobilized and soluble CXCL13 gradients