Oncogenic properties and signaling basis of the PAX8-GLIS3 fusion gene

Hyalinizing trabecular tumors of the thyroid are rare and mostly benign epithelial neoplasms of follicular cell origin, which have recently been shown to be underpinned by the PAX8-GLIS3 fusion gene. In our study, we sought to investigate the potential oncogenic mechanisms of the PAX8-GLIS3 fusion gene. Forced expression of PAX8-GLIS3 was found to increase proliferation, clonogenic potential and migration of human nonmalignant thyroid (Nthy-ori 3-1) and embryonic kidney (HEK-293) cells. Moreover, in xenografts, Nthy-ori 3-1 PAX8-GLIS3 expressing cells generated significantly larger and more proliferative tumors compared to controls. These oncogenic effects were found to be mediated through activation of the Sonic Hedgehog (SHH) pathway. Targeting of smoothened (SMO), a key protein in the SHH pathway, using the small molecule inhibitor Cyclopamine partially reversed the increased proliferation, colony formation and migration in PAX8-GLIS3 expressing cells. Our data demonstrate that the oncogenic effects of the PAX8-GLIS3 fusion gene are, at least in part, due to an increased activation of the SHH pathway.     

Respecting the circle of life: one year outcomes from a randomized controlled comparison of an HIV risk reduction intervention for American Indian adolescents

Potential for widespread transmission of HIV/AIDS among American Indian (AI) adolescents exists, yet no evidence-based interventions (EBIs) have been adapted and evaluated with this population. Intensive psychoeducation may improve knowledge and decision-making which could potentially translate to reductions in HIV risk behaviors. A peer group randomized controlled comparison of an adapted EBI vs. control was delivered over an eight-day summer basketball camp in one reservation-based tribal community to adolescents ages 13–19. Outcome data were gathered immediately post-camp and at 6 and 12 months follow-up. Self-selected peer groups were randomized to intervention (n = 138) or control (n = 129) conditions for a total sample of 267 participants (56.2% female), mean age 15.1 years (SD = 1.7). Intervention participants had better condom use self-efficacy post-camp (Adjusted Mean Difference [AMD] = ?0.75, p < 0.005) and at 6 (AMD = ?0.44, p < 0.005) and 12 months (AMD = ?0.23, p < 0.05) follow-up. Intervention participants also had higher HIV prevention and transmission knowledge (post-camp: AMD = 0.07, p < 0.01; 6 months: AMD = 0.06, p < 0.01) were more likely to believe condoms prevent sexually transmitted infections (post-camp: RR = 1.41, p < 0.005; 6 months: RR = 1.34, p < 0.05), to talk with an adult about HIV/AIDS (post-camp: RR=1.78, p < 0.005; 6 months: RR = 1.14, p < 0.005), had higher partner negotiation efficacy related to substance use during sex (post-camp: AMD = 0.37, p < 0.01), and were more likely to intend to use a condom (post-camp: RR = 1.39, p < 0.01). The adapted intervention had short- and medium-term impacts on AI adolescent risk for HIV/AIDS, but attenuated at 12 months. Intervention delivery through a community-based camp is feasible and acceptable with strong retention. Additional study is needed to evaluate the adapted intervention's impact on sexual risk behaviors and if booster sessions and parent involvement translate to long-term impacts.     

Providing context for a medical school basic science curriculum: The importance of the humanities

Introduction: To increase students’ understanding of what it means to be a physician and engage in the everyday practice of medicine, a humanities program was implemented into the preclinical curriculum of the medical school curriculum. The purpose of our study was to determine how medical students’ views of being a doctor evolved after participating in a required humanities course.

Methods: Medical students completing a 16-clock hour humanities course from 10 courses were asked to respond to an open-ended reflection question regarding changes, if any, of their views of being a doctor. The constant comparative method was used for coding; triangulation and a variety of techniques were used to provide evidence of validity of the analysis.

Results: A majority of first- and second-year medical students (rr?=?70%) replied, resulting in 100 pages of text. A meta-theme of Contextualizing the Purpose of Medicine and three subthemes: the importance of Treating Patients Rather than a Disease, Understanding Observation Skills are Important, and Recognizing that Doctors are Fallible emerged from the data.

Conclusions: Results suggest that requiring humanities as part of the required preclinical curriculum can have a positive influence on medical students and act as a bridge to contextualize the purpose of medicine.     

Alterations in intervertebral disc composition,matrix homeostasis and biomechanical behavior in the UCD‐T2DM rat model of type 2 diabetes

Type 2 diabetes (T2D) adversely affects many tissues, and the greater incidence of discogenic low back pain among diabetic patients suggests that the intervertebral disc is affected too. Using a rat model of polygenic obese T2D, we demonstrate that diabetes compromises several aspects of disc composition, matrix homeostasis, and biomechanical behavior. Coccygeal motion segments were harvested from 6‐month‐old lean Sprague‐Dawley rats, obese Sprague‐Dawley rats, and diabetic obese UCD‐T2DM rats (diabetic for 69 ± 7 days). Findings indicated that diabetes but not obesity reduced disc glycosaminoglycan and water contents, and these degenerative changes correlated with increased vertebral endplate thickness and decreased endplate porosity, and with higher levels of the advanced glycation end‐product (AGE) pentosidine. Consistent with their diminished glycosaminoglycan and water contents and their higher AGE levels, discs from diabetic rats were stiffer and exhibited less creep when compressed. At the matrix level, elevated expression of hypoxia‐inducible genes and catabolic markers in the discs from diabetic rats coincided with increased oxidative stress and greater interactions between AGEs and one of their receptors (RAGE). Taken together, these findings indicate that endplate sclerosis, increased oxidative stress, and AGE/RAGE‐mediated interactions could be important factors for explaining the greater incidence of disc pathology in T2D. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:738–746, 2015.     

Vertical palatal bone dimensions on lateral cephalometry and cone-beam computed tomography: implications for palatal implant placement

Objectives: To evaluate the necessity of three‐dimensional imaging (computed tomography [CT]/cone‐beam computed tomography [CBCT]) for paramedian insertion of palatal implants. Material and methods: Lateral radiographs and CBCT scans were performed from 18 human skulls. For lateral cephalometry, the nasal floor (right/left) and the oral hard palate of all skulls were lined with a tin foil for contrast enhancement. The quantity of vertical bone as measured on lateral radiographs was compared with CBCT measurements obtained in median and parasagittal planes and at minimum bone height. Spearman's rank correlation coefficients were determined for bivariate correlation analysis. Results: The median palatal bone height on CBCT (mean 8.98 mm; standard deviation [SD] 3.4) was markedly higher than the vertical height seen on lateral radiographs (mean 6.6 mm; SD 3.2). Comparing lateral cephalometry with CBCT, the strongest association was observed at the minimum palatal bone height (r=0.926; P<0.001; Spearman's rank correlation coefficient). Conclusions: Lateral radiographs allow accurate and adequate assessment of vertical bone before paramedian insertion of palatal implants. The vertical bone dimension as displayed on lateral cephalometry reflects the minimum bone height rather than maximum bone in the median plane. Therefore, a preoperative CT or CBCT is only indicated when the lateral cephalometry reveals a marginal quantity of bone. To cite this article:
Jung BA, Wehrbein H, Heuser L, Kunkel M. Vertical palatal bone dimensions on lateral cephalometry and cone‐beam computed tomography: implications for palatal implant placement.
Clin. Oral Impl. Res. 22 , 2011; 664–668
doi: 10.1111/j.1600‐0501.2010.02021.x