Leigh Jackson

Adult mesenchymal stem cells: Differentiation potential and therapeutic applications

Adult mesenchymal stem cells (MSCs) are a population of multipotent cells found primarily in the bone marrow. They have long been known to be capable of osteogenic, adipogenic and chondrogenic differentiation and are currently the subject of a number of trials to assess their potential use in the clinic. Recently, the plasticity of these cells has come under close scrutiny as it has been suggested that they may have a differentiation potential beyond the mesenchymal lineage. Myogenic and in particular cardiomyogenic potential has been shown in vitro. MSCs have also been shown to have the ability to form neural cells both in vitro and in vivo, although the molecular mechanisms underlying these apparent transdifferentiation events are yet to be elucidated. We describe here the cellular characteristics and differentiation potential of MSCs, which represent a promising stem cell population for future applications in regenerative medicine.

Direct-to-consumer genomic testing: systematic review of the literature on user perspectives

Genetic tests have traditionally been offered by health professionals. However, genomic tests have been available direct to the consumer for the last decade, increasingly via the Internet. The aim of this systematic review was to ascertain the evidence concerning use of direct-to-consumer genomic testing from the consumer perspective. Primary research was identified using the search terms ‘direct-to-consumer’ and ‘genomic or genetic’ in six bibliographic databases and citation searching of findings. In all, 17 papers were reviewed: 3 qualitative and 14 quantitative. Findings indicate a low level of awareness of direct-to-consumer genomic testing and, because of the hypothetical nature of many studies, little evidence from users of such tests. Although potential users appear to be interested in information about their risks of developing common diseases, concerns were expressed about privacy of genetic risk information and the reliability of genomic tests. Consumers were anxious about the nature of the results. There appeared to be a preference to access genomic tests via a health professional, or to discuss the results and obtain advice from a health professional. Authors of only two papers recruited participants who had used direct-to-consumer tests and samples from the large quantitative studies were not representative of the population. These factors limit the value of the available evidence. However, we conclude that there is public interest in direct-to-consumer genomic tests, and that this is likely to result in an increased workload for a range of health professionals. We also consider that there are educational implications for both consumers and health professionals.

Direct to consumer genetic testing: a systematic review of position statements, policies and recommendations

Skirton H, Goldsmith L, Jackson L, O’Connor A. Direct to consumer genetic testing: a systematic review of position statements, policies and recommendations.

Incidental findings in genetic research and clinical diagnostic tests: a systematic review.

Incidental findings arise when clinically relevant genetic information about a research participant or patient is identified outside the scope of the original research objective or diagnostic test being performed. These findings can relate to carrier status for a heritable condition, misattributed paternity or increased susceptibility to a medical condition. The decision whether to disclose these findings to the research subject or patient is underpinned by many ethical, moral, and potentially legal considerations. There is an urgent need for definitive guidelines for researchers and healthcare professionals. We performed a systematic review of the relevant literature concerning the disclosure of incidental findings, based on the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses recommendations, using the prescribed flowchart and checklist. At initial screening, 473 articles were retrieved. The inclusion and exclusion criteria aimed at obtaining data that were relevant and of sufficient quality were applied and a total of four relevant studies were identified, comprising 2,680 individual participants and 1,023 guidance documents. Major themes emerging from the included articles include patient autonomy, patient welfare, harmful secrets, and genetic literacy. The lack of relevant studies emphasizes the urgent need for empirical investigations into the disclosure or non‐disclosure of genetic incidental findings, and the provision of guidelines to assist healthcare professionals and researchers.

Quality in genetic counselling for presymptomatic testing — clinical guidelines for practice across the range of genetic conditions

Presymptomatic testing (PST) is the performance of a genetic test on an asymptomatic individual at risk of a condition to determine whether the person has inherited the disease-causing mutation. Although relevant guidelines exist for specific diseases, there is no overarching protocol that can be adapted to any disorder or clinical setting in which such testing is offered. The objective of this European project was to develop a set of coherent guidelines for PST (for adult-onset monogenic conditions) for use by health professionals working in a range of disciplines, countries or contexts. To ensure the guidelines were appropriate and practice based, we organised a workshop attended by an expert group of practitioners with relevant health professional backgrounds from 11 countries. Models of service for offering PST were presented, the group then discussed different aspects of testing and the standard of care required to ensure that patients were prepared to make decisions and deal with results and consequences. After the workshop, several rounds of consultation were used with a wider group of professionals to refine the guidelines. The guidelines include general principles governing the offer of testing (eg, autonomous choice of the patient), objectives of genetic counselling in this context (eg, facilitation of decision making), logistical considerations (eg, use of trained staff) and topics to be included during counselling discussion with the patient (eg, consequences of both positive and negative outcomes). We recommend the adoption of these guidelines to provide an equitable structure for those seeking PST in any country.

