Silencing of microRNAs in vivo with 'antagomirs'

MicroRNAs (miRNAs) are an abundant class of non-coding RNAs that are believed to be important in many biological processes through regulation of gene expression. The precise molecular function of miRNAs in mammals is largely unknown and a better understanding will require loss-of-function studies in vivo. Here we show that a novel class of chemically engineered oligonucleotides, termed 'antagomirs', are efficient and specific silencers of endogenous miRNAs in mice. Intravenous administration of antagomirs against miR-16, miR-122, miR-192 and miR-194 resulted in a marked reduction of corresponding miRNA levels in liver, lung, kidney, heart, intestine, fat, skin, bone marrow, muscle, ovaries and adrenals. The silencing of endogenous miRNAs by this novel method is specific, efficient and long-lasting. The biological significance of silencing miRNAs with the use of antagomirs was studied for miR-122, an abundant liver-specific miRNA. Gene expression and bioinformatic analysis of messenger RNA from antagomir-treated animals revealed that the 3' untranslated regions of upregulated genes are strongly enriched in miR-122 recognition motifs, whereas downregulated genes are depleted in these motifs. Analysis of the functional annotation of downregulated genes specifically predicted that cholesterol biosynthesis genes would be affected by miR-122, and plasma cholesterol measurements showed reduced levels in antagomir-122-treated mice. Our findings show that antagomirs are powerful tools to silence specific miRNAs in vivo and may represent a therapeutic strategy for silencing miRNAs in disease.

MODEL UPDATING AND STRUCTURAL HEALTH MONITORING OF HORIZONTAL AXIS WIND TURBINES VIA ADVANCED SPINNING FINITE ELEMENTS AND STOCHASTIC SUBSPACE IDENTIFICATION METHODS

Wind energy has been one of the most growing sectors of the nation’s renewable energy portfolio for the past decade, and the same tendency is being projected for the upcoming years given the aggressive governmental policies for the reduction of fossil fuel dependency. Great technological expectation and outstanding commercial penetration has shown the so called Horizontal Axis Wind Turbines (HAWT) technologies. Given its great acceptance, size evolution of wind turbines over time has increased exponentially. However, safety and economical concerns have emerged as a result of the newly design tendencies for massive scale wind turbine structures presenting high slenderness ratios and complex shapes, typically located in remote areas (e.g. offshore wind farms). In this regard, safety operation requires not only having first-hand information regarding actual structural dynamic conditions under aerodynamic action, but also a deep understanding of the environmental factors in which these multibody rotating structures operate. Given the cyclo-stochastic patterns of the wind loading exerting pressure on a HAWT, a probabilistic framework is appropriate to characterize the risk of failure in terms of resistance and serviceability conditions, at any given time. Furthermore, sources of uncertainty such as material imperfections, buffeting and flutter, aeroelastic damping, gyroscopic effects, turbulence, among others, have pleaded for the use of a more sophisticated mathematical framework that could properly handle all these sources of indetermination. The attainable modeling complexity that arises as a result of these characterizations demands a data-driven experimental validation methodology to calibrate and corroborate the model. For this aim, System Identification (SI) techniques offer a spectrum of well-established numerical methods appropriated for stationary, deterministic, and data-driven numerical schemes, capable of predicting actual dynamic states (eigenrealizations) of traditional time-invariant dynamic systems. As a consequence, it is proposed a modified data-driven SI metric based on the so called Subspace Realization Theory, now adapted for stochastic non-stationary and timevarying systems, as is the case of HAWT’s complex aerodynamics. Simultaneously, this investigation explores the characterization of the turbine loading and response envelopes for critical failure modes of the structural components the wind turbine is made of. In the long run, both aerodynamic framework (theoretical model) and system identification (experimental model) will be merged in a numerical engine formulated as a search algorithm for model updating, also known as Adaptive Simulated Annealing (ASA) process. This iterative engine is based on a set of function minimizations computed by a metric called Modal Assurance Criterion (MAC). In summary, the Thesis is composed of four major parts: (1) development of an analytical aerodynamic framework that predicts interacted wind-structure stochastic loads on wind turbine components; (2) development of a novel tapered-swept-corved Spinning Finite Element (SFE) that includes dampedgyroscopic effects and axial-flexural-torsional coupling; (3) a novel data-driven structural health monitoring (SHM) algorithm via stochastic subspace identification methods; and (4) a numerical search (optimization) engine based on ASA and MAC capable of updating the SFE aerodynamic model.

