BackgroundCraniopharyngiomas (CP) are locally invasive and frequently recurring neoplasms often resulting in neurological and endocrinological dysfunction in children. In addition, social-behavioral impairment is commonly reported following treatment for childhood CP, yet remains to be fully understood. The authors aimed to further characterize the prevalence of neurobehavioral, social, and emotional dysfunction in survivors of childhood craniopharyngiomas.Materials and MethodsA systematic literature review was conducted in PubMed to identify studies formally assessing neurobehavioral, social, and emotional outcomes in patients treated for CP prior to 18 years of age. Studies published between the years 1990-2012 that reported the primary outcome (prevalence of neurobehavioral, social, emotional/affective dysfunction, and/or impaired quality of life (QoL)) in ≥10 patients were included.ResultsOf the 471 studies screened, 11 met inclusion criteria. Overall neurobehavioral dysfunction was reported in 51 of 90 patients (57%) with available data. Social impairment (i.e. withdrawal, internalizing behavior) was reported in 91 of 222 cases (41%). School dysfunction was reported in 48 of 136 patients (35%). Emotional/affective dysfunction was reported in 58 of 146 patients (40%), primarily consisting of depressive symptoms. Health related quality of life was affected in 49 of 95 patients (52%). Common descriptors of behavior in affected children included irritability, impulsivity, aggressiveness, and emotional outbursts.ConclusionsNeurobehavioral, social, and emotional impairment is highly prevalent in survivors of childhood craniopharyngioma, and often affects quality of life. Thorough neurobehavioral/emotional screening and appropriate counseling is recommended in this population. Additional research is warranted to identify risk factors and treatment strategies for these disorders.
The variability within calculated protein residue pKa values calculated using Poisson-Boltzmann continuum theory with respect to small conformational fluctuations is investigated. As a general rule, sites buried in the protein core have the largest pKa fluctuations but the least amount of conformational variability; conversely, sites on the protein surface generally have large conformational fluctuations but very small pKa fluctuations. These results occur because of the heterogeneous or uniform nature of the electrostatic microenvironments at the protein core or surface, respectively. Atypical surface sites with large pKa fluctuations occur at the interfaces between significant anionic and cationic potentials.
Patients with small-cell lung cancer (SCLC), a highly metastatic type of lung cancer, show a dismal 5-year survival of only 5%. Effective therapies are urgently needed. Notably, about fifteen-percent of SCLC-patients harbor anti-Hu autoantibodies, which are associated with improved survival. This suggests that the anti-Hu response might be harnessed for immunotherapy. A conditional SCLC mouse model with floxed Rb1 and p53 alleles, in which the cancer is induced by instilling Cre-recombinase into the lungs via intratracheal intubation, offers a unique opportunity to study the immune response in detail. We have previously shown that, just like human SCLC patients, a fraction of these SCLC-carrying mice show an anti-Hu autoantibody response. Here we examine the presence of anti-Hu reactive T-cells using a prospective cohort (n=45) of SCLC-induced mice. All mice develop SCLC, showing systemic disease in 4-7 months following inactivation of floxed Rb1 and p53 alleles. Monthly autoantibody analysis by western blotting revealed an antibody response in a subset of mice, sometimes as early as 1 month after induction. Reactivity usually peaked approximately 3-4 months after induction and declined as disease progressed. This suggests an immune escape mechanism and/or antibody adsorption by the rapidly proliferating tumors. T-cells were isolated at euthanasia from the spleens of moribund mice. Proliferating anti-HuD CD4-positive T-cells were detected in fifty-one-percent of mice (eighteen out of thirty-five) by flow cytometry. Anti-HuD T-cell proliferation from spleen cells was validated in a subsequent prospective cohort (n=45) of SCLC-induced mice using thymidine incorporation. Stratifying for antibody positive and negative mice using an stringent cutoff, there was no significant difference in T cell response between the two groups (p=0.11), however four mice in the antibody positive group showed the most elevated anti-HuD T-cell response. Our observations warrant a much larger study, in which in-depth characterization of the humoral and cellular the anti-HuD immune response is carried out at multiple time points and correlated with a detailed analysis of the stage of tumor development and mestastasis. Preliminary data hints at a negative correlation between the anti-HuD antibody and T-cell response on one hand and tumor size and metastasis on the other. The observation that the Hu antigen in mice with SCLC is a target for both humoral and cellular immune responses underscores the utility of this mouse model in the preclinical evaluation the anti-Hu immune response for therapy and clinical translation. Citation Format: Mario A. Pulido, Vincent Lombardi, Diane Lee, Yiwei Wang, Eric Chung, Lina Wang, W. Martin Kast, Omid Akbari, Ite A. Laird-Offringa. Fluctuating antibody response and CD4-positive T-cells in a small-cell lung cancer mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3623. doi:10.1158/1538-7445.AM2014-3623
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