LEFTY2 inhibits endometrial receptivity by downregulating Orai1 expression and store-operated Ca²+ entry

Early embryo development and endometrial differentiation are initially independent processes, and synchronization, imposed by a limited window of implantation, is critical for reproductive success. A putative negative regulator of endometrial receptivity is LEFTY2, a member of the transforming growth factor (TGF)-β family. LEFTY2 is highly expressed in decidualizing human endometrial stromal cells (HESCs) during the late luteal phase of the menstrual cycle, coinciding with the closure of the window of implantation. Here, we show that flushing of the uterine lumen in mice with recombinant LEFTY2 inhibits the expression of key receptivity genes, including Cox2, Bmp2, and Wnt4, and blocks embryo implantation. In Ishikawa cells, a human endometrial epithelial cell line, LEFTY2 downregulated the expression of calcium release-activated calcium channel protein 1, encoded by ORAI1, and inhibited store-operated Ca2+ entry (SOCE). Furthermore, LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, as well as YM-58483, inhibited, whereas the Ca2+ ionophore, ionomycin, strongly upregulated COX2, BMP2 and WNT4 expression in decidualizing HESCs. These findings suggest that LEFTY2 closes the implantation window, at least in part, by downregulating Orai1, which in turn limits SOCE and antagonizes expression of Ca2+-sensitive receptivity genes

Resource dedication problem in a multi-project environment

There can be different approaches to the management of resources within the context of multi-project scheduling problems. In general, approaches to multiproject scheduling problems consider the resources as a pool shared by all projects. On the other hand, when projects are distributed geographically or sharing resources between projects is not preferred, then this resource sharing policy may not be feasible. In such cases, the resources must be dedicated to individual projects throughout the project durations. This multi-project problem environment is defined here as the resource dedication problem (RDP). RDP is defined as the optimal dedication of resource capacities to different projects within the overall limits of the resources and with the objective of minimizing a predetermined objective function. The projects involved are multi-mode resource constrained project scheduling problems with finish to start zero time lag and non-preemptive activities and limited renewable and nonrenewable resources. Here, the characterization of RDP, its mathematical formulation and two different solution methodologies are presented. The first solution approach is a genetic algorithm employing a new improvement move called combinatorial auction for RDP, which is based on preferences of projects for resources. Two different methods for calculating the projects’ preferences based on linear and Lagrangian relaxation are proposed. The second solution approach is a Lagrangian relaxation based heuristic employing subgradient optimization. Numerical studies demonstrate that the proposed approaches are powerful methods for solving this problem

Certification of breast centres in Germany: proof of concept for a prototypical example of quality assurance in multidisciplinary cancer care

<p>Abstract</p> <p>Background</p> <p>The main study objectives were: to develop a set of requirements of comprehensive breast centres; to establish a nationwide voluntary certification programme for breast centres based on such requirements, a certified quality management system (QMS), and scheduled independent, external audits and periodic recertification; and to demonstrate the general acceptance of such a certification programme with a view to introducing similar certification programmes for other major cancers.</p> <p>Methods</p> <p>Breast centres introduced a QMS and voluntarily participated in an external certification procedure based on guideline-derived Requirements of Breast Centres specifically developed for the application procedure, all subsequent audits and recertification. All data (numbers of pending and successful applications, sites/centre, etc.) were collected by a newly founded, independent organisation for certification of cancer services delivery. Data analysis was descriptive.</p> <p>Results</p> <p>Requirements of Breast Centres were developed by the German Cancer Society (DKG), the German Society of Senology (DGS) and other relevant specialist medical societies in the form of a questionnaire comprising 185 essential items based on evidence-based guidelines and the European Society of Breast Cancer Specialists' (EUSOMA) requirements of specialist breast units. From late 2002 to mid 2008, the number of participating breast centres rose from 1 to 175. As of mid 2008, 77% of an estimated 50,000 new breast cancers in Germany were diagnosed and treated at certified breast centres, 78% of which were single-site centres.</p> <p>Conclusion</p> <p>Nationwide voluntary certification of breast centres is feasible and well accepted in Germany. Dual certification of breast centres that involves certification of breast services to guideline-derived requirements in conjunction with independent certification of a mandatory QMS can serve as a model for other multidisciplinary site-specific cancer centres.</p

The Brustkrebs-Studien.de website for breast cancer patients: User acceptance of a German internet portal offering information on the disease and treatment options, and a clinical trials matching service

<p>Abstract</p> <p>Background</p> <p>The internet portal <url>http://www.brustkrebs-studien.de</url> (BKS) was launched in 2000 by the German Society of Senology (DGS) and the Baden-Württemberg Institute for Women's Health (IFG) to provide expert-written information on breast cancer online and to encourage and facilitate the participation of breast cancer patients in clinical trials. We describe the development of BKS and its applications, and report on website statistics and user acceptance.</p> <p>Methods</p> <p>Existing registries, including ClinicalTrials.gov, were analysed before we designed BKS, which combines a trial registry, a knowledge portal, and an online second opinion service. An advisory board guided the process. Log files and patient enquiries for trial participation and second opinions were analysed. A two-week user satisfaction survey was conducted online.</p> <p>Results</p> <p>During 10/2005-06/2010, the portal attracted 702,655 visitors, generating 15,507,454 page views. By 06/2010, the website's active scientific community consisted of 189 investigators and physicians, and the registry covered 163 clinical trial protocols. In 2009, 143 patients requested trial enrolment and 119 sought second opinions or individual treatment advice from the expert panel. During the two-week survey in 2008, 5,702 BKS visitors submitted 507 evaluable questionnaires. Portal acceptance was high. Respondents trusted information correctness (80%), welcomed self-matching to clinical trials (79%) and planned to use the portal in the future (76%) and recommend it to others (81%).</p> <p>Conclusions</p> <p>BKS is an established and trusted breast cancer information platform offering up-to-date resources and protocols to the growing physician and patient community to encourage participation in clinical trials. Further studies are needed to assess potential increases in trial enrolment by eligibility matching services.</p

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry.

BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts

ICAR: endoscopic skull‐base surgery

n/

Microbiome to Brain:Unravelling the Multidirectional Axes of Communication

The gut microbiome plays a crucial role in host physiology. Disruption of its community structure and function can have wide-ranging effects making it critical to understand exactly how the interactive dialogue between the host and its microbiota is regulated to maintain homeostasis. An array of multidirectional signalling molecules is clearly involved in the host-microbiome communication. This interactive signalling not only impacts the gastrointestinal tract, where the majority of microbiota resides, but also extends to affect other host systems including the brain and liver as well as the microbiome itself. Understanding the mechanistic principles of this inter-kingdom signalling is fundamental to unravelling how our supraorganism function to maintain wellbeing, subsequently opening up new avenues for microbiome manipulation to favour desirable mental health outcome

Breast cancer polygenic risk score and contralateral breast cancer risk

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18–1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02–1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547–0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies