ABSTRACT
The oncogenic fusion protein RET/PTC3 (RP3) that is expressed in papillary thyroid carcinoma (PTC) and thyroid epithelia in Hashimoto's thyroiditis activates nuclear factor-kappa B (NF-κB) and induces pro-inflammatory gene expression; however, the mechanism of this activation is unknown. To address this, we expressed RP3 in murine embryonic fibroblasts (MEFs) lacking key classical and noncanonical NF-κB signaling components. In wild-type MEFs, RP3 upregulated CCL2, CXCL1, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor expression and activated classical but not noncanonical NF-κB. RP3-activated NF-κB in IκB kinase (IKK)ß(-/-) MEFs but not IKKα- or NF-κB essential modulator (NEMO)-deficient cells and activation was inhibited by a peptide that blocks NEMO binding to the IKKs. RP3 increased the levels of NF-κB-inducing kinase (NIK) and did not activate NF-κB in NIK-deficient MEFs. Notably, NIK stabilization was not accompanied by TRAF3 degradation demonstrating that RP3 disrupts normal basal NIK regulation. Dominant-negative NIK blocked RP3-induced NF-κB activation and an RP3 signaling mutant (RP3(Y588F)) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-κB via NIK, NEMO and IKKα. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-κB activation via stabilization of NIK.
Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , NF-kappa B/metabolism , Oncogene Proteins, Fusion/genetics , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-ret/genetics , Animals , Enzyme Stability , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Expression Regulation , Humans , Mice , Oncogene Proteins, Fusion/metabolism , Proto-Oncogene Proteins c-ret/metabolism , Signal Transduction , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism , NF-kappaB-Inducing KinaseABSTRACT
The purpose of this study was to examine the effects of the presence of a companion animal on physiological arousal and behavioral distress exhibited by preschool children during a routine physical examination. A within-subject, time-series design was used to study 23 healthy children ages 3 years to 6 years during two physical examinations, with and without a dog. Statistically significant differences were found with greater reductions in subjects' systolic and mean arterial pressure, heart rate, and behavioral distress when the dog was present. Findings support the use of a companion animal in reducing stress experienced by children during a physical examination.
Subject(s)
Animals, Domestic , Physical Examination/psychology , Stress, Psychological/prevention & control , Analysis of Variance , Animals , Blood Pressure , Child , Child, Preschool , Dogs , Female , Heart Rate , Humans , Male , Nebraska , Skin Temperature , Stress, Psychological/physiopathology , Stress, Psychological/psychologyABSTRACT
OBJECTIVE: Identifying age-related changes in the postural control system is an important first step towards understanding the risk for falls in older adults. The purpose of this study was to determine whether age or gender had any effects on six relatively new postural control measures. DESIGN: Cross-sectional, 2 x 2 factorial design, representing two ages (younger [20 to 35 years], and older [60 to 75 years]) and both sexes. SETTING: University campus. PARTICIPANTS: Twenty-four community dwelling healthy adults (12 women, 12 men) participated in each of the younger and older groups. MAIN OUTCOME MEASURES: Outcome measures included five force platform measures and functional reach (cm). The force platform measures, obtained using the Balance Master system, included movement time and path length to targets, and sway area under conditions of eyes open, eyes closed, and with visual feedback. RESULTS: Although gender was not significant for any outcome measure, age was significant in all six outcome measures. Older adults demonstrated larger areas of sway regardless of condition (eyes open, eyes closed or with visual feedback). Older adults had longer movement times, longer path lengths, and shorter distances of functional reach when compared with younger adults. CONCLUSIONS: The results suggest that the measures studied are sensitive to age-related changes in healthy elderly.
Subject(s)
Postural Balance , Posture , Adult , Age Factors , Aged , Female , Humans , Male , Middle Aged , Movement/physiology , Postural Balance/physiology , Posture/physiology , Sex FactorsABSTRACT
Evaluated treatment for thumb-sucking in a randomized trial. Study included 22 children, ages 4-11, who displayed chronic thumb-sucking. Treatment included aversive taste and a reward system. Significant results were obtained at posttest, with 12 cessations at 3-month follow-up and 20 at 1 year. Participating parents, pediatricians, and pediatric psychologists validated treatment acceptability. Results support the treatment as an alternative to common medical and dental advice about thumb-sucking. Directions for future research are discussed.
Subject(s)
Behavior Therapy/methods , Fingersucking/therapy , Aversive Therapy/methods , Child , Child, Preschool , Female , Humans , Male , Randomized Controlled Trials as Topic , TasteABSTRACT
Cancer is one of the most serious health concerns facing the nation. Health care policy makers who determine cancer research and treatment priorities must analyze death rates as an indicator of public health priorities. Two additional indexes that account for premature death include years of potential life lost (YPLL) and potential years of life lost per death (YPLL/D). Data for ten leading causes of cancer death in men from 1974-1983 were analyzed and the YPLL and YPLL/D corresponding to these cancers was calculated. Each cancer was then ranked from most to least significant according to each index. The analyses show that using YPLL and YPLL/D to evaluate cancer death in men results in rankings that differ from those obtained when using death rates alone. The premature death indexes, when used in combination with traditional mortality indexes, would enhance the data base used by funding agencies who select and evaluate cancer treatment and prevention programs.
Subject(s)
Economics , Neoplasms/mortality , Value of Life , Adolescent , Adult , Age Factors , Aged , Cause of Death , Child , Child, Preschool , Health Education , Health Policy , Humans , Infant , Male , Middle Aged , Testicular Neoplasms/mortality , United StatesABSTRACT
Pediatricians are increasingly recognized as the providers of choice for children with functional encopresis. The presence of clinically significant behavior problems could interfere with pediatric regimens for encopresis, however. To study the extent to which encopretic children exhibit behavior problems, we compared the scores on a standardized behavioral checklist for three randomly selected samples: a sample group of children with encopresis, a sample group of children with behavior problems, and a sample group of children without encopresis or behavior problems. All three samples were matched for age and gender. An analysis of variance showed that the scores of children with encopresis did not differ from the normative sample but were significantly lower than the scores from the behavior problem sample (P less than .00001). The results support the appropriateness of the trend toward expanding the primary pediatrician's role in the treatment of encopresis.
Subject(s)
Encopresis/psychology , Child , Child Behavior Disorders/psychology , Child, Preschool , Encopresis/therapy , Female , Humans , Male , Pediatrics , Personality Inventory , Physician's RoleABSTRACT
This study evaluated the use of the MacKinnon splint upon grasp skills in three children, ages 2 1/2 to 7 1/2, with spastic hemiplegia. The MacKinnon splint was sequentially introduced in a multiple baseline design across subjects. The results indicated improvement in each child's grasp of eight different, randomly presented objects, after a MacKinnon splint was provided for daily wear.
