Can the stroma provide the clue to the cellular basis for mammographic density?

Mammographic density is recognised as a useful phenotypic biomarker of breast cancer risk. Deeper understanding is needed of the cellular basis, but evidence is limited because of difficulty in designing studies to validate hypotheses. The ductal epithelial components do not adequately explain the physical and dynamic features observed. The stroma is thought to interact with ductal structures in cancer initiation. Stromal tissues might account for the mammographic features, and this interplay can be hypothesised to relate risk to density. In a paper in this issue of Breast Cancer Research, Alowami has shown a relationship between density and stromal proteins, which might provide useful insight into mammographic density

Mammographic screening and mammographic patterns

Mammography is an effective screening modality for the early detection of breast cancer. The reduction in breast cancer mortality is greater for women aged over 50 at screening than for women aged under 50. Mammography can also contribute to an understanding of the biology of breast cancer. Screening trials provide good evidence for the dedifferentiation of a cancer as it develops over time, and the age dependency of this dedifferentiation explains much of the age difference in the effectiveness of screening. Mammographic density is an important predictor of future breast cancer risk, and has potential as an early endpoint in breast cancer prevention trials. Mammographic density is also an important determinant of mammographic screening sensitivity

Collagen density promotes mammary tumor initiation and progression

<p>Abstract</p> <p>Background</p> <p>Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma. Despite the strong clinical correlation, breast density has not been causally linked to tumorigenesis, largely because no animal model has existed for studying breast tissue density. Importantly, regions of high breast density are associated with increased stromal collagen. Thus, the influence of the extracellular matrix on breast carcinoma development and the underlying molecular mechanisms are not understood.</p> <p>Methods</p> <p>To study the effects of collagen density on mammary tumor formation and progression, we utilized a bi-transgenic tumor model with increased stromal collagen in mouse mammary tissue. Imaging of the tumors and tumor-stromal interface in live tumor tissue was performed with multiphoton laser-scanning microscopy to generate multiphoton excitation and spectrally resolved fluorescent lifetimes of endogenous fluorophores. Second harmonic generation was utilized to image stromal collagen.</p> <p>Results</p> <p>Herein we demonstrate that increased stromal collagen in mouse mammary tissue significantly increases tumor formation approximately three-fold (<it>p </it>< 0.00001) and results in a significantly more invasive phenotype with approximately three times more lung metastasis (<it>p </it>< 0.05). Furthermore, the increased invasive phenotype of tumor cells that arose within collagen-dense mammary tissues remains after tumor explants are cultured within reconstituted three-dimensional collagen gels. To better understand this behavior we imaged live tumors using nonlinear optical imaging approaches to demonstrate that local invasion is facilitated by stromal collagen re-organization and that this behavior is significantly increased in collagen-dense tissues. In addition, using multiphoton fluorescence and spectral lifetime imaging we identify a metabolic signature for flavin adenine dinucleotide, with increased fluorescent intensity and lifetime, in invading metastatic cells.</p> <p>Conclusion</p> <p>This study provides the first data causally linking increased stromal collagen to mammary tumor formation and metastasis, and demonstrates that fundamental differences arise and persist in epithelial tumor cells that progressed within collagen-dense microenvironments. Furthermore, the imaging techniques and signature identified in this work may provide useful diagnostic tools to rapidly assess fresh tissue biopsies.</p

Comprehensive plasma proteomic profiling reveals biomarkers for active tuberculosis

BACKGROUND. Tuberculosis (TB) kills more people than any other infection, and new diagnostic tests to identify active cases are required. We aimed to discover and verify novel markers for TB in nondepleted plasma. / METHODS. We applied an optimized quantitative proteomics discovery methodology based on multidimensional and orthogonal liquid chromatographic separation combined with high-resolution mass spectrometry to study nondepleted plasma of 11 patients with active TB compared with 10 healthy controls. Prioritized candidates were verified in independent UK (n = 118) and South African cohorts (n = 203). / RESULTS. We generated the most comprehensive TB plasma proteome to date, profiling 5022 proteins spanning 11 orders-of-magnitude concentration range with diverse biochemical and molecular properties. We analyzed the predominantly low–molecular weight subproteome, identifying 46 proteins with significantly increased and 90 with decreased abundance (peptide FDR ≤ 1%, q ≤ 0.05). Verification was performed for novel candidate biomarkers (CFHR5, ILF2) in 2 independent cohorts. Receiver operating characteristics analyses using a 5-protein panel (CFHR5, LRG1, CRP, LBP, and SAA1) exhibited discriminatory power in distinguishing TB from other respiratory diseases (AUC = 0.81). / CONCLUSION. We report the most comprehensive TB plasma proteome to date, identifying novel markers with verification in 2 independent cohorts, leading to a 5-protein biosignature with potential to improve TB diagnosis. With further development, these biomarkers have potential as a diagnostic triage test. / FUNDING. Colciencias, Medical Research Council, Innovate UK, NIHR, Academy of Medical Sciences, Program for Advanced Research Capacities for AIDS, Wellcome Centre for Infectious Diseases Research

Modelling knowlesi malaria transmission in humans: vector preference and host competence