Oral or transdermal opioids for osteoarthritis of the knee or hip

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in the elderly. Opioids may be a viable treatment option if patients suffer from severe pain or if other analgesics are contraindicated. However, the evidence about their effectiveness and safety is contradictory. OBJECTIVES: To determine the effects on pain and function and the safety of oral or transdermal opioids as compared with placebo or no intervention in patients with osteoarthritis of the hip or knee. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, and CINAHL (up to 28 July 2008), checked conference proceedings, reference lists, and contacted authors. SELECTION CRITERIA: Studies were included if they were randomised or quasi-randomised controlled trials that compared oral or transdermal opioids with placebo or no treatment in patients with osteoarthritis of the knee or hip. Studies of tramadol were excluded. No language restrictions were applied. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate. Standardised mean differences (SMDs) and 95% confidence intervals (CI) were calculated for pain and function, and risk ratios for safety outcomes. Trials were combined using inverse-variance random-effects meta-analysis. MAIN RESULTS: Ten trials with 2268 participants were included. Oral codeine was studied in three trials, transdermal fentanyl and oral morphine in one trial each, oral oxycodone in four, and oral oxymorphone in two trials. Overall, opioids were more effective than control interventions in terms of pain relief (SMD -0.36, 95% CI -0.47 to -0.26) and improvement of function (SMD -0.33, 95% CI -0.45 to -0.21). We did not find substantial differences in effects according to type of opioid, analgesic potency (strong or weak), daily dose, duration of treatment or follow up, methodological quality of trials, and type of funding. Adverse events were more frequent in patients receiving opioids compared to control. The pooled risk ratio was 1.55 (95% CI 1.41 to 1.70) for any adverse event (4 trials), 4.05 (95% CI 3.06 to 5.38) for dropouts due to adverse events (10 trials), and 3.35 (95% CI 0.83 to 13.56) for serious adverse events (2 trials). Withdrawal symptoms were more severe after fentanyl treatment compared to placebo (SMD 0.60, 95% CI 0.42 to 0.79; 1 trial). AUTHORS' CONCLUSIONS: The small to moderate beneficial effects of non-tramadol opioids are outweighed by large increases in the risk of adverse events. Non-tramadol opioids should therefore not be routinely used, even if osteoarthritic pain is severe.

Effect of automatic tube current modulation on radiation dose and image quality for low tube voltage multidetector row CT angiography: phantom study

RATIONALE AND OBJECTIVES: To evaluate the effect of automatic tube current modulation on radiation dose and image quality for low tube voltage computed tomography (CT) angiography. MATERIALS AND METHODS: An anthropomorphic phantom was scanned with a 64-section CT scanner using following tube voltages: 140 kVp (Protocol A), 120 kVp (Protocol B), 100 kVp (Protocol C), and 80 kVp (Protocol D). To achieve similar noise, combined z-axis and xy-axes automatic tube current modulation was applied. Effective dose (ED) for the four tube voltages was assessed. Three plastic vials filled with different concentrations of iodinated solution were placed on the phantom's abdomen to obtain attenuation measurements. The signal-to-noise ratio (SNR) was calculated and a figure of merit (FOM) for each iodinated solution was computed as SNR(2)/ED. RESULTS: The ED was kept similar for the four different tube voltages: (A) 5.4 mSv +/- 0.3, (B) 4.1 mSv +/- 0.6, (C) 3.9 mSv +/- 0.5, and (D) 4.2 mSv +/- 0.3 (P > .05). As the tube voltage decreased from 140 to 80 kVp, image noise was maintained (range, 13.8-14.9 HU) (P > .05). SNR increased as the tube voltage decreased, with an overall gain of 119% for the 80-kVp compared to the 140-kVp protocol (P < .05). The FOM results indicated that with a reduction of the tube voltage from 140 to 120, 100, and 80 kVp, at constant SNR, ED was reduced by a factor of 2.1, 3.3, and 5.1, respectively, (P < .001). CONCLUSIONS: As tube voltage decreases, automatic tube current modulation for CT angiography yields either a significant increase in image quality at constant radiation dose or a significant decrease in radiation dose at a constant image quality.

