Personalized Medicine Is the Postgenomic Condition

When President Obama laid out his vision for the U.S. Precision Medicine Initiative in a 2016 Boston Globe op‐ed, he cautioned, “[I]t only works if we collect enough information first.” “Collecting information” is an apt way to describe the subject of both books reviewed here. Jenny Reardon's The Postgenomic Condition: Ethics, Justice, and Knowledge after the Genome traces the history of the Human Genome Project and efforts around the globe to obtain blood samples to extract not only genetic data but also meaning from them. Barbara Prainsack's Personalized Medicine: Empowered Patients in the 21st Century? concerns the capture of digital, quantifiable, and computable information about nearly all aspects of people's lives in the pursuit of personalized medicine. Reardon and Prainsack critique scientists’ and corporations’ appeals to liberal democracy, justice, and empowerment to collect more and more information about people. They reveal the limitations and frequent superficiality of those appeals and remind us that person‐centric ethics rather than data‐centric research is needed to realize a more democratic, just, and empowered society.     

Primary and secondary hepatic manifestation of neuroendocrine tumors

BACKGROUND: In comparison with most other malignancies, in the treatment of metastatic neuroendocrine tumors one also has to consider endocrine symptoms and natural progression of disease. Since hepatic metastasis predominates and endocrine symptoms correlate with functional tumor mass, hepatic resection may improve prognosis or even cure patients. PATIENTS AND METHODS: We reviewed 41 consecutive patients with metastatic neuroendocrine tumors and four patients with primary hepatic disease presenting between 1989 and 1999. The neuroendocrine tumors were classified according to their origin, pattern of metastasis, endocrine activity, and histology. Operative therapy including hepatic resections of different extent, liver transplantation, and removal of the primary tumor was analyzed. The median survival after initial diagnosis and after hepatic resection were major parameters of outcome. RESULTS: There were 26 low-grade malignant, 12 high-grade malignant, 2 biphasically differentiated neuroendocrine carcinomas, and 5 pancreatic endocrine tumors. Hepatic resections were performed in 25 patients, resections of the primary tumor in 40 patients. The median survival after initial diagnosis was 49 months; 50.5 months in patients with hepatic resection versus 47 months in those with no liver surgery. CONCLUSION: Hepatic resection improved the outcome of patients with liver metastasis due to neuroendocrine tumors tendentiously but not significantly.     

Gene conversion is a likely cause of mutation in PKD1

Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease ( PKD1 ) is replicated in several highly homologous copies located more proximally on chromosome 16. We recently have described a novel technique for mutation detection in the duplicated region of PKD1 that circumvents the difficulties posed by these homologs. We have used this method to identify two patients with a nearly identical cluster of base pair substitutions in exon 23. Since pseudogenes are known to be reservoirs for mutation via gene conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a result of this mechanism. Using changes in restriction digest patterns, we were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. This is the first example of gene conversion in PKD1 , and our findings highlight the importance of using gene-specific reagents in defining PKD1 mutations.      

Cytomegalovirus infection after orthotopic liver transplantation is restricted by a pre-existing antiviral immune response of the recipient

Infection of the liver by the human cytomegalovirus (HCMV) frequently occurs after orthotopic liver transplantation (OLT). However, the role of viral replication and the inflammatory reaction in the development of HCMV-associated liver dysfunction is unclear. To address this question in vivo, 84 liver biopsy specimens from 74 patients who received an orthotopic liver transplant were investigated by immunohistochemical detection of viral antigens and cell type specific marker proteins. The extent of viral replication was correlated with the HCMV antibody status of donor and recipient. HCMV immediate early antigens were found in 25 of 84 liver tissue sections investigated, hepatocytes being the predominant target cells. Bile duct epithelial cells, endothelial cells, mesenchymal cells and sinusoidal lining cells were also found susceptible to HCMV infection. The detection of viral capsid antigens, nuclear inclusions in infected cells and foci of infected cells were suggestive of permissive infection in these cells. In 25 HCMV-positive liver biopsy specimens, the median extent of HCMV infection was 0.33 (0.02-5.67) infected cells/mm(2) liver tissue. Primary infection of liver transplant recipients (D+/R-) was associated with a significantly higher extent of organ involvement as compared to reinfection or reactivation (D+/R+). In contrast, the extent of inflammatory infiltrates in areas of infected liver cells was higher in tissues of patients with pre-existing immunoreactivity (R+) compared to patients without pre-existing immunoreactivity (R-). In conclusion, these results favour the assumption that the immune response to HCMV is effective in restricting viral spread in the liver.     

Epigenetic modulation at birth – altered DNA-methylation in white blood cells after Caesarean section

Aim:  Delivery by C-section (CS) has been associated with increased risk for allergy, diabetes and leukaemia. Whereas the underlying cause is unknown, epigenetic change of the genome has been suggested as a candidate molecular mechanism for perinatal contributions to later disease risk. We hypothesized that mode of delivery affects epigenetic activity in newborn infants.
Methods:  A total of 37 newborn infants were included. Spontaneous vaginal delivery (VD) occurred in 21, and 16 infants were delivered by elective CS. Blood was sampled from the umbilical cord and 3–5 days after birth. DNA-methylation was analyzed in leucocytes.
Results:  Infants born by CS exhibited higher DNA-methylation in leucocytes compared with that of those born by VD (p < 0.001). After VD, newborn infants exhibited stable levels of DNA-methylation, as evidenced by comparing cord blood values with those 3–5 days after birth (p = 0.55). On postnatal days 3–5, DNA-methylation had decreased in the CS group (p = 0.01) and was no longer significantly different from that of VD (p = 0.10).
Conclusion:  DNA-methylation is higher in infants delivered by CS than in infants vaginally born. Although currently unknown how gene expression is affected, or whether epigenetic differences related to mode of delivery are long-lasting, our findings open a new area of clinical research with potentially important public health implications.