Prenatal maternal plasma DNA screening for cystic fibrosis: A computer modelling study of screening performance.

Background: Prenatal cystic fibrosis (CF) screening is currently based on determining the carrier status of both parents. We propose a new method based only on the analysis of DNA in maternal plasma. Methods: The method relies on the quantitative amplification of the CF gene to determine the percentage of DNA fragments in maternal plasma at targeted CF mutation sites that carry a CF mutation. Computer modelling was carried out to estimate the distributions of these percentages in pregnancies with and without a fetus affected with CF. This was done according to the number of DNA fragments counted and fetal fraction, using the 23 CF mutations recommended by the American College of Medical Genetics for parental carrier testing. Results: The estimated detection rate (sensitivity) is 70% (100% of those detected using the 23 mutations), the false-positive rate 0.002%, and the odds of being affected given a positive screening result 14:1, compared with 70%, 0.12%, and 1:3, respectively, with current prenatal screening based on parental carrier testing. Conclusions: Compared with current screening practice based on parental carrier testing, the proposed method would substantially reduce the number of invasive diagnostic procedures (amniocentesis or chorionic villus sampling) without reducing the CF detection rate. The expected advantages of the proposed method justify carrying out the necessary test development for use in a clinical validation study.The author(s) declared that no grants were involved in supporting this work

Safety-by-design and engineered nanomaterials: the need to move from theory to practice

As the governance of engineered nanomaterials (ENMs) evolves, innovations in the prevention, mitigation, management, and transfer of risk shape discussion of how nanotechnology may mature and reach various marketplaces. Safety-by-Design (SbD) is one leading concept that, while equally philosophy as well as risk-based practice, can uniquely help address lingering uncertainties and concerns stemming from regulatory evaluation of ENM risk across worker, consumer, and environmental safety. This paper provides a discussion on the SbD concept across different disciplines aiming to identify different approaches and needs to meet regulatory requirements—ultimately, we argue that SbD is evolving both to meet the needs and discourse of various disciplines, and to apply within differing marketplaces and national regulatory structures. Understanding how SbD has evolved within ENM can yield a more practical application and development of SbD, and help guide or unify national and international ENM governance around a core set of safety-driven principles

CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.Stand Up 2 Cancer, Lustgarten Foundation, NIH

A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause

Background Anti-Müllerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. Methodology/Principal Findings By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined ) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.Publisher PDFPeer reviewe

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Polycystic ovary syndrome

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.Robert J Norman, Ruijin Wu and Marcin T Stankiewic