Haemonchus contortus acetylcholine receptors of the DEG-3 subfamily and their role in sensitivity to monepantel

Gastro-intestinal nematodes in ruminants, especially Haemonchus contortus, are a global threat to sheep and cattle farming. The emergence of drug resistance, and even multi-drug resistance to the currently available classes of broad spectrum anthelmintics, further stresses the need for new drugs active against gastro-intestinal nematodes. A novel chemical class of synthetic anthelmintics, the Amino-Acetonitrile Derivatives (AADs), was recently discovered and the drug candidate AAD-1566 (monepantel) was chosen for further development. Studies with Caenorhabditis elegans suggested that the AADs act via nicotinic acetylcholine receptors (nAChR) of the nematode-specific DEG-3 subfamily. Here we identify nAChR genes of the DEG-3 subfamily from H. contortus and investigate their role in AAD sensitivity. Using a novel in vitro selection procedure, mutant H. contortus populations of reduced sensitivity to AAD-1566 were obtained. Sequencing of full-length nAChR coding sequences from AAD-susceptible H. contortus and their AAD-1566-mutant progeny revealed 2 genes to be affected. In the gene monepantel-1 (Hco-mptl-1, formerly named Hc-acr-23H), a panel of mutations was observed exclusively in the AAD-mutant nematodes, including deletions at intron-exon boundaries that result in mis-spliced transcripts and premature stop codons. In the gene Hco-des-2H, the same 135 bp insertion in the 5' UTR created additional, out of frame start codons in 2 independent H. contortus AAD-mutants. Furthermore, the AAD mutants exhibited altered expression levels of the DEG-3 subfamily nAChR genes Hco-mptl-1, Hco-des-2H and Hco-deg-3H as quantified by real-time PCR. These results indicate that Hco-MPTL-1 and other nAChR subunits of the DEG-3 subfamily constitute a target for AAD action against H. contortus and that loss-of-function mutations in the corresponding genes may reduce the sensitivity to AADs.

A novel succinate dehydrogenase subunit B gene mutation, H132P, causes familial malignant sympathetic extraadrenal paragangliomas

We report a family with malignant sympathetic paragangliomas (PGL) exhibiting a new type of germline mutation in the succinate dehydrogenase subunit B (SDHB) gene. Two affected brothers, presenting with symptoms at the ages of 25 and 52 yr, suffered from malignant abdominal extraadrenal sympathetic PGL. They died of their disease at ages 43 and 61 yr. Their mother had the same history of signs and symptoms, suggesting a catecholamine-producing tumor at the age of 55 yr. Analysis of the germline DNA from these three patients revealed a novel mutation in exon 4 (H132P) of the SDHB gene. This mutation was absent in 160 control chromosomes. Loss of heterozygosity analysis of the tumors showed a loss of one SDHB allele, and RT-PCR-based expression analysis confirmed the exclusive expression of the mutated allele in both tumors. A review of the published PGL families revealed malignant tumors in seven of 12 well-documented families with SDHB mutation-associated extraadrenal PGL. These findings, as well as findings of the family reported here, suggest a strong causal relationship of SDHB germline mutations with malignant extraadrenal abdominal PGL and imply the necessity of a close follow-up of affected individuals and family members.

