Mathematical Modeling Links Pregnancy-Associated Changes and Breast Cancer Risk

Recent debate has concentrated on the contribution of bad luck to cancer development. The tight correlation between the number of tissue-specific stem cell divisions and cancer risk of the same tissue suggests that bad luck has an important role to play in tumor development, but the full extent of this contribution remains an open question. Improved understanding of the interplay between extrinsic and intrinsic factors at the molecular level is one promising route to identifying the limits on extrinsic control of tumor initiation, which is highly relevant to cancer prevention. Here, we use a simple mathematical model to show that recent data on the variation in numbers of breast epithelial cells with progenitor features due to pregnancy are sufficient to explain the known protective effect of full-term pregnancy in early adulthood for estrogen receptor-positive (ER+) breast cancer later in life. Our work provides a mechanism for this previously ill-understood effect and illuminates the complex influence of extrinsic factors at the molecular level in breast cancer. These findings represent an important contribution to the ongoing research into the role of bad luck in human tumorigenesis

РОЗКРИТТЯ ІНФОРМАЦІЇ ПРО НАСЛІДКИ НАДЗВИЧАЙНИХ СИТУАЦІЙ У СИСТЕМІ БУХГАЛТЕРСЬКОГО ОБЛІКУ

Nowadays accounting statements is one of the most dynamic accounting method elements. First and foremost it is related to the correspondence of its subject-matter to the demands of different users willing to know economic conditions in reality changing rapidly. Thus, applying methods of economic analysis on the basis of accounting data it is possible to calculate a range of figures giving an opportunity to estimate both financial condition and economic potential of the enterprise in the future and the past. That is why to calculate such figures in the copes of accounting there should be information about emergency consequences cases affecting the production processes, product cost and further the enterprise’s financial results. This condition will allow estimate their influence on the financial figures and economic potential of the enterprise. The directions of financial statement’s expanding in content and form are articulated. Financial statement is improved in order to reflect information about emergency consequences through expanding factors in already existing chapters (as a part of other costs) and formation of the new chapter V «External and internal risks environmental impact» containing information about separation of emergency consequences from activity costs. Fragments of notes to the annual financial statement are developed giving an opportunity to estimate the impact of emergency consequences on noncurrent and current assets and the production process. Building specific information for internal use about emergency consequences is performed on the basis of justified directions of internal reporting formation and development of ways and mechanisms of their factors formation. It allowed to increase quality of information space of business activity management in emergency conditions. The use of suggestions in practice contributed to increasing the information space quality in users’ decision-making and developing a complex of measures to prevent and address the emergency consequences. In its turn analytical measures calculated on the basis of their facts will take into account a number of factors allowing to fully estimate the financial condition and economic potential.На сьогодні бухгалтерська звітність є одним з найбільш динамічних елементів методу обліку. Перш за все, це пов’язано з відповідністю його предметa вимогам різних користувачів, які бажають дізнатися, що економічні умови в реальності швидко змінюються. Тому, застосовуючи методи економічного аналізу на основі даних бухгалтерського обліку, можна розрахувати діапазон цифр, що дають можливість оцінити як фінансовий стан, так і економічний потенціал підприємства в майбутньому і минулому. Тому для обчислення таких цифр у справах бухгалтерського обліку повинна бути інформація про надзвичайні наслідки, що впливають на виробничі процеси, вартість продукції і фінансові результати підприємства. Ця умова дозволить оцінити їхній вплив на фінансові показники та економічний потенціал підприємства. Сформульовано напрями розширення фінансової звітності за змістом і формою. Фінансова звітність удосконалюється з метою відображення інформації про надзвичайні наслідки за рахунок розширення факторів у наявних главах (як частина інших витрат) і формування нової глави V «Зовнішні та внутрішні ризики впливу на навколишнє середовище», що містить інформацію про відокремлення надзвичайних наслідків від витрати на діяльність. Фрагменти приміток до річної фінансової звітності розроблено, що дає можливість оцінити вплив надзвичайних наслідків на необоротні та оборотні активи і виробничий процес. Побудова конкретної інформації для внутрішнього використання про надзвичайні наслідки здійснюється на основі обґрунтованих напрямів формування внутрішньої звітності та розроблення шляхів і механізмів формування їхніх факторів. Це дозволило підвищити якість інформаційного простору управління діловою діяльністю в надзвичайних умовах. Використання пропозицій на практиці сприяло підвищенню якості інформаційного простору при ухваленні рішень користувачами і розробленні комплексу заходів щодо запобігання надзвичайним наслідкам та їх ліквідації . У свою чергу, аналітичні заходи, розраховані на основі їхніх фактів, ураховуватимуть низку факторів, що дозволяють повністю оцінити фінансовий стан та економічний потенціал

Characteristic length of random knotting for cylindrical self-avoiding polygons

We discuss the probability of random knotting for a model of self-avoiding polygons whose segments are given by cylinders of unit length with radius $r$. We show numerically that the characteristic length of random knotting is roughly approximated by an exponential function of the chain thickness $r$.Comment: 5 pages, 4 figure

Rapid induction of p21WAF1 but delayed down-regulation of Cdc25A in the TGF-β-induced cell cycle arrest of gastric carcinoma cells