Background: Plasmodium knowlesi, a malaria species that normally infects long-tailed macaques, was recently found to be prevalent in humans in Southeast Asia. While human host competency has been demonstrated experimentally, the extent to which the parasite can be transmitted from human back to mosquito vector in nature is unclear. Methods. Using a mathematical model, the influence of human host competency on disease transmission is assessed. Adapting a standard model for vector-borne disease transmission and using an evolutionary invasion analysis, the paper explores how differential host competency between humans and macaques can facilitate the epidemiological processes of P. knowlesi infection between different hosts. Results. Following current understanding of the evolutionary route of other human malaria vectors and parasites, an increasing human population in knowlesi malaria endemic regions will select for a more anthropophilic vector as well as a parasite that preferentially transmits between humans. Applying these adaptations, evolutionary invasion analysis yields threshold conditions under which this macaque disease may become a significant public health issue. Conclusions. These threshold conditions are discussed in the context of malaria vector-parasite co-evolution as a function of anthropogenic effects

Self-organization in the olfactory system: one shot odor recognition in insects

We show in a model of spiking neurons that synaptic plasticity in the mushroom bodies in combination with the general fan-in, fan-out properties of the early processing layers of the olfactory system might be sufficient to account for its efficient recognition of odors. For a large variety of initial conditions the model system consistently finds a working solution without any fine-tuning, and is, therefore, inherently robust. We demonstrate that gain control through the known feedforward inhibition of lateral horn interneurons increases the capacity of the system but is not essential for its general function. We also predict an upper limit for the number of odor classes Drosophila can discriminate based on the number and connectivity of its olfactory neurons

Very Cold Gas and Dark Matter

We have recently proposed a new candidate for baryonic dark matter: very cold molecular gas, in near-isothermal equilibrium with the cosmic background radiation at 2.73 K. The cold gas, of quasi-primordial abundances, is condensed in a fractal structure, resembling the hierarchical structure of the detected interstellar medium. We present some perspectives of detecting this very cold gas, either directly or indirectly. The H$_2$ molecule has an "ultrafine" structure, due to the interaction between the rotation-induced magnetic moment and the nuclear spins. But the lines fall in the km domain, and are very weak. The best opportunity might be the UV absorption of H$_2$ in front of quasars. The unexpected cold dust component, revealed by the COBE/FIRAS submillimetric results, could also be due to this very cold H$_2$ gas, through collision-induced radiation, or solid H$_2$ grains or snowflakes. The $\gamma$-ray distribution, much more radially extended than the supernovae at the origin of cosmic rays acceleration, also points towards and extended gas distribution.Comment: 16 pages, Latex pages, crckapb macro, 3 postscript figures, uuencoded compressed tar file. To be published in the proceeedings of the "Dust-Morphology" conference, Johannesburg, 22-26 January, 1996, D. Block (ed.), (Kluwer Dordrecht

The remnants of galaxy formation from a panoramic survey of the region around M31

In hierarchical cosmological models, galaxies grow in mass through the continual accretion of smaller ones. The tidal disruption of these systems is expected to result in loosely bound stars surrounding the galaxy, at distances that reach $10 - 100$ times the radius of the central disk. The number, luminosity and morphology of the relics of this process provide significant clues to galaxy formation history, but obtaining a comprehensive survey of these components is difficult because of their intrinsic faintness and vast extent. Here we report a panoramic survey of the Andromeda galaxy (M31). We detect stars and coherent structures that are almost certainly remnants of dwarf galaxies destroyed by the tidal field of M31. An improved census of their surviving counterparts implies that three-quarters of M31's satellites brighter than $M_V < -6$ await discovery. The brightest companion, Triangulum (M33), is surrounded by a stellar structure that provides persuasive evidence for a recent encounter with M31. This panorama of galaxy structure directly confirms the basic tenets of the hierarchical galaxy formation model and reveals the shared history of M31 and M33 in the unceasing build-up of galaxies.Comment: Published in Nature. Supplementary movie available at https://www.astrosci.ca/users/alan/PANDAS/Latest%20news%3A%20movie%20of%20orbit.htm

DOORS syndrome and a recurrent truncating ATP6V1B2 variant

PURPOSE: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant. METHODS: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants. RESULTS: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found. CONCLUSION: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions

A case control study of premorbid and currently reported physical activity levels in chronic fatigue syndrome

BACKGROUND: Patients with chronic fatigue syndrome typically report high levels of physical activity before becoming ill. Few studies have examined premorbid and current activity levels in chronically fatigued patients. METHODS: In a case-control study, 33 patients with chronic, unexplained, disabling fatigue attending a university-based clinic specializing in fatigue were compared to 33 healthy, age- and sex-matched controls. Patients rated their activity levels before their illness and currently, using scales designed for this purpose. Controls reported their level of activity of 2 years previously and currently. Chi-square analyses, Student's t tests, and Wilcoxon signed rank tests were used in pair matched analyses. RESULTS: Compared to healthy controls, patients with chronic, unexplained fatigue rated themselves as more active before their illness (p ≤ 0.001) and less active currently (p ≤ 0.001). The patients also reported they currently stood or walked less than the controls (median [inter-quartile range] = 4 [2-5] versus 9 [7.5–12] hours, p ≤ 0.001), and spent more time reclining (median [inter-quartile range] = 12 [10-16] versus 8 [8–9.5] hours, p ≤ 0.001). These differences remained significant for the subset of patients who met strict criteria for chronic fatigue syndrome or fibromyalgia. CONCLUSION: Patients with chronic, unexplained, disabling fatigue reported being more active before becoming ill than healthy controls. This finding could be explained by greater premorbid activity levels that could predispose to illness, or by an overestimation of previous activity. Either possibility could influence patients' perceptions of their current activity levels and their judgments of recovery. Perceived activity should be addressed as part of management of the illness