The impact of maternal adiposity specialization on infant birthweight: upper versus lower body fat.

BACKGROUND: The specialization of human fat deposits is an inquiry of special importance in the study of fetal growth. It has been theorized that maternal lower-body fat is designated specifically for lactation and not for the growth of the fetus. OBJECTIVE: Our goal was to compare the contributions of maternal upper-body versus lower-body adiposity to infant birth weight. We hypothesized that upper-body adiposity would be strongly associated with infant birth weight and that lower-body adiposity would be weakly or negligibly associated with infant birth weight-after adjusting for known determinants. STUDY DESIGN: In this prospective cohort study, 355 women initiated medical pre-natal care during the first trimester of pregnancy at The University of Oklahoma Health Sciences Center during 1990-1993. Maternal anthropometric measurements were assessed at the first clinic visit: (a) height; (b) weight; (c) circumferences of the upper arm, forearm, and thigh; and, (d) skin-fold measurements of the bicep, subscapular region, and thigh. RESULTS: Infant birth weight was regressed on known major determinants to create the foundational model. Maternal anthropometric variables subsequently were added one at a time into this multiple regression model. The highest contribution by a single anthropometric variable to infant birthweight was, in order: subscapular skin-fold, forearm circumference, and thigh circumference. With one upper-body (subscapular skin-fold) and one lower-body (circumference of the thigh) adiposity measure in the model, the z-score regression coefficient (s.e.) was 85.7g (30.8) [p=0.0057] for maternal subscapular skin-fold and 19.0g (31.6) [p=0.5477] for circumference of the thigh. When the second-best upper-body contributor to infant birthweight (circumference of the forearm) was entered with one lower-body measure into the model, the z-score regression coefficient (s.e.) was 77.5g (38.5) [p=0.0451] for maternal forearm circumference and 14.1g (38.5) [p=0.7146] for circumference of the thigh. When both subscapular skinfold and forearm circumference were added to the model in place of BMI, the explained variance (r2=0.5478) was similar to the model using BMI (r2=0.5487). CONCLUSION: Upper-body adiposity - whether operationalized by subscapular skin-fold or circumference of the forearm - was a markedly larger determinant of infant birth weight than lower-body adiposity.

Hedgehog pathway blockade inhibits melanoma cell growth in vitro and in vivo.

Previous reports have demonstrated a role for hedgehog signaling in melanoma progression, prompting us to explore the therapeutic benefit of targeting this pathway in melanoma. We profiled a panel of human melanoma cell lines and control melanocytes for altered expression of hedgehog pathway members and determined the consequences of both genetic and pharmacological inhibition of the hedgehog pathway activator Smoothened (SMO) in melanoma, both in vitro and in vivo. We also examined the relationship between altered expression of hedgehog pathway mediators and survival in a well-characterized cohort of metastatic melanoma patients with prospectively collected follow up information. Studies revealed that over 40% of the melanoma cell lines examined harbored significantly elevated levels of the hedgehog pathway mediators SMO, GLI2, and PTCH1 compared to melanocytes (p < 0.05). SMO inhibition using siRNA and the small molecule inhibitor, NVP-LDE-225, suppressed melanoma growth in vitro, particularly in those cell lines with moderate SMO and GLI2 expression. NVP-LDE-225 also induced apoptosis in vitro and inhibited melanoma growth in a xenograft model. Gene expression data also revealed evidence of compensatory up-regulation of two other developmental pathways, Notch and WNT, in response to hedgehog pathway inhibition. Pharmacological and genetic SMO inhibition also downregulated genes involved in human embryonic stem cell pluripotency. Finally, increased SMO expression and decreased expression of the hedgehog pathway repressor GLI3 correlated with shorter post recurrence survival in metastatic melanoma patients. Our data demonstrate that hedgehog pathway inhibition might be a promising targeted therapy in appropriately selected metastatic melanoma patients.

Papular variant of annular elastolytic giant-cell granuloma.

A 53-year-old woman presented with a six-month history of non-pruritic, erythematous papules and papular-plaques that were localized to the anterior and lateral aspects of the neck. A biopsy specimen showed elastolysis and granuloma formation, which were consistent with a diagnosis of annular elastolytic giant-cell granuloma. This is one of the few reported cases of this entity that consists predominantly of papular lesions rather than annular plaques.

Chemical leukoderma.

Chemical leukoderma is defined as an acquired, hypopigmented dermatosis that results from repeated cutaneous application of an agent that destroys epidermal melanocytes in genetically susceptible patients. Chemical leukoderma may develop both at the site of contact with the chemical as well as remotely from the exposure. Avoidance of the causative agent may lead to spontaneous repigmentation, but treatments commonly used in vitiligo, such as narrow-band ultraviolet B phototherapy, PUVA photchemotherapy, or topical immunosuppressants, often are necessary. We present a case of chemical leukoderma secondary to pyrethroid insecticides that has progressed despite avoidance of the agent for over ten years.

Phosphorylated 4E-BP1 is associated with poor survival in melanoma.