Offering prenatal diagnostic tests: European guidelines for clinical practice

For over four decades, it has been possible to offer prenatal diagnostic testing for fetal abnormalities. Prenatal testing is now available for a wide range of monogenic disorders as well as chromosomal abnormalities and should be provided within the ethical framework of informed consent and autonomous choice. However, there are no published guidelines for health professionals from varied disciplines who offer prenatal diagnosis (PND) in a range of possible settings including departments of maternity, obstetrics and clinical genetics. We used an Expert Group technique to develop a set of guidelines for provision of prenatal diagnostic services. Thirteen European health professionals, all experts in PND, participated in a workshop to develop the guidelines, which were then subjected to a wide consultation process. The objective of PND was defined as providing prenatal diagnostic testing services (for genetic conditions) that enable families to make informed choices consistent with their individual needs and values and which support them in dealing with the outcome of such testing. General principles, logistical considerations, clinical care and counselling topics are all described and are equally applicable to invasive and non-invasive testing. These guidelines provide a framework for ethical clinical care; however, they are flexible enough to enable practitioners to adapt them to their particular setting. Ideally, an individualised approach to each family is required to ensure autonomous choice and informed consent regarding prenatal diagnostic testing within the local ethical and legal framework.

Non‐invasive prenatal testing for aneuploidy: a systematic review of Internet advertising to potential users by commercial companies and private health providers

The development of non‐invasive prenatal testing has increased accessibility of fetal testing. Companies are now advertising prenatal testing for aneuploidy via the Internet.

A role for two-pore potassium (K2P) channels in endometrial epithelial function

The human endometrial epithelium is pivotal to menstrual cycle progression, implantation and early pregnancy. Endometrial function is directly regulated by local factors that include pH, oxygen tension and ion concentrations to generate an environment conducive to fertilization. A superfamily of potassium channels characterized by two‐pore domains (K2P) and encoded by KCNK genes is implicated in the control of the cell resting membrane potential through the generation of leak currents and modulation by various physicochemical stimuli. The aims of the study were to determine the expression and function of K2P channel subtypes in proliferative and secretory phase endometrium obtained from normo‐ovulatory women and in an endometrial cancer cell line. Using immunochemical methods, real‐time qRT‐PCR proliferation assays and electrophysiology. Our results demonstrate mRNA for several K2P channel subtypes in human endometrium with molecular expression of TREK‐1 shown to be higher in proliferative than secretory phase endometrium (P < 0.001). The K2P channel blockers methanandamide, lidocaine, zinc and curcumin had antiproliferative effects (P < 0.01) in an endometrial epithelial cancer cell line indicating a role for TASK and TREK‐1 channels in proliferation. Tetraethylammonium‐ and 4‐aminopyridine‐insensitive outwards currents were inhibited at all voltages by reducing extracellular pH from 7.4 to 6.6. Higher expression of TREK‐1 expression in proliferative phase endometrium may, in part, underlie linked to increased cell division. The effects of pH and a lack of effect of non‐specific channel blockers of voltage‐gated potassium channels imply a role for K2P channels in the regulation of human endometrial function.

Impact of presymptomatic genetic testing on young adults: a systematic review.

Presymptomatic and predictive genetic testing should involve a considered choice, which is particularly true when testing is undertaken in early adulthood. Young adults are at a key life stage as they may be developing a career, forming partnerships and potentially becoming parents: presymptomatic testing may affect many facets of their future lives. The aim of this integrative systematic review was to assess factors that influence young adults’ or adolescents’ choices to have a presymptomatic genetic test and the emotional impact of those choices. Peer-reviewed papers published between January 1993 and December 2014 were searched using eight databases. Of 3373 studies identified, 29 were reviewed in full text: 11 met the inclusion criteria. Thematic analysis was used to identify five major themes: period befeore testing, experience of genetic counselling, parental involvement in decision-making, impact of test result communication, and living with genetic risk. Many participants grew up with little or no information concerning their genetic risk. The experience of genetic counselling was either reported as an opportunity for discussing problems or associated with feelings of disempowerment. Emotional outcomes of disclosure did not directly correlate with test results: some mutation carriers were relieved to know their status, however, the knowledge they may have passed on the mutation to their children was a common concern. Parents appeared to have exerted pressure on their children during the decision-making process about testing and risk reduction surgery. Health professionals should take into account all these issues to effectively assist young adults in making decisions about presymptomatic genetic testing.

Differences in the Pattern and Regulation of Mineral Deposition in Human Cell Lines of Osteogenic and Non-Osteogenic Origin

Bone marrow-derived mesenchymal stem cells (MSCs) are widely used as a cellular model of bone formation, and can mineralize in vitro in response to osteogenic medium (OM). It is unclear, however, whether this property is specific to cells of mesenchymal origin. We analysed the OM response in 3 non-osteogenic lines, HEK293, HeLa and NTera, compared to MSCs. Whereas HEK293 cells failed to respond to OM conditions, the 2 carcinoma-derived lines NTera and HeLa deposited a calcium phosphate mineral comparable to that present in MSC cultures. However, unlike MSCs, HeLa and NTera cultures did so in the absence of dexamethasone. This discrepancy was confirmed, as bone morphogenetic protein inhibition obliterated the OM response in MSCs but not in HeLa or NTera, indicating that these 2 models can deposit mineral through a mechanism independent of established dexamethasone or bone morphogenetic protein signalling.