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Biomedical subjects

Eric P Smith

Publications and source records attributed to Eric P Smith.

13 recordsLinked to original sources
PubMed2006

Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo.

PURPOSE: Papillary thyroid carcinomas are associated with nonoverlapping activating mutations of RET, NTRK, RAS and BRAF, which altogether are present in approximately 70% of cases. We postulated that compounds that inhibit a distal effector in the mitogen-activated protein kinase (MAPK) pathway would inhibit growth and tumorigenicity of human thyroid cancer cell lines with mutations of RET or BRAF. EXPERIMENTAL DESIGN AND RESULTS: We first examined the effects of AAL-881 and LBT-613, two inhibitors of RAF kinase activity, on RAF-MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK activation in thyroid PCCL3 cells after conditional induction of expression of H-RAS(G12V) or BRAF(V600E). Both compounds blocked RAS and RAF-dependent MEK and ERK phosphorylation. They also potently blocked MEK phosphorylation in human thyroid cancer cell lines with either RET/PTC1 (TPC1) or BRAF(V600E) (NPA, ARO, and FRO) mutations. Inhibition of ERK phosphorylation was transient in TPC1 and ARO cells, with recovery of ERK phosphorylation associated with concomitant down-regulation of the MAPK phosphatases MKP-3 and DUSP5. Both compounds inhibited growth of all cell lines, with LBT-613 being approximately 10-fold more potent than AAL-881. TPC1 cells were more sensitive to growth inhibition (IC50 0.1-0.25 and approximately 0.05 micromol/L for AAL-881 and LBT-613, respectively) than BRAF + lines (IC50 2.5-5 and 0.1-0.5 micromol/L, respectively). Growth inhibition was associated with G1 arrest, and induction of cell death. Growth of ARO and NPA tumor xenografts was inhibited by LBT-613 or AAL-881. MEK and ERK phosphorylation was inhibited by both compounds in ARO but not in NPA cell xenografts. CONCLUSIONS: Compounds that inhibit kinase activity are effective growth inhibitors for poorly differentiated thyroid cancer cell lines with either RET or RAF mutations, and hold promise for treatment of most forms of papillary thyroid carcinoma.

Animals↗
PubMed2005

Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation.

The BRAFT1799A mutation is the most common genetic alteration in papillary thyroid carcinomas (PTC). It is also found in a subset of papillary microcarcinomas, consistent with a role in tumor initiation. PTCs with BRAFT1799A are often invasive and present at a more advanced stage. BRAFT1799A is found with high prevalence in tall-cell variant PTCs and in poorly differentiated and undifferentiated carcinomas arising from PTCs. To explore the role of BRAFV600E in thyroid cancer pathogenesis, we targeted its expression to thyroid cells of transgenic FVB/N mice with a bovine thyroglobulin promoter. Two Tg-BRAFV600E lines (Tg-BRAF2 and Tg-BRAF3) were propagated for detailed analysis. Tg-BRAF2 and Tg-BRAF3 mice had increased thyroid-stimulating hormone levels (>7- and approximately 2-fold, respectively). This likely resulted from decreased expression of thyroid peroxidase, sodium iodine symporter, and thyroglobulin. All lines seemed to successfully compensate for thyroid dysfunction, as serum thyroxine/triiodothyronine and somatic growth were normal. Thyroid glands of transgenic mice were markedly enlarged by 5 weeks of age. In Tg-BRAF2 mice, PTCs were present at 12 and 22 weeks in 14 of 15 and 13 of 14 animals, respectively, with 83% exhibiting tall-cell features, 83% areas of invasion, and 48% foci of poorly differentiated carcinoma. Tg-BRAF3 mice also developed PTCs, albeit with lower prevalence (3 of 12 and 4 of 9 at 12 and 22 weeks, respectively). Tg-BRAF2 mice had a 30% decrease in survival at 5 months. In summary, thyroid-specific expression of BRAFV600E induces goiter and invasive PTC, which transitions to poorly differentiated carcinomas. This closely recapitulates the phenotype of BRAF-positive PTCs in humans and supports a key role for this oncogene in its pathogenesis.