PURPOSE: Both phosphatidylinositol 3-kinase/AKT and RAS/mitogen-activated protein kinase signal transduction pathways mediate 4E-BP1 phosphorylation, releasing 4E-BP1 from the mRNA cap and permitting translation initiation. Given the prevalence of PTEN and BRAF mutations in melanoma, we first examined translation initiation, as measured by phosphorylated 4E-BP1 (p-4E-BP1), in metastatic melanoma tissues and cell lines. We then tested the association between amounts of total and p-4E-BP1 and patient survival. EXPERIMENTAL DESIGN: Seven human metastatic melanoma cells lines and 72 metastatic melanoma patients with accessible metastatic tumor tissues and extended follow-up information were studied. Expression of 4E-BP1 transcript, total 4E-BP1 protein, and p-4E-BP1 was examined. The relationship between 4E-BP1 transcript and protein expression was assessed in a subset of patient tumors (n = 41). The association between total and p-4E-BP1 levels and survival was examined in the larger cohort of patients (n = 72). RESULTS: 4E-BP1 was hyperphosphorylated in 4 of 7 melanoma cell lines harboring both BRAF and PTEN mutations compared with untransformed melanocytes or RAS/RAF/PTEN wild-type melanoma cells. 4E-BP1 transcript correlated with 4E-BP1 total protein levels as measured by the semiquantitative reverse-phase protein array (P = 0.012). High levels of p-4E-BP1 were associated with worse overall and post-recurrence survival (P = 0.02 and 0.0003, respectively). CONCLUSION: Our data show that translation initiation is a common event in human metastatic melanoma and correlates with worse prognosis. Therefore, effective inhibition of the pathways responsible for 4E-BP1 phosphorylation should be considered to improve the treatment outcome of metastatic melanoma patients.

Integrating screening and interventions for unhealthy behaviors into primary care practices.

BACKGROUND: Four unhealthy behaviors (tobacco use, unhealthy diet, physical inactivity, and risky alcohol use) contribute to almost 37% of deaths in the U.S. However, routine screening and interventions targeting these behaviors are not consistently provided in primary care practices. METHODS: This was an implementation study conducted between October 2005 and May 2007 involving nine practices in three geographic clusters. Each cluster of practices received a multicomponent intervention sequentially addressing the four behaviors in three 6-month cycles (unhealthy diet and physical inactivity were combined). The intervention included baseline and monthly audits with feedback; five training modules (addressing each behavior plus stages of change [motivational interviewing]); practice facilitation; and bimonthly quality-circle meetings. Nurses, medical assistants, or both were taught to do screening and very brief interventions such as referrals and handouts. The clinicians were taught to do brief interventions. Outcomes included practice-level rates of adoption, implementation, and maintenance. RESULTS: Adoption: Of 30 clinicians invited, nine agreed to participate (30%). IMPLEMENTATION: Average screening and brief-intervention rates increased 25 and 10.8 percentage points, respectively, for all behaviors. However, the addition of more than two behaviors was generally unsuccessful. Maintenance: Screening increases were maintained across three of the behaviors for up to 12 months. For both unhealthy diet and risky alcohol use, screening rates continued to increase throughout the study period, even during the periods when the practices focused on the other behaviors. The rate of combined interventions returned to baseline for all behaviors 6 and 12 months after the intervention period. CONCLUSIONS: It appears that the translational strategy resulted in increased screening and interventions. There were limits to the number of interventions that could be added within the time limits of the project. Inflexible electronic medical records, staff turnover, and clinicians' unwillingness to allow greater nurse or medical-assistant involvement in care were common challenges.

mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.

Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.

The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells.

Tumor cells with mutated PTEN proliferate in an EGFR-independent manner. Induction of PTEN sensitizes cells to EGFR inhibition, and the combination causes synergistic apoptosis. Synergy is due to inhibition of two parallel pathways that phosphorylate the proapoptotic protein BAD at distinct sites. Serine 112 phosphorylation is EGFR/MEK/MAPK dependent, whereas serine 136 phosphorylation is PI3K/Akt dependent. Either phosphorylation is sufficient to sequester BAD to 14-3-3. BAD is released and apoptosis is induced only if both serines are dephosphorylated in response to inhibition of both pathways. Reduction of BAD expression by RNA interference prevents apoptosis in response to pathway inhibition. Thus, BAD integrates the antiapoptotic effects of both pathways. Combined inhibition of EGFR and PI3K signaling may be a useful therapeutic strategy.

Photo-caged agonists of the nuclear receptors RARgamma and TRbeta provide unique time-dependent gene expression profiles for light-activated gene patterning.

Light-activated gene expression systems hold promise as new tools for studying spatial and temporal gene patterning in multicellular systems. Photo-caged forms of nuclear receptor agonists have recently been shown to mediate photo-dependent transcription in mammalian cells, however, because intracellularly released agonists can rapidly diffuse out of cells, the photo-initiated transcription response is only transient and limited to only a few hours in reported examples. Herein we describe a photo-caged thyroid hormone receptor agonist that provides a robust 36 h transcription response to a single irradiation event. These findings are in contrast to a closely related system, which uses a caged retinoic acid receptor agonist, which provides only a short transcription response. Comparison of the two systems, show that the duration of transcription response is not controlled by the rate of diffusion of free ligand out of the cell, but perhaps by the duration of ligand-induced transcription/stability of the active transcription complex.