Genetic diversity of Swiss sheep breeds in the focus of conservation research

There is constant pressure to improve evaluation of animal genetic resources in order to prevent their erosion. Maintaining the integrity of livestock species as well as their genetic diversity is of paramount interest for long-term agricultural policies. One major use of DNA techniques in conservation is to reveal genetic diversity within and between populations. Forty-one microsatellites were analysed to assess genetic diversity in nine Swiss sheep breeds and to measure the loss of the overall diversity when one breed would become extinct. The expected heterozygosities varied from 0.65 to 0.74 and 10.8% of the total genetic diversity can be explained by the variation among breeds. Based on the proportion of shared alleles, each of the nine breeds were clearly defined in their own cluster in the neighbour-joining tree describing the relationships among the breeds. Bayesian clustering methods assign individuals to groups based on their genetic similarity and infer the number of populations. In STRUCTURE, this approach pooled the Valais Blacknose and the Valais Red. With BAPS method the two Valais sheep breeds could be separated. Caballero & Toro approach (2002) was used to calculate the loss or gain of genetic diversity when each of the breeds would be removed from the set. The changes in diversity based on between-breed variation ranged from -12.2% (Valais Blacknose) to 0% (Swiss Black Brown Mountain and Mirror Sheep); based on within-breed diversity the removal of a breed could also produce an increase in diversity (-0.6% to + 0.6%). Allelic richness ranged from 4.9 (Valais Red) to 6.7 (Brown Headed Meat sheep and Red Engadine Sheep). Breed conservation decisions cannot be limited to genetic diversity alone. In Switzerland, conservation goals are embedded in the desire to carry the cultural legacy over to future generations.

Long-term outcomes of dental implants with a titanium plasma-sprayed surface: a 20-year prospective case series study in partially edentulous patients

BACKGROUND Long-term studies of ≥10 years are important milestones to get a better understanding of potential factors causing implant failures or complications. PURPOSE The present study investigated the long-term outcomes of titanium dental implants with a rough, microporous surface (titanium plasma sprayed [TPS]) and the associated biologic and technical complications in partially edentulous patients with fixed dental prostheses over a 20-year follow-up period. MATERIALS AND METHODS Sixty-seven patients, who received 95 implants in the 1980s, were examined with well-established clinical and radiographic parameters. Based on these findings, each implant was classified as either successful, surviving, or failed. RESULTS Ten implants in nine patients were lost during the observation period, resulting in an implant survival rate of 89.5%. Radiographically, 92% of the implants exhibited crestal bone loss below 1 mm between the 1- and 20-year follow-up examinations. Only 8% yielded peri-implant bone loss of >1 mm and none exhibited severe bone loss of more than 1.8 mm. During the observation period, 19 implants (20%) experienced a biologic complication with suppuration. Of these 19 implants, 13 implants (13.7%) had been treated and were successfully maintained over the 20-year follow-up period. Therefore, the 20-year implant success rate was 75.8 or 89.5% depending on the different success criteria. Technical complications were observed in 32%. CONCLUSION The present study is the first to report satisfactory success rates after 20 years of function of dental implants with a TPS surface in partially edentulous patients.

Strategies for Optimizing Value of Finished Cattle in Value-Based Marketing Grids

Performance and carcass data from 624 steers in three experiments were used to evaluate potential strategies that might be used with incoming feeders to remove animals that produce low value carcasses when cattle are sold in a valuebased grid. Removing 10% of the carcasses with the lowest net value from each group increased the overall average net value of the remaining carcasses $17.50 to $21.09. Carcass weight was found to be the most significant factor determining net value of the carcass. Gain of the steers during the first 3 to 5 weeks of the feeding period was significantly related to average final gain and carcass value, but accounted for a small portion of the overall variation in gain or carcass value. Use of initial gain was successful in identifying ten of the sixty-four carcasses with least net value in a value-based grid. Adding frame score and measurement of initial thickness of backfat along with initial gain did not significantly improve identification of the low-value carcasses. Sorting the steers as feeders based on frame score and initial thickness of backfat resulted in differences in performance and carcass measurements. The low-value carcasses tended to be concentrated in the smaller-framed steers.

