The protective role of pregnancy in breast cancer

Epidemiological, clinical, and experimental data indicate that the risk of developing breast cancer is strongly dependent on the ovary and on endocrine conditions modulated by ovarian function, such as early menarche, late menopause, and parity. Women who gave birth to a child when they were younger than 24 years of age exhibit a decrease in their lifetime risk of developing breast cancer, and additional pregnancies increase the protection. The breast tissue of normally cycling women contains three identifiable types of lobules, the undifferentiated Lobules type 1 (Lob 1) and the more developed Lobules type 2 and Lobules type 3. The breast attains its maximum development during pregnancy and lactation (Lobules type 4). After menopause the breast regresses in both nulliparous and parous women containing only Lob 1. Despite the similarity in the lobular composition of the breast at menopause, the fact that nulliparous women are at higher risk of developing breast cancer than parous women indicates that Lob 1 in these two groups of women might be biologically different, or might exhibit different susceptibility to carcinogenesis. Based on these observations it was postulated that Lob 1 found in the breast of nulliparous women and of parous women with breast cancer never went through the process of differentiation, retaining a high concentration of epithelial cells that are targets for carcinogens and are therefore susceptible to undergo neoplastic transformation. These epithelial cells are called Stem cells 1, whereas Lob 1 structures found in the breast of early parous postmenopausal women free of mammary pathology, on the contrary, are composed of an epithelial cell population that is refractory to transformation, called Stem cells 2. It was further postulated that the degree of differentiation acquired through early pregnancy has changed the 'genomic signature' that differentiates Lob 1 of the early parous women from that of the nulliparous women by shifting the Stem cells 1 to Stem cells 2 that are refractory to carcinogenesis, making this the postulated mechanism of protection conferred by early full-term pregnancy. The identification of a putative breast stem cell (Stem cells 1) has, in the past decade, reached a significant impulse, and several markers also reported for other tissues have been found in the mammary epithelial cells of both rodents and humans. Although further work needs to be carried out in order to better understand the role of the Stem cells 2 and their interaction with the genes that confer them a specific signature, collectively the data presently available provide evidence that pregnancy, through the process of cell differentiation, shifts Stem cells 1 to Stem cells 2 – cells that exhibit a specific genomic signature that could be responsible for the refractoriness of the mammary gland to carcinogenesis

Can we ‘seize’ the gut microbiota to treat epilepsy?

The gut-microbiota, the complex intestinal microbial ecosystem essential to health, is an emerging concept in medicine. Several studies demonstrate a microbiota-gut-brain bidirectional connection via neural, endocrine, metabolic and immune pathways. Accordingly, the gut microbiota has a crucial role in modulating intestinal permeability, to alter local/peripheral immune responses and in production of essential metabolites and neurotransmitters. Its alterations may consequently influence all these pathways that contribute to neuronal hyper-excitability and mirrored neuroinflammation in epilepsy and similarly other neurological conditions. Indeed, pre- and clinical studies support the role of the microbiome in pathogenesis, seizure modulation and responses to treatment in epilepsy. Up to now, researchers have focussed attention above all on the brain to develop antiepileptic treatments, but considering the microbiome, could extend our possibilities for developing novel therapies in the future. We provide here a comprehensive overview of the available data on the potential role of gut microbiota in the physiopathology and therapy of epilepsy and the supposed underlying mechanisms

Increased expression of transketolase-like-1 in papillary thyroid carcinomas smaller than 1.5 cm in diameter is associated with lymph-node metastases.

