Genotypic and phenotypic analysis of familial male breast cancer shows under representation of the HER2 and basal subtypes in BRCA-associated carcinomas

BACKGROUND: Male breast cancer (MBC) is an uncommon and relatively uncharacterised disease accounting for <1% of all breast cancers. A significant proportion occurs in families with a history of breast cancer and in particular those carrying BRCA2 mutations. Here we describe clinicopathological features and genomic BRCA1 and BRCA2 mutation status in a large cohort of familial MBCs. METHODS: Cases (n=60) included 3 BRCA1 and 25 BRCA2 mutation carries, and 32 non-BRCA1/2 (BRCAX) carriers with strong family histories of breast cancer. The cohort was examined with respect to mutation status, clinicopathological parameters including TNM staging, grade, histological subtype and intrinsic phenotype. RESULTS: Compared to the general population, MBC incidence was higher in all subgroups. In contrast to female breast cancer (FBC) there was greater representation of BRCA2 tumours (41.7% vs 8.3%, p=0.0008) and underrepresentation of BRCA1 tumours (5.0% vs 14.4%, p=0.0001). There was no correlation between mutation status and age of onset, disease specific survival (DSS) or other clincopathological factors. Comparison with sporadic MBC studies showed similar clinicopathological features. Prognostic variables affecting DSS included primary tumour size (p=0.003, HR:4.26 95%CI 1.63-11.11), age (p=0.002, HR:4.09 95%CI 1.65-10.12), lymphovascular (p=0.019, HR:3.25 95%CI 1.21-8.74) and perineural invasion (p=0.027, HR:2.82 95%CI 1.13-7.06). Unlike familial FBC, the histological subtypes seen in familial MBC were more similar to those seen in sporadic MBC with 46 (76.7%) pure invasive ductal carcinoma of no special type (IDC-NST), 2 (3.3%) invasive lobular carcinomas and 4 (6.7%) invasive papillary carcinoma. A further 8 (13.3%) IDC-NST had foci of micropapillary differentiation, with a strong trend for co-occurrence in BRCA2 carriers (p=0.058). Most tumours were of the luminal phenotype (89.7%), with infrequent HER2 (8.6%) and basal (1.7%) phenotype tumours seen. CONCLUSION: MBC in BRCA1/2 carriers and BRCAX families is different to females. Unlike FBC, a clear BRCA1 phenotype is not seen but a possible BRCA2 phenotype of micropapillary histological subtype is suggested. Comparison with sporadic MBCs shows this to be a high-risk population making further recruitment and investigation of this cohort of value in further understanding these uncommon tumours

Mass Spectrometric Analysis of Ehrlichia chaffeensis Tandem Repeat Proteins Reveals Evidence of Phosphorylation and Absence of Glycosylation

Ehrlichia chaffeensis has a small subset of immunoreactive secreted, acidic (pI approximately 4), tandem repeat (TR)-containing proteins (TRPs), which exhibit abnormally large electrophoretic masses that have been associated with glycosylation of the TR domain.In this study, we examined the extent and nature of posttranslational modifications on the native TRP47 and TRP32 using mass spectrometry. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) demonstrated that the mass of native TRP47 (33,104.5 Da) and TRP32 (22,736.8 Da) were slightly larger (179- and 288-Da, respectively) than their predicted masses. The anomalous migration of native and recombinant TRP47, and the recombinant TR domain (C-terminal region) were normalized by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) modification of negatively charged carboxylates to neutral amides. Exhaustive tandem mass spectrometric analysis (92% coverage) performed on trypsin and Asp-N digested native TRP47 identified peptides consistent with their predicted masses. Two TRP47 peptides not identified were located in the normally migrating amino (N)-terminal region of TRP47 and contained predicted phosphorylation sites (tyrosine and serine residues). Moreover, native TRP47 was immunoprecipitated from E. chaffeensis-infected cell lysate with anti-phosphotyrosine (anti-pTyr) antibody.TRP47 and TRP32 are not modified by glycans and the substantial net negative charge of the ehrlichial TRPs, and particularly the highly acidic TRs present within the ehrlichial TRPs, is responsible for larger-than-predicted masses. Furthermore, this study provides evidence that the N-terminal region of the TRP47 is tyrosine phosphorylated

Linear systems with adiabatic fluctuations

We consider a dynamical system subjected to weak but adiabatically slow fluctuations of external origin. Based on the ``adiabatic following'' approximation we carry out an expansion in \alpha/|\mu|, where \alpha is the strength of fluctuations and 1/|\mu| refers to the time scale of evolution of the unperturbed system to obtain a linear differential equation for the average solution. The theory is applied to the problems of a damped harmonic oscillator and diffusion in a turbulent fluid. The result is the realization of `renormalized' diffusion constant or damping constant for the respective problems. The applicability of the method has been critically analyzed.Comment: Plain Latex, no figure, 21 page

Langevin dynamics with dichotomous noise; direct simulation and applications

We consider the motion of a Brownian particle moving in a potential field and driven by dichotomous noise with exponential correlation. Traditionally, the analytic as well as the numerical treatments of the problem, in general, rely on Fokker-Planck description. We present a method for direct numerical simulation of dichotomous noise to solve the Langevin equation. The method is applied to calculate nonequilibrium fluctuation induced current in a symmetric periodic potential using asymmetric dichotomous noise and compared to Fokker-Planck-Master equation based algorithm for a range of parameter values. Our second application concerns the study of resonant activation over a fluctuating barrier.Comment: Accepted in Journal of Statistical Mechanics: Theory and Experimen

