Quantitative Assessment of Whole-Body Tumor Burden in Adult Patients with Neurofibromatosis

Patients with neurofibromatosis 1 (NF1), NF2, and schwannomatosis are at risk for multiple nerve sheath tumors and premature mortality. Traditional magnetic resonance imaging (MRI) has limited ability to assess disease burden accurately. The aim of this study was to establish an international cohort of patients with quantified whole-body internal tumor burden and to correlate tumor burden with clinical features of disease.We determined the number, volume, and distribution of internal nerve sheath tumors in patients using whole-body MRI (WBMRI) and three-dimensional computerized volumetry. We quantified the distribution of tumor volume across body regions and used unsupervised cluster analysis to group patients based on tumor distribution. We correlated the presence and volume of internal tumors with disease-related and demographic factors.WBMRI identified 1286 tumors in 145/247 patients (59%). Schwannomatosis patients had the highest prevalence of tumors (P = 0.03), but NF1 patients had the highest median tumor volume (P = 0.02). Tumor volume was unevenly distributed across body regions with overrepresentation of the head/neck and pelvis. Risk factors for internal nerve sheath tumors included decreasing numbers of café-au-lait macules in NF1 patients (P = 0.003) and history of skeletal abnormalities in NF2 patients (P = 0.09). Risk factors for higher tumor volume included female gender (P = 0.05) and increasing subcutaneous neurofibromas (P = 0.03) in NF1 patients, absence of cutaneous schwannomas in NF2 patients (P = 0.06), and increasing age in schwannomatosis patients (p = 0.10).WBMRI provides a comprehensive phenotype of neurofibromatosis patients, identifies distinct anatomic subgroups, and provides the basis for investigating molecular biomarkers that correlate with unique disease manifestations

Environmental and Molecular Mutagenesis Meeting Report Assessing Human Germ-Cell Mutagenesis in the Post-Genome Era: A Celebration of the Legacy of William Lawson (Bill) Russell

ABSTRACT Although numerous germ-cell mutagens have been identified in animal model systems, to date, no human germ-cell mutagens have been confirmed. Because the genomic integrity of our germ cells is essential for the continuation of the human species, a resolution of this enduring conundrum is needed. To facilitate such a resolution, we organized a workshop at The Jackson Laboratory in Bar Harbor, Maine on September [28][29][30] 2004. This interactive workshop brought together scientists from a wide range of disciplines to assess the applicability of emerging molecular methods for genomic analysis to the field of human germ-cell mutagenesis. Participants recommended that focused, coordinated human germ-cell mutation studies be conducted in relation to important societal exposures. Because cancer survivors represent a unique cohort with well-defined exposures, there was a consensus that studies should be designed to assess the mutational impact on children born to parents who had received certain types of mutagenic cancer chemotherapy prior to conceiving their children. Within this high-risk cohort, parents and children could be evaluated for inherited changes in (a) gene sequences and chromosomal structure, (b) repeat sequences and minisatellite regions, and (c) global gene expression and chromatin. Participants also recommended studies to examine trans-generational effects in humans involving mechanisms such as changes in imprinting and methylation patterns, expansion of nucleotide repeats, or induction of mitochondrial DNA mutations. Workshop participants advocated establishment of a bio-bank of human tissue samples that could be used to conduct a multiple-endpoint, comprehensive, and collaborative effort to detect exposure-induced heritable alterations in the human genome. Appropriate animal models of human germ-cell mutagenesis should be used in parallel with human studies to provide insights into the mechanisms of mammalian germ-cell mutagenesis. Finally, participants recommended that 4 scientific specialty groups be convened to address specific questions regarding the potential germ-cell mutagenicity of environmental, occupational, and lifestyle exposures. Strong support from relevant funding agencies and engagement of scientists outside the fields of genomics and germ-cell mutagenesis will be required to launch a full-scale assault on some of the most pressing and enduring questions in environmental mutagenesis: Do human germ-cell mutagens exist, what risk do they pose to future generations, and are some parents at higher risk than others for acquiring and transmitting germ-cell mutations?

Measurement of tangential contact stiffness in frictional contacts: the effect of normal pressure

The tangential contact stiffness of frictional interfaces affects both the vibration response and structural integrity of structures comprising frictional joints. Vibration and structural response of monolithic structures can be predicted very accurately; however, when assemblies of components involve frictional interfaces, additional damping and compliance are present due to these interfaces. These features make it more challenging to predict the vibration characteristics of assemblies with the same degree of accuracy as can be achieved for single components. If these interface properties can be determined, it should then be possible to significantly enhance current models of the vibration of engineering assemblies. Measurements of both force and displacement in the tangential direction are obtained from a series of in-line fretting tests involving flat pads with rounded corners clamped against the flat surface of a specimen which is oscillated by a hydraulic tensile testing machine. In order to measure the local displacement field very close to the contact interface, the digital image correlation (DIC) method is employed. The effect of normal contact pressure on tangential contact stiffness is investigated. Multiple experiments with the same parameters show good repeatability given the number of variables involved. © (2011) Trans Tech Publications, Switzerland

Investigation of the friction variation with sliding which is commonly observed in individual fretting test cycles

