Mannose-capped Lipoarabinomannan from Mycobacterium tuberculosis induces soluble tumor necrosis factor receptor production through tumor necrosis factor alpha-converting enzyme activation.

Primary Mycobacterium tuberculosis infection results in granuloma formation in lung tissue. A granuloma encapsulates mycobacterium-containing cells, thereby preventing dissemination and further infection. Tumor necrosis factor alpha (TNF-α) is a host-protective cytokine during M. tuberculosis infection due to its role in promoting and sustaining granuloma formation. TNF activity is regulated through the production of soluble TNF receptors (sTNFRI and sTNFRII). Therefore, we examined the potential production of endogenous sTNFRs during M. tuberculosis infection. Using the murine model of aerosol M. tuberculosis infection, we determined that levels of sTNFR production were elevated in bronchoalveolar lavage fluid 1 month following infection. An investigation of M. tuberculosis cell wall components identified that the known virulence factor mannose-capped lipoarabinomannan (ManLAM) was sufficient to induce sTNFR production, with sTNFRII being produced preferentially compared with sTNFRI. ManLAM stimulated the release of sTNFRs without TNF production, which corresponded to an increase in TNF-α-converting enzyme (TACE) activity. To determine the relevance of these findings, serum samples from M. tuberculosis-infected patients were tested and found to have an increase in the sTNFRII/sTNFRI ratio. These data identify a mechanism by which M. tuberculosis infection can promote the neutralization of TNF and furthermore suggest the potential use of the sTNFRII/sTNFRI ratio as an indicator of tuberculosis disease.

ß-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina.

BACKGROUND: The zebrafish retina maintains two populations of stem cells: first, the germinal zone or ciliary marginal zone (CMZ) contains multipotent retinal progenitors that add cells to the retinal periphery as the fish continue to grow; second, radial glia (Müller cells) occasionally divide asymmetrically to generate committed progenitors that differentiate into rod photoreceptors, which are added interstitially throughout the retina with growth. Retinal injury stimulates Müller glia to dedifferentiate, re-enter the cell cycle, and generate multipotent retinal progenitors similar to those in the CMZ to replace missing neurons. The specific signals that maintain these two distinct populations of endogenous retinal stem cells are not understood. RESULTS: We used genetic and pharmacological manipulation of the ß-catenin/Wnt signaling pathway to show that it is required to maintain proliferation in the CMZ and that hyperstimulation of ß-catenin/Wnt signaling inhibits normal retinal differentiation and expands the population of proliferative retinal progenitors. To test whether similar effects occur during regeneration, we developed a method for making rapid, selective photoreceptor ablations in larval zebrafish with intense light. We found that dephosphorylated ß-catenin accumulates in Müller glia as they re-enter the cell cycle following injury, but not in Müller glia that remain quiescent. Activation of Wnt signaling is required for regenerative proliferation, and hyperstimulation results in loss of Müller glia from the INL as all proliferative cells move into the ONL. CONCLUSIONS: ß-catenin/Wnt signaling is thus required for the maintenance of retinal progenitors during both initial development and lesion-induced regeneration, and is sufficient to prevent differentiation of those progenitors and maintain them in a proliferative state. This suggests that the ß-catenin/Wnt cascade is part of the shared molecular circuitry that maintains retinal stem cells for both homeostatic growth and epimorphic regeneration.

Factors associated with nonparticipation in one-year quality-of-life assessment in patients with head and neck squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: To identify factors associated with nonparticipation in long-term quality-of-life (QOL) analysis in head and neck squamous cell cancer (HNSCC) patients. STUDY DESIGN: Restrospective analysis of prospectively collected data. METHODS: Two hundred sixty-one previously untreated HNSCC patients were prospectively evaluated using the University of Washington QOL questionnaire. Questionnaires were administered before treatment and at 1 year following treatment. Patients without data at 1 year were classified as nonparticipants. RESULTS: At 1 year, 152 patients (58%) had complete QOL data. Nonparticipants differed from participants by stage, comorbidity, and disease status, with a greater proportion of patients with advanced stage disease, advanced comorbidity, and recurrent disease participating in QOL analysis at 1 year (P < .05). No significant differences were found between nonparticipants and participants with respect to age, race, primary site, treatment, travel distance, or socioeconomic variables. Multiple linear regression analysis showed differences in initial QOL scores between participants and nonparticipants only for activity, with lower mean initial scores for nonparticipants (beta = -9.9, 95% confidence interval, -16.8 to -3.0; P = .005). Multiple logistic regression demonstrated significant differences in the odds of nonparticipation at 1 year for males (odds ratio [OR] 0.4, P = .01), T4 disease (OR 0.3, P = .001), uninsured patients (OR 2.8, P = .007), recurrent disease (OR 0.2, P < .0001), and comorbidity (OR 0.5, P = .025), after controlling for all other variables. CONCLUSIONS: Long-term QOL analysis may be biased by greater participation from patients who require greater medical attention because of advanced tumor stage, recurrent disease, or comorbidity, whereas patients without insurance are under-represented. These findings suggest limitations to the interpretation and application of long-term QOL data.

Characteristics of participants in a free oral, head and neck cancer screening program.

OBJECTIVE: Early detection of head and neck cancer is associated with improved survival. It is unclear if screening programs successfully target high-risk populations. We sought to determine the characteristics of participants presenting for a free oral, head and neck cancer screening. MATERIALS AND METHODS: Prospective analysis of 89 participants in a one-day, free oral, head, and neck cancer screening. RESULTS: The majority of participants were female (57%) and not tobacco users (71%) with a mean age of 56 years (range, 23-83). Symptoms associated with head and neck cancer were reported by 59 participants (66%), but only 31 (35%) were aware of an association between symptoms and head and neck cancer. There was no correlation between symptom prevalence and exam findings (r = 0.1161). Ten participants (11%) had findings concerning for neoplasia and were referred for immediate consultation. Demographically, 64 (72%) of participants had attended college and 51 (57%) earned an annual income greater then $30,000. The majority of participants (85%) believed that screening increased their awareness and knowledge of oral and head and neck cancer. CONCLUSIONS: Free oral, head and neck cancer screenings increase awareness of oral and head and neck cancer and identify a subset of individuals requiring further evaluation. However, participants do not share characteristics of the population at greatest risk for the development of head and neck cancer based on risk factors and socioeconomic status. These findings suggest that early detection efforts need to be designed to target high-risk populations.