Role of CRD-BP in the growth of human basal cell carcinoma cells.

Although the number of new cases of basal cell carcinoma (BCC) has increased rapidly in the last few decades, the molecular basis of its pathogenesis is not completely understood. Activation of the Hedgehog (Hh) signaling pathway has been shown to be a key factor driving the development of BCC. The Wnt/ß-catenin signaling pathway was also shown to be activated in BCCs and to perhaps modulate the activity of the Hh pathway. We have previously identified a mechanism by which Wnt signaling regulates the transcriptional outcome of the Hh signaling pathway. We demonstrated that coding region determinant-binding protein (CRD-BP), a direct target of the Wnt/ß-catenin signaling, binds to GLI1 mRNA, stabilizes it, and consequently upregulates its levels (mRNA and protein) and activities. We hypothesized that Wnt-induced and CRD-BP-dependent regulation of GLI1 expression and activities is important for the development of BCC. In this study, we show that CRD-BP is overexpressed in BCC and that its expression positively correlates with the activation of both Wnt and Hh signaling pathways. We also describe the generation and characterization of a human BCC cell line. This cell line was utilized to demonstrate the importance of CRD-BP-dependent regulation of GLI1 expression and activities in the development of BCC.

Task-dependent posterior cingulate activation in mild cognitive impairment.

Neuroimaging research has demonstrated that the posterior cingulate cortex (PCC) is functionally compromised in individuals diagnosed with amnestic mild cognitive impairment (MCI), a major risk factor for the development of Alzheimer's disease (AD). In functional MRI studies with healthy participants, this same region is active during self-appraisal (requiring retrieval of semantic knowledge about the self) as well as episodic recognition of previously learned information. Administering both types of tasks to people with MCI may reveal important information on the role of the PCC in recollection. This study investigated fMRI activation in the PCC in individuals with MCI and matched controls across two tasks. The first task was a visual episodic recognition task. The second task was an autobiographical self-appraisal task in which subjects rated themselves on a set of trait adjectives. Results of a conjunction analysis revealed the PCC as the sole region commonly active during both tasks in the healthy older adults. Furthermore, additional analysis revealed an interaction in the PCC, indicating a task-dependent response in the MCI group. MCI participants showed PCC activation during self-appraisal, but not episodic retrieval. This result suggests in MCI that the PCC shows functional degradation during episodic retrieval; however, the PCC's role in retrieval and evaluation of highly elaborated information regarding the self is more well-preserved.

Neural correlates of self-evaluative accuracy after traumatic brain injury.

Individuals who have sustained a traumatic brain injury (TBI) often exhibit an array of cognitive deficits, yet perhaps most maladaptive of these sequelae is the frequent occurrence of reduced insight into one's own condition. In such cases, TBI individuals may overestimate their post-injury level of socio-cognitive functioning, leading to disparities between how they perceive themselves and what others observe. This functional MRI (fMRI) investigation examined the relationship between level of insight into one's post-injury condition (i.e. trait/ability status) and neural activation evoked during an fMRI task involving self-appraisal of one's traits and abilities. Twenty TBI patients (8-12 weeks post-injury, ER Glasgow Coma Scale Average = 10.9+/-2.8) were selected on the criterion that they overestimate their current trait/abilities (as detected on the patient competency rating scale, PCRS). fMRI activation on the self-appraisal task was compared between the TBI patients and 20 matched controls. For both groups, the fMRI task evoked activation at mid-line prefrontal and retrosplenial cortices. TBI patients exhibited greater signal change in the anterior cingulate, precuneus and right temporal pole. Subsequently, a linear regression analysis was conducted for the TBI group, with the PCRS and a measure of cognitive speed entered as predictor variables to determine the selective effect of insight on self-evaluative brain activation. A more accurate level of trait/ability-based insight was related to increased signal change in the right anterior dorsal prefrontal cortex (PFC). The results suggest that one's post-injury level of self-referential insight is related to a network inclusive of the medial and right dorsal PFC.

A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation.

BACKGROUND: Dietary vitamin K is usually inadequate to maximize serum osteocalcin gamma-carboxylation. Phylloquinone supplementation increases osteocalcin gamma-carboxylation; however, the amount required to maximize carboxylation is not known. OBJECTIVE: This study assessed the ability of various doses of phylloquinone (vitamin K(1)) to facilitate osteocalcin gamma-carboxylation. DESIGN: Healthy adults aged 19-36 y participated in 2 substudies. In an initial dose-finding study (substudy A), 6 women and 4 men received a placebo daily for 1 wk and then phylloquinone daily for 3 wk: 500, 1000, and 2000 micro g during weeks 2, 3, and 4, respectively. Osteocalcin and undercarboxylated osteocalcin were measured at baseline and after each week of supplementation. Subsequently, to further delineate the gamma-carboxylation response of osteocalcin to various doses of vitamin K, 58 women and 42 men were randomly assigned to receive placebo or phylloquinone supplementation (250, 375, 500, and 1000 micro g/d) for 2 wk (substudy B). The percentage of undercarboxylated osteocalcin (%ucOC) was measured at baseline and weeks 1 and 2. RESULTS: In substudy A, %ucOC decreased with phylloquinone supplementation (P < 0.0001); a greater reduction was observed with 1000 and 2000 micro g than with 500 micro g (P < 0.05). In substudy B, %ucOC decreased in all supplemented groups by week 1 (P for the trend < 0.0001), which was sustained through week 2. Phylloquinone supplementation decreased %ucOC dose-dependently; %ucOC was significantly different between the 250- micro g and the placebo groups and between the 1000- and 500- micro g groups but not between the 250-, 375-, and 500- micro g groups. CONCLUSION: A daily phylloquinone intake of approximately 1000 micro g is required to maximally gamma-carboxylate circulating osteocalcin.

Short-term vitamin A supplementation does not affect bone turnover in men.

Limited data in humans and animals indicate that excess vitamin A stimulates bone resorption and inhibits bone formation, effects that over time might lead to bone loss and fracture. Thus, it is possible that vitamin A supplementation is a currently unrecognized risk factor for the development of osteoporosis. To further evaluate this possibility, a prospective, randomized, single-blind study of vitamin A supplementation was conducted in 80 healthy men age 18-58 y. One half received 7576 microg (25,000 IU) of retinol palmitate daily with their evening meal; the others took a placebo. Blood was collected from fasting subjects and serum prepared at baseline and after 2, 4 and 6 wk of supplementation. Serum bone specific alkaline phosphatase (BSAP) and N-Telopeptide of type 1 collagen (NTx) were measured at all time points. Serum osteocalcin (Oc) was measured at baseline and after 6 wk of supplementation. BSAP, NTx and Oc did not differ between the supplemented and placebo-treated groups over the course of the study. In conclusion, short-term vitamin A supplementation at this dosage in healthy men does not alter serum markers of skeletal turnover. Thus, it is unlikely that short-term administration of vitamin A would contribute to the development of osteoporosis. Whether long-term vitamin A supplementation might have adverse skeletal effects remains to be determined.