Many researchers that have carried out fretting wear tests have presented results which show a variation (usually an increase) in the friction force during the sliding phase of individual cycles. This phenomenon is contrary to the Amontons/Coulomb model of friction which predicts a constant friction force as sliding proceeds. An in-line fretting test involving an abrupt increase in amplitude was used to show that the effect is a result of wear scar interaction effects. A pair of rotational fretting tests were then carried out to determine whether these interaction effects originate from interaction of the wear scar ends, or whether such interaction occurs throughout the nominal contact area. A new experimental rig designed to adapt conventional in-line test machines for rotational fretting was designed and built for this purpose. Results show that the friction variation occurs whether or not wear scar ends are present. After testing, the worn surface topography of each fretting pair was scanned using a focus variation microscope, and these surface images revealed the existence (and size) of many distributed local peaks and troughs distributed throughout the contact area. In conclusion, the friction variation commonly observed in the literature arises predominantly from the interaction of local wear scar features distributed over the contact region. © (2011) Trans tech publications Switzerland

An elastic-plastic asperity interaction model for sliding friction

A finite-element model of the interaction of an elastic-plastic asperity junction based on cylindrical or spherical asperities is used to predict sliding friction coefficients. The modelling differs from previous work by permitting greater asperity overlaps, enforcing an interface adhesional shear strength, and allowing material failure. The results of the modelling were also used to predict friction coefficients for a stochastic rough surface. The asperities were based on the titanium alloy Ti-6Al-4V, and the magnitudes of the predicted friction coefficients were generally representative of experimental measurements of sliding friction. The results suggest that friction arises from both plasticity and tangential interface adhesion. © 2011 Elsevier Ltd. All rights reserved

Determination of the Frictional Properties of Titanium and Nickel Alloys Using the Digital Image Correlation Method

The paper describes experiments to investigate the frictional properties of a Titanium alloy (Ti-6Al-4V) and a Nickel alloy (Udimet 720) under representative engineering conditions. Flat fretting pads with rounded corners were clamped against a flat specimen and a servo-hydraulic tensile testing machine was used to apply cyclic displacement to the specimen. Slip displacement between the specimen and pad was measured remotely using an LVDT and locally using digital image correlation. The latter approach allowed accurate determination of the tangential contact stiffness from frictional hysteresis loops. The results obtained show that the contacts are significantly less stiff than would be predicted by a smooth elastic contact analysis. A finite element model of the experimental contact geometry was constructed and it was shown that good agreement with the experimental measurements of contact stiffness can be obtained with a suitable choice of elastic modulus for a compliant surface layer. © 2010 Society for Experimental Mechanics

Investigation of non-Coulomb friction behaviour in reciprocating sliding

A commonly observed phenomenon where the friction force increases during the gross slip phase of individual fretting cycles is investigated with the aim of identifying the physical origins of this type of frictional behaviour. Measurements of sliding friction from linear and torsional fretting tests, using the aerospace nickel alloy Udimet 720, and subsequent analysis of the post-test worn surfaces were used to investigate the phenomenon. It was found that this friction variation is due to wear-scar interaction effects. These interactions were primarily found to occur at sites distributed throughout the nominal contact area via the interference of local interlocking peaks and troughs on the worn surfaces. Cross-correlation and auto-correlation analysis of the worn surfaces was used to identify, and to show the approximate size of, these local features. Many of the features were found to be similar in size to the applied fretting stroke, but on average, the features were somewhat larger. A simple one degree-of-freedom model of the interaction of an idealised surface peak with a corresponding surface groove was developed to show how these interactions produce the type of friction variation which is commonly observed during the sliding phase. © 2011 Elsevier B.V

A Comparison of Contact Stiffness Measurements Obtained by the Digital Image Correlation and Ultrasound Techniques

The digital image correlation (DIC) and ultrasound techniques have both previously been employed to measure the contact stiffness of real engineering interfaces, but a comprehensive comparison of these techniques has not previously been carried out. Such a comparison is addressed in the present paper. The principal novelty in this work is that DIC and ultrasound are used to simultaneously measure contact stiffness in the same tests and on the same contact interface. The results show that ultrasound measures somewhat higher contact stiffness magnitudes than DIC: at an average normal contact pressure of 70 MPa, ultrasound was around three times stiffer. Given that the techniques are vastly different in their measurement approach (DIC measures micron-scale relative displacements from external side-on images of the interface, while ultrasound uses the reflection of an Ångstrom scale ultrasonic perturbation from the interior of the interface itself), this level of agreement is thought to be encouraging. The difference in results can partly be explained by consideration of inherent physical differences between the techniques which have previously received little attention. Ultrasound measurement will always give the local elastic 'unloading stiffness' (even at a plastically deforming contact); whereas, a load-deflection technique like DIC, will give the 'loading stiffness'. The reason for this difference is discussed in the paper and tests carried out under increasing tangential load in the pre-sliding regime illustrate this difference experimentally. Under normal loading, the increase in real contact area obscures the effect to some extent as both DIC and ultrasound stiffnesses increase with normal load. The results suggest that rough interfaces may be satisfactorily modelled as a variable stiffness spring whose stiffness increases with contact pressure as the smooth contact case is approached. © 2013 Society for Experimental Mechanics

The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN–PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN–PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN–PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets