Is personalized medicine finally arriving?

It's no gold rush, but dozens of players are emerging in personalized medicine, with biotechs, big and small, leading the way. Some big pharma companies and even payers remain skeptical, but economics aside, the real winners will be patients.     

Should direct-to-consumer personalized genomic medicine remain unregulated?: a rebuttal of the defenses

Direct-to-consumer personalized genomic medicine has recently grown into a small industry that sells mail-order DNA sample kits and then provides disease risk assessments, typically based upon results from genome-trait association studies. The companies selling these services have been largely exempted from FDA regulation in the United States. Testing kit companies and their supporters have defended the industry's unregulated status using two arguments. First, defenders have argued that mere absence of harm is all that must be proved for mail-order tests to be acceptable. Second, defenders of mail-order testing have argued that there is an individual right to the tests' information. This article rebuts these arguments. The article demonstrates that the direct-to-consumer market has resulted in the sidelining of clinical utility (medical value to patients), leading to the development of certain mail-order tests that do not promote customers' interests and to defenders' downplaying of a potentially damaging empirical study of mail-order genomic testing's effects on consumers. The article also shows that the notion of an individual right to these tests rests on a flawed reading of the key service provided by mail-order companies, which is the provision of medical interpretations, not simply genetic information. Absent these two justifications, there is no reason to exempt direct-to-consumer personalized genomic medicine from stringent federal oversight.     

Pharmacomicrobiomics: a novel route towards personalized medicine?

Inter-individual heterogeneity in drug response is a serious problem that affects the patient’s wellbeing and poses enormous clinical and financial burdens on a societal level. Pharmacogenomics has been at the forefront of research into the impact of individual genetic background on drug response variability or drug toxicity, and recently the gut microbiome, which has also been called the second genome, has been recognized as an important player in this respect. Moreover, the microbiome is a very attractive target for improving drug efficacy and safety due to the opportunities to manipulate its composition. Pharmacomicrobiomics is an emerging field that investigates the interplay of microbiome variation and drugs response and disposition (absorption, distribution, metabolism and excretion). In this review, we provide a historical overview and examine current state-of-the-art knowledge on the complex interactions between gut microbiome, host and drugs. We argue that combining pharmacogenomics and pharmacomicrobiomics will provide an important foundation for making major advances in personalized medicine.     

DNA patenting: the end of an era?

Debates on patenting DNA must evolve to reflect the global decline in filings and regional disparities in patenting activity.     

Is there a place for nuclear medicine in the radioembolization of liver tumors?

This is purposely an ultraprovocative title for the broad nuclear medicine community (including radiophysics and radiopharmacy) which leads us to ask questions about how we should correctly use ⁹⁰Yttrium (MSY90) microspheres in the treatment of liver tumors.     

Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine?

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two major forms of primary liver cancers (PLC), accounting for approximately 90% and 5% respectively. The incidence of each is increasing rapidly in the western world, however our knowledge of the underlying mechanisms remains limited and the outcome, dismal. The etiologies of each vary geographically; nevertheless, chronic inflammation has been identified in more than 80% of the cases and appears to be a key mediator in altering the liver microenvironment, increasing the risk of carcinogenesis. However, since not all HCC and especially ICC cases have a recognized risk factor, there are currently two proposed models for liver carcinogenesis. The clonal evolution model demonstrates a multi-step process of tumor development from precancerous lesions to metastatic carcinoma, arising from the accumulation of genetic and epigenetic changes in a cell in the setting of chronic inflammation. While the majority of cases do occur as a consequence of chronic inflammation, most individuals with chronic infection do not develop PLC, suggesting the involvement of individual genetic and environmental factors. Further, since hepatocytes and cholangiocytes both have regenerative potential and arise from the same bi-potential progenitor cell, the more recently proposed cancer stem cell model is gaining its due attention. The integration of these models and the constant improvement in molecular profiling platforms is enabling a broader understanding of the mechanisms underlying these two devastating malignancies, perhaps moving us closer to a new world of molecularly-informed personalized medicine.     

Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine?

Background

It remains unclear whether retroviruses can encode and express an intragenomic microRNA (miRNA). Some have suggested that processing by the Drosha and Dicer enzymes might preclude the viability of a replicating retroviral RNA genome that contains a cis-embedded miRNA. To date, while many studies have shown that lentiviral vectors containing miRNAs can transduce mammalian cells and express the inserted miRNA efficiently, no study has examined the impact on the replication of a lentivirus such as HIV-1 after the deliberate intragenomic insertion of a bona fide miRNA.

Results

We have constructed several HIV-1 molecular clones, each containing a discrete cellular miRNA positioned in Nef. These retroviral genomes express the inserted miRNA and are generally replication competent in T-cells. The inserted intragenomic miRNA was observed to elicit two different consequences for HIV-1 replication. First, the expression of miRNAs with predicted target sequences in the HIV-1 genome was found to reduce viral replication. Second, in one case, where an inserted miRNA was unusually well-processed by Drosha, this processing event inhibited viral replication.

Conclusion

This is the first study to examine in detail the replication competence of HIV-1 genomes that express cis-embedded miRNAs. The results indicate that a replication competent retroviral genome is not precluded from encoding and expressing a viral miRNA.     

Lymph node fine‐needle cytology in the era of personalised medicine. Is there a role?

The 2016 World Health Organisation revised classification of lymphoma has sub‐classified well‐defined entities and added a number of provisional entities on the basis of new knowledge on genetic, epigenetics and phenotypical data; prognostic and predictive features are also part of this classification. New knowledge on well‐defined entities further enlightens the mechanisms of lymphomagenesis, which are more complex and multifactorial than once believed. Therapies are also more complex because traditional clinical trials have been integrated with new drugs and compounds with unique mechanisms of actions against distinct molecular targets. As lymphoma acquires additional genetic and phenotypic features over the time, pathological assessment is also necessary. Histological evaluation and tissue collection by surgical biopsies are necessary for phenotypical and molecular purposes; however, these are demanding procedures for both the patient and the health care system. At the same time, the choice of the best treatment for a specific entity, in different phases and different patients requires information that may not be available when the biopsy is performed. Fine needle aspiration cytology (FNAC) is successfully used in lymph nodes (LNs) in combination with different ancillary techniques and might be used to assess the phenotypic and genetic profile of specific targets and to get key information for therapy, in different phases and stages of the disease, with the option to re‐check the same target over time, without surgical excision. This brief review describes LN‐FNAC diagnostic criteria, current therapies for lymphomas and the potential role of LN‐FNAC in selecting non‐Hodgkin lymphomas patients for specific targeted treatments.     

Do we know enough? A scientific and ethical analysis of the basis for genetic-based personalized nutrition

This article discusses the prospects and limitations of the scientific basis for offering personalized nutrition advice based upon individual genetic information. Two divergent scientific positions are presented, with an ethical comment. The crucial question is whether the current knowledge base is sufficiently strong for taking an ethically responsible decision to offer personalized nutrition advice based upon gene–diet–health interaction. According to the first position, the evidence base for translating the outcomes of nutrigenomics research into personalized nutritional advice is as yet immature. There is also limited evidence that genotype-based dietary advice will motivate appropriate behavior changes. Filling the gaps in our knowledge will require larger and better randomized controlled trials. According to the second position, personalized nutrition must be evaluated in relation to generally accepted standard dietary advice—partly derived from epidemiological observations and usually not proven by clinical trials. With personalized nutrition, we cannot demand stronger evidence. In several specific cases of gene–diet interaction, it may be more beneficial for individuals with specific genotypes to follow personalized advice rather than general dietary recommendations. The ethical comment, finally, considers the ethical aspects of deciding how to proceed in the face of such uncertainty. Two approaches for an ethically responsible way forward are proposed. Arguing from a precautionary approach, it is suggested that personalized dietary advice should be offered only when there is strong scientific evidence for health effects, followed by stepwise evaluation of unforeseen behavioral and psychological effects. Arguing from theoretical and applied ethics as well as psychology, it is also suggested that personalized advice should avoid paternalism and instead focus on supporting the autonomous choice of each person.     

Regenerative medicine for the treatment of spinal cord injury: more than just promises?

Spinal cord injury triggers a complex set of events that lead to tissue healing without the restoration of normal function due to the poor regenerative capacity of the spinal cord. Nevertheless, current knowledge about the intrinsic regenerative ability of central nervous system axons, when in a supportive environment, has made the prospect of treating spinal cord injury a reality. Among the range of strategies under investigation, cell‐based therapies offer the most promising results, due to the multifactorial roles that these cells can fulfil. However, the best cell source is still a matter of debate, as are clinical issues that include the optimal cell dose as well as the timing and route of administration. In this context, the role of biomaterials is gaining importance. These can not only act as vehicles for the administered cells but also, in the case of chronic lesions, can be used to fill the permanent cyst, thus creating a more favourable and conducive environment for axonal regeneration in addition to serving as local delivery systems of therapeutic agents to improve the regenerative milieu. Some of the candidate molecules for the future are discussed in view of the knowledge derived from studying the mechanisms that facilitate the intrinsic regenerative capacity of central nervous system neurons. The future challenge for the multidisciplinary teams working in the field is to translate the knowledge acquired in basic research into effective combinatorial therapies to be applied in the clinic.     

A structural analysis of glycosaminoglycans from lethal and nonlethal breast cancer tissues: toward a novel class of theragnostics for personalized medicine in oncology?

Cancer is one of the leading noncommunicable diseases that vastly impacts both developed and developing countries. Truly innovative diagnostics that inform disease susceptibility, prognosis, and/or response to treatment (theragnostics) are seriously needed for global public health and personalized medicine for patients with cancer. This study examined the structure and content of glycosaminoglycans (GAGs) in lethal and nonlethal breast cancer tissues from six patients. The glycosaminoglycan content isolated from tissue containing lethal cancer tumors was approximately twice that of other tissues. Molecular weight analysis showed that glycosaminoglycans from cancerous tissue had a longer weight average chain length by an average of five disaccharide units, an increase of approximately 15%. Dissacharide analysis found differences in sulfation patterns between cancerous and normal tissues, as well as sulfation differences in GAG chains isolated from patients with lethal and nonlethal cancer. Specifically, cancerous tissue showed an increase in sulfation at the "6S" position of CS chains and an increase in the levels of the HS disaccharide NSCS. Patients with lethal cancer showed a decrease in HS sulfation, with lower levels of "6S" and higher levels of the unsulfated "0S" disaccharide. Although these findings come from a limited sample size, they indicate that structural changes in GAGs exist between cancerous and noncancerous tissues and between tissues from patients with highly metastatic cancer and cancer that was successfully treated by chemotherapy. Based on these findings, we hypothesize that (1) there are putative changes in the body's construction of GAGs as tissue becomes cancerous; (2) there may be innate structural person-to-person variations in GAG composition that facilitate the metastasis of tumors in some patients when they develop cancer.     

Is there still a need for candidate gene approaches in the era of genome-wide association studies?

Most genetic variants associated with complex diseases in humans are believed to have a small impact on risk. With traditional candidate gene/pathway approaches several associations with disease risk could be identified. However, now that genome-wide association studies are feasible, the question arises if there is still a need for these approaches. By using HapMap data, we evaluated to which extent commercially available microarrays cover, through linkage disequilibrium, all currently known genes and biological processes in different populations. Furthermore, we estimated the power to detect an association with any specific SNP. Our study shows that coverage of individual genes and pathways by current commercial genotyping platforms is satisfactory for the vast majority of RefSeq gene regions. However, depending on the gene or the population, there may still be a need for candidate gene approaches, especially when looking at polymorphisms with low allele frequencies.