BACKGROUND: Patients with small papillary thyroid carcinoma (PTC) may have a high incidence of regional lymph-node (LN) metastases at presentation, and these are considered to be an independent risk factor for tumor recurrence. A mutated transketolase transcript (TKTL1) has been found up-regulated in different human malignancies, and strong TKTL1 protein expression has been associated with aggressiveness and poor patient survival in several epithelial cancers. METHODS: TKTL1 protein expression was analyzed in 256 consecutive cases of PTCs <or=1.5 cm by immunohistochemistry with a specific anti-TKTL1 antibody. RNA analysis was performed by real-time polymerase chain reaction (PCR) in all cases for which frozen material was available, which resulted in 55 fragments of PTC. RESULTS: Increased levels of TKTL1 transcript were detected in 50 of 55 analyzed tumors compared with their corresponding normal tissues. Significant differences in TKTL1 transcript levels were found between cases of PTC with and without LN metastases. In primary tumors, immunoreactivity for TKTL1 was detected in the majority of cases, ranging from 0% to 95.0% (mean, 50.11% +/- 27.75%). A significant association was found between TKTL1 protein expression and the presence of multifocality, bilaterality, extrathyroidal extension, vascular invasion, sclerosis, and LN metastases. In cases with LN metastases, a positive correlation was found between the TKTL1 protein expression in primary tumors and the number of metastatic LNs as well as the diameter of the largest metastatic area in LNs. CONCLUSIONS: These findings suggest that TKTL1 overexpression in PTC <or=1.5 cm may be considered a factor that facilitates tumor growth and progression. (c) 2008 American Cancer Society

Pelvic actinomycosis presenting as a malignant pelvic mass: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pelvic actinomycosis constitutes 3% of all human actinomycosis infections. It is usually insidious, and is often mistaken for other conditions such as diverticulitis, abscesses, inflammatory bowel disease and malignant tumors, presenting a diagnostic challenge pre-operatively; it is identified post-operatively in most cases. Here we present a case that presented as pelvic malignancy and was diagnosed as pelvic actinomycosis post-operatively.</p> <p>Case presentation</p> <p>A 48-year-old Caucasian Turkish woman presented to our clinic with a three-month history of abdominal pain, weight loss and difficulty in defecation. She had used an intra-uterine device for 16 years, however it had recently been removed. The rectosigmoidoscopy revealed narrowing of the lumen at 12 cm due to a mass lesion either in the wall or due to an extrinsic lesion that prevented the passage of the endoscope. On examination, there was no gynecological pathology. Magnetic resonance imaging showed a mass, measuring 5.5 × 4 cm attached to the rectum posterior to the uterus. The ureter on that side was dilated. Surgically there was a pelvic mass adhered to the rectum and uterine adnexes, measuring 10 × 12 cm. It originated from uterine adnexes, particularly ones from the left side and formed a conglomerated mass with the uterus and nearby organs; the left ureter was also dilated due to the pelvic mass. Because of concomitant tubal abscess formation and difficulty in dissection planes, total abdominal hysterectomy and bilateral salphingo-oophorectomy was performed (our patient was 48 years old and had completed her childbearing period). The cytology revealed inflammatory cells with aggregates of <it>Actinomyces</it>. Penicillin therapy was given for six months without any complication.</p> <p>Conclusions</p> <p>Pelvic actinomycosis should always be considered in patients with a pelvic mass especially in ones using intra-uterine devices, and who have a history of appendectomy, tonsillectomy or dental infection. Surgeons should be aware of this infection in order to avoid excessive surgical procedures.</p

D1D5 microstate geometries from string amplitudes

We reproduce the asymptotic expansion of the D1D5 microstate geometries by computing the emission amplitudes of closed string states from disks with mixed D1D5 boundary conditions. Thus we provide a direct link between the supergravity and D-brane descriptions of the D1D5 microstates at non-zero string coupling. Microscopically, the profile functions characterizing the microstate solutions are encoded in the choice of a condensate for the twisted open string states connecting D1 and D5 branes.Comment: 21 pages; added reference

A cross-national study on the antecedents of work–life balance from the fit and balance perspective

Drawing on the perceived work–family fit and balance perspective, this study investigates demands and resources as antecedents of work–life balance (WLB) across four countries (New Zealand, France, Italy and Spain), so as to provide empirical cross-national evidence. Using structural equation modelling analysis on a sample of 870 full time employees, we found that work demands, hours worked and family demands were negatively related to WLB, while job autonomy and supervisor support were positively related to WLB. We also found evidence that resources (job autonomy and supervisor support) moderated the relationships between demands and work–life balance, with high resources consistently buffering any detrimental influence of demands on WLB. Furthermore, our study identified additional predictors of WLB that were unique to some national contexts. For example, in France and Italy, overtime hours worked were negatively associated with WLB, while parental status was positively associated with WLB. Overall, the implications for theory and practice are discussed.Peer ReviewedPostprint (author's final draft