Transforming growth factor-beta (TGF-beta) is a multifunctional polypeptide that inhibits cellular proliferation in most epithelial cells. cdk4 and several cyclin-dependent kinase (cdk) inhibitors (p15(INK4B), p21(WAFI/Cip1) and p27(Kip1)) have been implicated in the TGF-beta-induced cell cycle arrest. More recently, down-regulation of Cdc25A, a cdk activator, was additionally suggested as a mechanism underlying growth inhibition by TGF-beta. The existence of diverse cellular mediators, of TGF-beta, however, raises the question of whether their involvement might occur in a redundant manner or coordinately in a certain cell type. Using two TGF-beta-sensitive gastric carcinoma cell lines (SNU-16 and -620), we addressed the contributory roles of several cdk inhibitors, and of cdk4 and Cdc25A, in TGF-beta-induced cell cycle arrest by comparing their temporal expression pattern in response to TGF-beta. Among the cdk inhibitors examined, p21 mRNA was most rapidly (in less than 1 h) and prominently induced by TGF-beta. In contrast, p15 mRNA was more slowly induced than p21 in SNU-620: cells, and not expressed in SNU-16 cells harbouring homozygous deletion of p15. Western blotting results confirmed the rapid increase of p21 while opposite patterns of p27 expression were observed in the two cell lines. The down-regulation of Cdc25A mRNA occurred, but was more delayed than that of p15 or p21. Until G1 arrest was established, changes in the protein levels of both Cdc25A and cdk4 were marginal. Co-immunoprecipitation with anti-cdk4 antibody showed that induced p21 associates with cdk4, and that its kinase activity is reduced by TGF-beta, which kinetically correlates closely with G1 arrest following TGF-beta treatment of both cell lines. These results suggest that in certain human epithelial cells, p21 may play an early role in TGF-beta-induced cell cycle arrest, and its cooperation with other cdk inhibitors is different depending on cell type. Delayed down-regulation of Cdc25A and cdk4 may contribute to cell adaptation to the quiescent state in the two gastric carcinoma cell lines studied

Self-association of the Shigella flexneri IcsA autotransporter protein

The IcsA autotransporter protein is a major virulence factor of the human intracellular pathogen Shigella flexneri. IcsA is distributed at the poles in the outer membrane (OM) of S. flexneri and interacts with components of the host actin-polymerization machinery to facilitate intracellular actin-based motility and subsequent cell-to-cell spreading of the bacterium. We sought to characterize the biochemical properties of IcsA in the bacterial OM. Chemical cross-linking data suggested that IcsA exists in a complex in the OM. Furthermore, reciprocal co-immunoprecipitation of differentially epitope-tagged IcsA proteins indicated that IcsA is able to self-associate. The identification of IcsA linker-insertion mutants that were negatively dominant provided genetic evidence of IcsA–IcsA interactions. From these results, we propose a model whereby IcsA self-association facilitates efficient actin-based motility.Kerrie L. May, Marcin Grabowicz, Steven W. Polyak and Renato Moron

Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers

Objective: Identification of patients at risk of developing epilepsy before the first spontaneous seizure may promote the development of preventive treatment providing opportunity to stop or slow down the disease. // Methods: As development of novel radiotracers and on‐site setup of existing radiotracers is highly time‐consuming and expensive, we used dual‐centre in vitro autoradiography as an approach to characterize the potential of innovative radiotracers in the context of epilepsy development. Using brain slices from the same group of rats, we aimed to characterise the evolution of neuroinflammation and expression of inhibitory and excitatory neuroreceptors during epileptogenesis using translational positron emission tomography (PET) tracers; 18F‐flumazenil (18F‐FMZ; GABAA receptor), 18F‐FPEB (metabotropic glutamate receptor 5; mGluR5), 18F‐flutriciclamide (translocator protein; TSPO, microglia activation) and 18F‐deprenyl (monoamine oxidase B, astroglia activation). Autoradiography images from selected time points after pilocarpine‐induced status epilepticus (SE; baseline, 24 and 48 hours, 5, 10 and 15 days and 6 and 12‐14 weeks after SE) were normalized to a calibration curve, co‐registered to an MRI‐based 2D region‐of‐interest atlas, and activity concentration (Bq/mm2) was calculated. // Results: In epileptogenesis‐associated brain regions, 18F‐FMZ and 18F‐FPEB showed an early decrease after SE. 18F‐FMZ decrease was maintained in the latent phase and further reduced in the chronic epileptic animals, while 18F‐FPEB signal recovered from day 10, reaching baseline levels in chronic epilepsy. 18F‐flutriciclamide showed an increase of activated microglia at 24 hours after SE, peaking at 5‐15 days and decreasing during the chronic phase. On the other hand, 18F‐deprenyl autoradiography showed late astrogliosis, peaking in the chronic phase. // Significance: Autoradiography revealed different evolution of the selected targets during epileptogenesis. Our results suggest an advantage of combined imaging of inter‐related targets like glutamate and GABAA receptors, or microglia and astrocyte activation, in order to identify important interactions, especially when using PET imaging for the evaluation of novel treatments