Health of farmed fish: its relation to fish welfare and its utility as welfare indicator

This brief review focuses on health and biological function as cornerstones of fish welfare. From the function-based point of view, good welfare is reflected in the ability of the animal to cope with infectious and non-infectious stressors, thereby maintaining homeostasis and good health, whereas stressful husbandry conditions and protracted suffering will lead to the loss of the coping ability and, thus, to impaired health. In the first part of the review, the physiological processes through which stressful husbandry conditions modulate health of farmed fish are examined. If fish are subjected to unfavourable husbandry conditions, the resulting disruption of internal homeostasis necessitates energy-demanding physiological adjustments (allostasis/acclimation). The ensuing energy drain leads to trade-offs with other energy-demanding processes such as the functioning of the primary epithelial barriers (gut, skin, gills) and the immune system. Understanding of the relation between husbandry conditions, allostatic responses and fish health provides the basis for the second theme developed in this review, the potential use of biological function and health parameters as operational welfare indicators (OWIs). Advantages of function- and health-related parameters are that they are relatively straightforward to recognize and to measure and are routinely monitored in most aquaculture units, thereby providing feasible tools to assess fish welfare under practical farming conditions. As the efforts to improve fish welfare and environmental sustainability lead to increasingly diverse solutions, in particular integrated production, it is imperative that we have objective OWIs to compare with other production forms, such as high-density aquaculture. However, to receive the necessary acceptance for legislation, more robust scientific backing of the health- and function-related OWIs is urgently needed.

An Economic Comparison of Rotational Grazing Systems to Eight Crop Alternatives and the CRP Option for Highly Erodible Land in Southwest Iowa

Economic comparisons of income on highly erodible land (HEL) in Adams County were made utilizing five years of grazing data collected from a 13- paddock intensive-rotational grazing system and a four-paddock rotational-grazing system and four years of data collected from an 18-paddock intensive-rotational grazing system, all at the Adams County CRP Research and Demonstration Farm near Corning. Net income from the average grazing weight-gain of Angus-sired calves nursing crossbred cows was compared to the net income from grazing yearling steers, to the net income of eight NRCS-recommended crop rotations, and to the Conservation Reserve Program (CRP) option. Results of these comparisons show the 13-paddock intensive rotational grazing system with cow-calf pairs to be the most profitable alternative, with a net return of $19.86 per acre per year. The second most profitable alternative is the CRP option, with a net return of $13.09 per acre, and the third most profitable option is the fourpaddock rotation with cows and calves with a net return of $12.53 per acre. An 18-paddock system returned a net income of $2.47 per acre per year with cows and calves in 1993, but lost an average of $107.69 per acre each year in 1994 and 1995 with yearling steers. Each year, the steers were purchased high and sold low, contributing to the large loss per acre. The following recommended crop rotations all show net losses on these 9-14 % slope, Adair-Shelby Complex soils (ApD3): continuous corn; corn-soybean rotation; corn-soybean rotation with a farm program deficiency payment; corn-corn-corn-oats-meadow-meadow rotation with grass headlands; continuous corn to “T” with grass headlands and buffer strips; continuous corn to “T” with grass headlands, buffer strips, and a deficiency payment; corn-corn-oats-meadow rotation to “T”; and corn-soybeans-oats-meadow-meadow-meadow-meadow rotation to “T”. Per-acre yield assumptions of 90 bushels for corn, 30 bushels for soybeans, 45 bushels for oats, and four tons for alfalfa were used, with per-bushel prices of $2.40 on corn, $5.50 on soybeans, and $1.50 on oats. Alfalfa hay was priced at $40.00 per ton and grass hay at $33.33 per ton. The calf weight-gain in the cow/ calf systems was valued at $.90 per pound. All crop expenses except land costs were calculated from ISU publication Fm 1712, “Estimated Costs of Crop Production in Iowa - 1995.” Land costs were determined by using an opportunity cost and actual property tax figures for the land at the grazing site. In preparation for the end of the CRP beginning in 1996, further economic comparisons will be made after additional grazing seasons and data collection. This project is an interagency cooperative effort sponsored by the Southern Iowa Forage and Livestock Committee which has special permission from the USDA Farm Service Agency (FSA) to use CRP land for research and demonstration.