Gravity duals of supersymmetric gauge theories on three-manifolds

We study gravity duals to a broad class of N=2 supersymmetric gauge theories defined on a general class of three-manifold geometries. The gravity backgrounds are based on Euclidean self-dual solutions to four-dimensional gauged supergravity. As well as constructing new examples, we prove in general that for solutions defined on the four-ball the gravitational free energy depends only on the supersymmetric Killing vector, finding a simple closed formula when the solution has U(1) x U(1) symmetry. Our result agrees with the large N limit of the free energy of the dual gauge theory, computed using localization. This constitutes an exact check of the gauge/gravity correspondence for a very broad class of gauge theories with a large N limit, defined on a general class of background three-manifold geometries.Comment: 74 pages, 2 figures; v2: minor change

The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

1Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito

Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort

Abstract Introduction Although pregnancy-related factors such as nulliparity and late age at first full-term pregnancy are well-established risk factors for invasive breast cancer, the roles of these factors in the natural history of breast cancer development remain unclear. Methods Among 52,464 postmenopausal women participating in the California Teachers Study (CTS), 624 were diagnosed with breast carcinoma in situ (CIS) and 2,828 with invasive breast cancer between 1995 and 2007. Multivariable Cox proportional hazards regression methods were used to estimate relative risks associated with parity, age at first full-term pregnancy, breastfeeding, nausea or vomiting during pregnancy, and preeclampsia. Results Compared with never-pregnant women, an increasing number of full-term pregnancies was associated with greater risk reduction for both breast CIS and invasive breast cancer (both P trend &lt; 0.01). Women having four or more full-term pregnancies had a 31% lower breast CIS risk (RR = 0.69, 95% CI = 0.51 to 0.93) and 18% lower invasive breast cancer risk (RR = 0.82, 95% CI = 0.72 to 0.94). Parous women whose first full-term pregnancy occurred at age 35 years or later had a 118% greater risk for breast CIS (RR = 2.18, 95% CI = 1.36 to 3.49) and 27% greater risk for invasive breast cancer (RR = 1.27, 95% CI = 0.99 to 1.65) than those whose first full-term pregnancy occurred before age 21 years. Furthermore, parity was negatively associated with the risk of estrogen receptor-positive (ER+) or ER+/progesterone receptor-positive (PR+) while age at first full-term pregnancy was positively associated with the risk of ER+ or ER+/PR+ invasive breast cancer. Neither of these factors was statistically significantly associated with the risk of ER-negative (ER-) or ER-/PR- invasive breast cancer, tests for heterogeneity between subtypes did not reach statistical significance. No clear associations were detected for other pregnancy-related factors. Conclusions These results provide some epidemiologic evidence that parity and age at first full-term pregnancy are involved in the development of breast cancer among postmenopausal women. The role of these factors in risk of in situ versus invasive, and hormone receptor-positive versus -negative breast cancer merits further exploration

Stochastic Gravity: Theory and Applications

Whereas semiclassical gravity is based on the semiclassical Einstein equation with sources given by the expectation value of the stress-energy tensor of quantum fields, stochastic semiclassical gravity is based on the Einstein-Langevin equation, which has in addition sources due to the noise kernel. In the first part, we describe the fundamentals of this new theory via two approaches: the axiomatic and the functional. In the second part, we describe three applications of stochastic gravity theory. First, we consider metric perturbations in a Minkowski spacetime, compute the two-point correlation functions of these perturbations and prove that Minkowski spacetime is a stable solution of semiclassical gravity. Second, we discuss structure formation from the stochastic gravity viewpoint. Third, we discuss the backreaction of Hawking radiation in the gravitational background of a black hole and describe the metric fluctuations near the event horizon of an evaporating black holeComment: 100 pages, no figures; an update of the 2003 review in Living Reviews in Relativity gr-qc/0307032 ; it includes new sections on the Validity of Semiclassical Gravity, the Stability of Minkowski Spacetime, and the Metric Fluctuations of an Evaporating Black Hol