Virulence Attenuation of Candida albicans Genetic Variants Isolated from a Patient with a Recurrent Bloodstream Infection

The incidence of Candida albicans infections and the relapse episodes after antifungal treatment have increased in recent decades. Recurrences are mainly due to the persistence of the original infecting strain that may present genetic and genomic rearrangements during interaction with the host, reflecting strain adaptation. In this study, four isolates recovered from a patient during recurrent candidemia episodes were genotyped by microsatellite length polymorphism (MLP) and by multilocus sequence typing (MLST) and found to be genetic variants of the same strain. Using experimental mouse infections, a progressive reduction in the virulence of the four isolates was observed, with the first two isolates more virulent than the third and fourth. Additionally, in the mouse model, the first isolate resisted host control more efficiently, resulting in higher kidney fungal burdens and necrosis as compared to the third isolate. The resolution of inflammation was delayed in mice challenged with the first isolate and the message for IFN-γ and TNF-α in the spleen was lower within the first few hours post-infection. Original and recurrent isolates also displayed different phenotypes regarding activity of secreted enzymes and response to stress agents. Overall, the comparative analysis indicated that the virulence decrease of these isolates was related to a lower ability to resist to the host anticandida effector mechanisms. We showed for the first time that C. albicans genetic variants of the same strain, sequentially isolated from an immunocompromised patient, underwent adaptations in the human host that resulted in virulence attenuation when tested in mice

Fluctuation-dissipation relationship in chaotic dynamics

We consider a general N-degree-of-freedom dissipative system which admits of chaotic behaviour. Based on a Fokker-Planck description associated with the dynamics we establish that the drift and the diffusion coefficients can be related through a set of stochastic parameters which characterize the steady state of the dynamical system in a way similar to fluctuation-dissipation relation in non-equilibrium statistical mechanics. The proposed relationship is verified by numerical experiments on a driven double well system.Comment: Revtex, 23 pages, 2 figure

Time-dependent excitation and ionization modelling of absorption-line variability due to GRB 080310

We model the time-variable absorption of FeII, FeIII, SiII, CII and CrII detected in UVES spectra of GRB 080310, with the afterglow radiation exciting and ionizing the interstellar medium in the host galaxy at a redshift of z=2.42743. To estimate the rest-frame afterglow brightness as a function of time, we use a combination of the optical VRI photometry obtained by the RAPTOR-T telescope array -- which are presented in this paper -- and Swift's X-Ray Telescope observations. Excitation alone, which has been successfully applied for a handful of other GRBs, fails to describe the observed column-density evolution in the case of GRB 080310. Inclusion of ionization is required to explain the column-density decrease of all observed FeII levels (including the ground state 6D9/2) and increase of the FeIII 7S3 level. The large population of ions in this latter level (up to 10% of all FeIII) can only be explained through ionization of FeII, whereby a large fraction of the ionized FeII ions -- we calculate 31% using the Flexible Atomic (FAC) and Cowan codes -- initially populate the 7S3 level of FeIII rather than the ground state. This channel for producing a significant FeIII 7S3 level population may be relevant for other objects in which absorption lines from this level -- the UV34 triplet -- are observed, such as BAL quasars and Eta Carinae. This provides conclusive evidence for time-variable ionization in the circumburst medium, which to date has not been convincingly detected. However, the best-fit distance of the neutral absorbing cloud to the GRB is 200--400 pc, i.e. similar to GRB-absorber distance estimates for GRBs without any evidence for ionization. We find that the presence of time-varying ionization in GRB 080310 is likely due to a combination of the super-solar iron abundance ([Fe/H]=+0.2) and the low HI column density (log N(HI)=18.7). [abridged]Comment: 14 pages, 6 figures; accepted for publication in A&A (on August 8, 2012

Theory of Adiabatic fluctuations : third-order noise

We consider the response of a dynamical system driven by external adiabatic fluctuations. Based on the `adiabatic following approximation' we have made a systematic separation of time-scales to carry out an expansion in $\alpha |\mu|^{-1}$, where $\alpha$ is the strength of fluctuations and $|\mu|$ is the damping rate. We show that probability distribution functions obey the differential equations of motion which contain third order terms (beyond the usual Fokker-Planck terms) leading to non-Gaussian noise. The problem of adiabatic fluctuations in velocity space which is the counterpart of Brownian motion for fast fluctuations, has been solved exactly. The characteristic function and the associated probability distribution function are shown to be of stable form. The linear dissipation leads to a steady state which is stable and the variances and higher moments are shown to be finite.Comment: Plain Latex, no figures, 28 pages; to appear in J. Phys.

Analytical and numerical investigation of escape rate for a noise driven bath

We consider a system-reservoir model where the reservoir is modulated by an external noise. Both the internal noise of the reservoir and the external noise are stationary, Gaussian and are characterized by arbitrary decaying correlation functions. Based on a relation between the dissipation of the system and the response function of the reservoir driven by external noise we numerically examine the model using a full bistable potential to show that one can recover the turn-over features of the usual Kramers' dynamics when the external noise modulates the reservoir rather than the system directly. We derive the generalized Kramers' rate for this nonequilibrium open system. The theoretical results are verified by numerical simulation.Comment: Revtex, 25 pages, 5 figures. To appear in Phys. Rev.