Five-year results evaluating the effects of platelet-rich plasma on the healing of intrabony defects treated with enamel matrix derivative and natural bone mineral

BACKGROUND Regenerative periodontal surgery using the combination of enamel matrix derivative (EMD) and natural bone mineral (NBM) with and without addition of platelet-rich plasma (PRP) has been shown to result in substantial clinical improvements, but the long-term effects of this combination are unknown. METHODS The goal of this study was to evaluate the long-term (5-year) outcomes after regenerative surgery of deep intrabony defects with either EMD + NBM + PRP or EMD + NBM. Twenty-four patients were included. In each patient, one intrabony defect was randomly treated with either EMD + NBM + PRP or EMD + NBM. Clinical parameters were evaluated at baseline and 1 and 5 years after treatment. The primary outcome variable was clinical attachment level (CAL). RESULTS The sites treated with EMD + NBM + PRP demonstrated a mean CAL change from 10.5 ± 1.6 to 6.0 ± 1.7 mm (P <0.001) at 1 year and 6.2 ± 1.5 mm (P <0.001) at 5 years. EMD + NBM-treated defects showed a mean CAL change from 10.6 ± 1.7 to 6.1 ± 1.5 mm (P <0.001) at 1 year and 6.3 ± 1.4 mm (P <0.001) at 5 years. At 1 year, a CAL gain of ≥4 mm was measured in 83% (10 of 12) of the defects treated with EMD + NBM + PRP and in 100% (all 12) of the defects treated with EMD + NBM. Compared to baseline, in both groups at 5 years, a CAL gain of ≥4 mm was measured in 75% (nine of 12 in each group) of the defects. Four sites in the EMD + PRP + NBM group lost 1 mm of the CAL gained at 1 year. In the EMD + NBM group, one defect lost 2 mm and four other defects lost 1 mm of the CAL gained at 1 year. No statistically significant differences in any of the investigated parameters were observed between the two groups. CONCLUSIONS Within their limits, the present results indicate that: 1) the clinical outcomes obtained with both treatments can be maintained up to a period of 5 years; and 2) the use of PRP does not appear to improve the results obtained with EMD + NBM.

Ten-year results following treatment of intrabony defects with an enamel matrix protein derivative combined with either a natural bone mineral or a β-tricalcium phosphate

BACKGROUND The purpose of the present study is to evaluate the 10-year results following treatment of intrabony defects treated with an enamel matrix protein derivative (EMD) combined with either a natural bone mineral (NBM) or β-tricalcium phosphate (β-TCP). METHODS Twenty-two patients with advanced chronic periodontitis and displaying one deep intrabony defect were randomly treated with a combination of either EMD + NBM or EMD + β-TCP. Clinical evaluations were performed at baseline and at 1 and 10 years. The following parameters were evaluated: plaque index, bleeding on probing, probing depth, gingival recession, and clinical attachment level (CAL). The primary outcome variable was CAL. RESULTS The defects treated with EMD + NBM demonstrated a mean CAL change from 8.9 ± 1.5 mm to 5.3 ± 0.9 mm (P <0.001) and to 5.8 ± 1.1 mm (P <0.001) at 1 and 10 years, respectively. The sites treated with EMD + β-TCP showed a mean CAL change from 9.1 ± 1.6 mm to 5.4 ± 1.1 mm (P <0.001) at 1 year and 6.1 ± 1.4 mm (P <0.001) at 10 years. At 10 years two defects in the EMD + NBM group had lost 2 mm, whereas two other defects had lost 1 mm of the CAL gained at 1 year. In the EMD + β-TCP group three defects had lost 2 mm, whereas two other defects had lost 1 mm of the CAL gained at 1 year. Compared with baseline, at 10 years, a CAL gain of ≥3 mm was measured in 64% (i.e., seven of 11) of the defects in the EMD + NBM group and in 82% (i.e., nine of 11) of the defects in the EMD + β-TCP group. No statistically significant differences were found between the 1- and 10-year values in either of the two groups. Between the treatment groups, no statistically significant differences in any of the investigated parameters were observed at 1 and 10 years. CONCLUSION Within their limitations, the present findings indicate that the clinical improvements obtained with regenerative surgery using EMD + NBM or EMD + β-TCP can be maintained over a period of 10 years.

Long-term clinical, microbiological, and radiographic outcomes of Brånemark™ implants installed in augmented maxillary bone for fixed full-arch rehabilitation

PURPOSE The purpose of this study was to document the long-term outcome of Brånemark implants installed in augmented maxillary bone and to identify parameters that are associated with peri-implant bone level. MATERIAL AND METHODS Patients of a periodontal practice who had been referred to a maxillofacial surgeon for iliac crest bone grafting in the atrophic maxilla were retrospectively recruited. Five months following grafting, they received 7-8 turned Brånemark implants. Following submerged healing of another 5 months, implants were uncovered and restorative procedures for fixed rehabilitation were initiated 2-3 months thereafter. The primary outcome variable was bone level defined as the distance from the implant-abutment interface to the first visible bone-to-implant contact. Secondary outcome variables included plaque index, bleeding index, probing depth, and levels of 40 species in subgingival plaque samples as identified by means of checkerboard DNA-DNA hybridization. RESULTS Nine out of 16 patients (eight females, one male; mean age 59) with 71 implants agreed to come in for evaluation after on average 9 years (SD 4; range 3-13) of function. One implant was deemed mobile at the time of inspection. Clinical conditions were acceptable with 11% of the implants showing pockets ≥ 5 mm. Periodontopathogens were encountered frequently and in high numbers. Clinical parameters and bacterial levels were highly patient dependent. The mean bone level was 2.30 mm (SD 1.53; range 0.00-6.95), with 23% of the implants demonstrating advanced resorption (bone level > 3 mm). Regression analysis showed a significant association of the patient (p < .001) and plaque index (p = .007) with bone level. CONCLUSIONS The long-term outcome of Brånemark implants installed in iliac crest-augmented maxillary bone is acceptable; however, advanced peri-implant bone loss is rather common and indicative of graft resorption. This phenomenon is patient dependent and seems also associated with oral hygiene.

EGFR exon-level biomarkers of the response to bevacizumab/erlotinib in non-small cell lung cancer

Activating epidermal growth factor receptor (EGFR) mutations are recognized biomarkers for patients with metastatic non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs can also have activity against NSCLC without EGFR mutations, requiring the identification of additional relevant biomarkers. Previous studies on tumor EGFR protein levels and EGFR gene copy number revealed inconsistent results. The aim of the study was to identify novel biomarkers of the response to TKIs in NSCLC by investigating whole genome expression at the exon-level. We used exon arrays and clinical samples from a previous trial (SAKK19/05) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response: EGFR, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and vascular endothelial growth factor (VEGFA). We identified the expression of EGFR exon 18 as a new predictive marker for patients with untreated metastatic NSCLC treated with bevacizumab and erlotinib in the first line setting. The overexpression of EGFR exon 18 in tumor was significantly associated with tumor shrinkage, independently of EGFR mutation status. A similar significant association could be found in blood samples. In conclusion, exonic EGFR expression particularly in exon 18 was found to be a relevant predictive biomarker for response to bevacizumab and erlotinib. Based on these results, we propose a new model of EGFR testing in tumor and blood.