Animals↗
PubMed2005

Modified superlong pulse 810 nm diode laser in the treatment of pseudofolliculitis barbae in skin types V and VI.

BACKGROUND: Laser hair removal is a well-established therapy for pseudofolliculitis barbae, but there have been few studies on the use of a very-long-pulse 810 nm diode laser for this condition. OBJECTIVE: To determine the efficacy and tolerability of a modified 810 nm superlong-pulse diode laser (Palomar Medical, Burlington, MA, USA) in the treatment of pseudofolliculitis barbae (PFB) in subjects with type V and VI skin. METHODS: Thirteen patients were treated three times at 2-week intervals on one side of their neck with varying fluences. They were evaluated for (1) reduction of shaving bumps and (2) pain tolerance on the treated versus the untreated side. RESULTS: There was a statistically significant improvement in shaving bumps. The treatment side showed a baseline PFB lesion count of 22.5 (+/- 20 SD), which decreased to a mean of 5 (+/- 5 SD) (p<.05). The control baseline mean count was 27.6 (+/- 22 SD) and at the end of the study was 15 (+/- 12 SD) (p = .13). Pain was rated at 2.5 of 10 for subjects treated both with and without anesthetic. The margin of safety was greater in type V compared with type VI skin. CONCLUSION: A modified 810 nm superlong-pulse diode laser is both effective and well tolerated in the reduction of shaving bumps, especially in patients with type V skin.

Folliculitis↗
PubMed2005

Material properties of human rib cortical bone from dynamic tension coupon testing.

The purpose of this study was to develop material properties of human rib cortical bone using dynamic tension coupon testing. This study presents 117 human rib cortical bone coupon tests from six cadavers, three male and three female, ranging in age from 18 to 67 years old. The rib sections were taken from the anterior, lateral, and posterior regions on ribs 1 through 12 of each cadaver's rib cage. The cortical bone was isolated from each rib section with a low speed diamond saw, and milled into dog bone shaped tension coupons using a small computer numerical control machine. A high-rate servo-hydraulic Material Testing System equipped with a custom slack adaptor, to provide constant strain rates, was used to apply tension loads to failure at an average rate of 0.5 strains/sec. The elastic modulus, yield stress, yield strain, ultimate stress, ultimate strain, and strain energy density were determined from the resulting stress versus strain curves. The overall average of all cadaver data gives an elastic modulus of 13.9 GPa, a yield stress of 93.9 MPa, a yield strain of 0.88 %, an ultimate stress of 124.2 MPa, an ultimate strain of 2.7 %, and a strain energy density of 250.1 MPa-microstrain. For all cadavers, the plastic region of the stress versus strain curves was substantial and contributed approximately 60 % to the strain energy and over 80 % in the tests with the 18 year old cadaver. The rib cortical bone becomes more brittle with increasing age, shown by an increase in the modulus (p < 0.01) and a decrease in peak strain (p < 0.01). In contrast to previous three-bending tests on whole rib and rib cortical bone coupons, there were no significant differences in material properties with respect to rib region or rib level. When these results are considered in conjunction with the previous three-point bending tests, there is regional variation in the structural response of the human rib cage, but this variation appears to be primarily a result of changes in the local geometry of each rib while the material properties remain nearly constant within an individual.

Journal Article↗
PubMed2005

Eruptive syringomas: an unusual presentation on the buttocks.

Syringomas are benign, eccrine, sweat gland tumors. Eruptive syrin-gomas are rare variants that typically develop on the body's anterior surface. We present the case of a 21-year-old black man with multiple, eruptive, asymptomatic syringomas on his buttocks that had persisted for 3 months. This case is unusual in that the patient's age, race, and sex and the location of the lesions are not considered typical for eruptive syringomas. We also present a review of eruptive syringomas and recent literature.

Adult↗
PubMed2004

Smooth muscle overexpression of IGF-I induces a novel adaptive response to small bowel resection.

Prior studies of intestinal adaptation after massive small bowel resection (SBR) have focused on growth factors and their effects on amplification of the gut mucosa. Because adaptive changes have also been described in intestinal smooth muscle, we sought to determine the effect of targeted smooth muscle growth factor overexpression on resection-induced intestinal adaptation. Male transgenic mice with smooth muscle cell overexpression of insulin-like growth factor I (IGF-I) by virtue of an alpha-smooth muscle actin promoter were obtained. SMP8 IGF-I transgenic (IGF-I TG) and nontransgenic (NT) littermates underwent 50% proximal SBR or sham operation and were then killed after 3 or 28 days. NT mice showed the expected alterations in mucosal adaptive parameters after SBR, such as increased wet weight and villus height. The IGF-I TG mice had inherently taller villi, which did not increase significantly after SBR. In addition, IGF-I TG mice had a 50% postresection persistent increase in remnant intestinal length, which was associated with an early decline and later increase in relative mucosal surface area. These results indicate that growth factor overexpression within the muscularis layer of the bowel wall induces significant postresection adaptive intestinal lengthening and a unique mucosal response. IGF-I signaling within the muscle wall may play an important role in the pathogenesis of resection-induced adaptation.

Adaptation, Physiological↗
PubMed2004

Lateral and posterior dynamic bending of the mid-shaft femur: fracture risk curves for the adult population.

The purpose of this study was to develop injury risk functions for dynamic bending of the human femur in the lateral-to-medial and posterior-to-anterior loading directions. A total of 45 experiments were performed on human cadaver femurs using a dynamic three-point drop test setup. An impactor of 9.8 kg was dropped from 2.2 m for an impact velocity of 5 m/s. Five-axis load cells measured the impactor and support loads, while an in situ strain gage measured the failure strain and subsequent strain rate. All 45 tests resulted in mid-shaft femur fractures with comminuted wedge and oblique fractures as the most common fracture patterns. In the lateral-to-medial bending tests the reaction loads were 4180 +/- 764 N, and the impactor loads were 4780 +/- 792 N. In the posterior-to-anterior bending tests the reaction loads were 3780 +/- 930 N, and the impactor loads were 4310 +/- 1040 N. The difference between the sum of the reaction forces and the applied load is due to inertial effects. The reaction loads were used to estimate the mid-shaft bending moments at failure since there was insufficient data to include the inertial effects in the calculations. The resulting moments are conservative estimates (lower bounds) of the mid-shaft bending moments at failure and are appropriate for use in the assessment of knee restraints and pedestrian impacts with ATD measurements. Regression analysis was used to identify significant parameters, and parametric survival analysis was used to estimate risk functions. Femur cross-sectional area, area moment of inertia (I), maximum distance to the neutral axis (c), I/c, occupant gender, and occupant mass are shown to be significant predictors of fracture tolerance, while no significant difference is shown for loading direction, bone mineral density, leg aspect and age. Risk functions are presented for femur cross-sectional area and I/c as they offer the highest correlation to peak bending moment. The risk function that utilizes the most highly correlated (R2 = 0.82) and significant (p = 0.0001) variable, cross-sectional area, predicts a 50 percent risk of femur fracture of 240 Nm, 395 Nm, and 562 Nm for equivalent cross-sectional area of the 5(th) percentile female, 50(th) percentile male, and 95(th) percentile male respectively.

Journal Article↗
PubMed2004

Upper extremity interaction with a helicopter side airbag: injury criteria for dynamic hyperextension of the female elbow joint.

This paper describes a three part analysis to characterize the interaction between the female upper extremity and a helicopter cockpit side airbag system and to develop dynamic hyperextension injury criteria for the female elbow joint. Part I involved a series of 10 experiments with an original Army Black Hawk helicopter side airbag. A 5(th) percentile female Hybrid III instrumented upper extremity was used to demonstrate side airbag upper extremity loading. Two out of the 10 tests resulted in high elbow bending moments of 128 Nm and 144 Nm. Part II included dynamic hyperextension tests on 24 female cadaver elbow joints. The energy source was a drop tower utilizing a three-point bending configuration to apply elbow bending moments matching the previously conducted side airbag tests. Post-test necropsy showed that 16 of the 24 elbow joint tests resulted in injuries. Injury severity ranged from minor cartilage damage to more moderate joint dislocations and severe transverse fractures of the distal humerus. Peak elbow bending moments ranged from 42.4 Nm to 146.3 Nm. Peak bending moment proved to be a significant indicator of any elbow injury (p = 0.02) as well as elbow joint dislocation (p = 0.01). Logistic regression analyses were used to develop single and multiple variate injury risk functions. Using peak moment data for the entire test population, a 50% risk of obtaining any elbow injury was found at 56 Nm while a 50% risk of sustaining an elbow joint dislocation was found at 93 Nm for the female population. These results indicate that the peak elbow bending moments achieved in Part I are associated with a greater than 90% risk for elbow injury. Subsequently, the airbag was re-designed in an effort to mitigate this as well as the other upper extremity injury risks. Part III assessed the redesigned side airbag module to ensure injury risks had been reduced prior to implementing the new system. To facilitate this, 12 redesigned side airbag deployments were conducted using the same procedures as Part I. Results indicate that the re-designed side airbag has effectively mitigated elbow injury risks induced by the original side airbag design. It is anticipated that this study will provide researchers with additional injury criteria for assessing upper extremity injury risk caused by both military and automotive side airbag deployments.

Journal Article↗
PubMed2003

Early orchiopexy restores fertility in the Hoxa 11 gene knockout mouse.

PURPOSE: We investigated whether infertility could be reversed in cryptorchid mice (with disrupted expression of the homeobox gene Hoxa 11) by orchiopexy and mating such animals with females of proven fertility. MATERIALS AND METHODS: Hoxa 11 mutant and WT male mice were genotyped by polymerase chain reaction. Surgery (orchiopexy or sham operation) was performed at age 18 days and fertility was assessed at ages 6 to 8 weeks. Animals were sacrificed at ages 6 to 9 months and computer assisted semen analysis was performed on fluid obtained by epididymal puncture. RESULTS: Five of 28 mutant mice proved fertile following orchiopexy versus 0 of 22 after sham operation (p <0.05). Values in WT mice were 18 of 35 and 25 of 33, respectively (p <0.01). Mean spermatozoa counts +/- SEM were 21.7 +/- 5.9 x 106/ml in 8 mutant mice with orchiopexy, 2.78 +/- 1.59 x 106/ml in 8 sham operated mutant mice (p <0.002), 15.6 +/- 4.9 x 106/ml in 7 WT mice with orchiopexy and 36.3 +/- 10.5 x 106/ml in 9 sham operated WT mice (p <0.02). CONCLUSIONS: Testicular position following orchiopexy is important to achieve fertility but the surgical procedure was associated with a degree of damage. Since mutant animals did not attain the fertility rates observed in WT animals following orchiopexy, other factors (possibly vaso-epididymal) may be necessary for normal spermatogenesis. Further studies of this model may allow the identification of such factors.

Animals↗
PubMed2003

Defining regional variation in the material properties of human rib cortical bone and its effect on fracture prediction.

This paper presents the results of dynamic material tests and computational modeling that elucidate the effects of regional rib mechanical properties on thoracic fracture patterns. First, a total of 80 experiments were performed using small cortical bone samples from 23 separate locations on the rib cages of four cadavers (2 male, 2 female). Each specimen was subjected to dynamic three-point bending resulting in an average strain rate of 5 +/- 1.5 strain/s. Test coupon modeling was used to verify the test setup. Regional variation was defined by location as anterior, lateral, or posterior as well as by rib level 1 through 12. The specimen stiffness and ultimate stress and strain were analyzed by location and rib level. Second, these material properties were incorporated into a human body computational model. The rib cage was partitioned into anterior, lateral, and posterior segments and the material properties were varied by location using an elastic-plastic material model. A total of 12 simulations with a rigid impactor were performed including 2 separate material assumptions, original and modified rib properties for regional variations, 3 separate impactor velocities, and 2 directions, anterior and lateral. The data from the material tests for all subjects indicate a statistically significant increase in the average stiffness and average ultimate stress for the cortical bone specimens located in the lateral (11.9 GPa modulus, 153.5 MPa ultimate stress) portion of the ribs versus the anterior (7.51 GPa, 116.7 MPa) and posterior (10.7 GPa, 127.7 MPa) rib locations. In addition, the stiffness, ultimate stress, and ultimate strain for all subjects are significantly different by rib level with each variable generally increasing with increasing rib number. The results from the computational modeling for both frontal and lateral impacts illustrate that the location and number of rib fractures are altered by the inclusion of rib material properties that vary by region.

Journal Article↗
PubMed2003

Predicting sediment toxicity using logistic regression: a concentration-addition approach.

The question posed in this article is how useful the chemical concentration measurements for predicting the outcome of sediment toxicity tests are. Using matched data on sediment toxicity and sediment chemical concentrations from a number of studies, we investigated several approaches for predicting toxicity based on multiple logistic regression with concentration-addition models. Three models were found to meet criteria for acceptability. The first model uses individual chemicals selected using stepwise selection. The second uses derived variables to reflect combined metal contamination, polycyclic aromatic hydrocarbon (PAH) contamination, and the interaction between metals and PAHs. The third and final model is a separate species model with derived variables. Overall, these models suggest that toxicity may be correctly predicted approximately 77% of the time, although prediction is better for samples identified as nontoxic than for those known to be toxic.

Animals↗
PubMed2002

Targeted expression of a protease-resistant IGFBP-4 mutant in smooth muscle of transgenic mice results in IGFBP-4 stabilization and smooth muscle hypotrophy.

The insulin-like growth factor-binding protein 4 (IGFBP-4), the most abundant IGF-binding protein produced by rodent smooth muscle cells (SMC), is degraded by specific protease(s) potentially releasing IGF-I for local bioactivity. IGFBP-4 protease(s) recognizes basic residues within the midregion of the molecule. We constructed a mutant IGFBP-4 with the cleavage domain substitution 119-KHMAKVRDRSKMK-133 to 119-AAMAAVADASAMA-133. Myc-tagged native and IGFBP-4.7A retained equivalent IGF-I binding affinity. Whereas native IGFBP-4 was cleaved by SMC-conditioned medium, IGFBP-4.7A was completely resistant to proteolysis. To explore the function of the protease-resistant IGFBP-4 in vivo, expression of the mutant and native proteins was targeted to SMC of transgenic mice by means of a smooth muscle alpha-actin promoter. Transgene expression was confined to SMC-rich tissues in all lines. Bladder and aortic immunoreactive IGFBP-4/transgene mRNA ratios in SMP8-BP4.7A mice were increased by 2- to 4-fold relative to SMP8-BP4 mice, indicating that the IGFBP-4.7A protein was stabilized in vivo. SMP8-BP4.7A mice had lower aortic, bladder, and stomach weight and intestinal length relative to SMP8-BP4 counterparts matched for protein expression by Western blotting. Thus, IGFBP-4.7A results in greater growth inhibition than equivalent levels of native IGFBP-4 in vivo, demonstrating a role for IGFBP-4 proteolysis in the regulation of IGF-I action.

Alanine↗