Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer

Thrombopoietin and its receptor (MPL) are important regulators of megakaryopoiesis. We have identified an activating mutation of MPL using a combination of a retrovirus-mediated gene transfer and polymerase chain reaction-driven random mutagenesis. This point mutation causes a single amino acid substitution from Ser498 to Asn498 in the transmembrane region and abrogates factor-dependency of all interleukin-3-dependent cell lines tested. Murine interleukin-3- dependent Ba/F3 cells expressing the mutated but not the normal form of MPL were tumorigenic when transduced into syngeneic mice. Analysis of intracellular signaling pathways indicated that the mutant MPL protein constitutively activated two distinct signaling pathways, SHC-Raf-MAPK and JAK2-STAT3/STAT5.     

The molecular epidemiology of HIV type 1 among Vietnamese Australian injecting drug users in Melbourne, Australia

The proportion of human immunodeficiency virus type 1 (HIV-1) among Vietnamese injecting drug users (IDUs) in Melbourne, Australia exceeds that of the background population. To investigate the molecular epidemiology of HIV-1 among this group, the C2-V4 region of the HIV-1 envelope was directly sequenced from 11 Vietnamese Australians and 19 non-Vietnamese Australian controls. A significant difference in the distribution of the HIV-1 subtypes was demonstrated, with greater than 50% of Vietnamese Australian IDU shown to be infected with CRF01_AE-the predominant subtype in Southeast Asia, rather than subtype B, which dominates the Australian epidemic and which was found in 89.5% of the non-Vietnamese controls. The genetic diversity of the CRF01_AE epidemic in Vietnamese Australian IDUs was substantially lower that that of the background subtype B, consistent with a more recent introduction of a limited number of viral strains from Vietnam. These results support public health policy targeting Australian IDUs of Vietnamese ethnicity as a distinct vulnerable population.     

Characterizing patient-oncologist communication in genomic tumor testing: The 21-gene recurrence score as an exemplar

ObjectiveWomen with early-stage, ER + breast cancer are recommend to receive genomic profiling tests, such as the 21-gene Recurrence Score (RS) test, to guide treatment decisions. We examined test- and treatment-related information discussed and the associations between RS categories and aspects of communication during patient-oncologist clinical encounters.MethodsAs part of a larger trial, clinical encounters (N = 46) were audiorecorded and coded for 1) RS- and treatment-related information, 2) shared decision making, 3) patient active participation, and 4) oncologist patient-centered communication. We examined differences by RS category using mixed models, adjusting for nesting within oncologist.ResultsPatients with a high RS were more likely to receive a chemotherapy recommendation (p < .01), hear about the risks/side effects of chemotherapy (p < .01), and offer their preferences (p = .02) than those with intermediate or low RS. Elements of shared decision making increased with RS. Oncologist patient-centered communication (M = 4.09/5, SD = .25) and patient active participation (M = 3.5/4, SD = 1.0) were high across RS.ConclusionFindings suggest that disease severity, rather than clinical uncertainty, impact treatment recommendations and shared decision making.Practice implicationsOncologists adjust test- and treatment-related information and shared decision making by disease severity. This information provides a framework to inform decision making in complex cancer and genomics settings.     

Consulting the community: public expectations and attitudes about genetics research

Genomic discoveries and technologies promise numerous opportunities for improving health. Key to these potential health improvements, however, are health-care consumers'' understanding and acceptance of these new developments. We identified community groups and invited them to a public information-consultation session in order to explore public awareness, perception and expectations about genetics and genomics research. One hundred and four members of seven community groups in Newfoundland, Canada took part in the community sessions. Content analysis of participant comments revealed they were largely hopeful about genetics research in its capacity to improve health; however, they did not accept such research uncritically. Complex issues arose during the community consultations, including the place of genetics in primary care, the value of genetics for personal health, and concerns about access to and uses of genetic information. Participants unequivocally endorsed the value of public engagement with these issues. The rapid pace of discoveries in genomics research offers exciting opportunities to improve population health. However, public support will be crucial to realize health improvements. Our findings suggest that regular, transparent dialog between researchers and the public could allow a greater understanding of the research process, as well as assist in the design of efficient and effective genetic health services, informed by the public that will use them.     

Traumatic Brain Injury and Suicidal Ideation Among U.S. Operation Enduring Freedom and Operation Iraqi Freedom Veterans

Traumatic brain injury (TBI) is associated with suicidal behavior among veterans, and gender differences in the strength of associations may exist. Almost all research has been limited to Veterans Health Administration (VHA) patients, and it is unclear if findings generalize to veterans who do not use VHA services. We examined gender‐ and VHA‐user‐specific associations between TBI related to deployment and postdeployment suicidal ideation in a U.S. national sample of 1,041 female and 880 male Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans. Path analysis was used to estimate TBI and suicidal ideation association, and examine PTSD and depression symptomatology in these associations. TBI was associated with suicidal ideation among male VHA users, OR = 3.64, 95% CI [2.21, 6.01]; and male and female nonusers, OR = 2.24, 95% CI [1.14, 4.44] and OR = 2.65, 95% CI [1.26, 5.58], respectively, in unadjusted analyses. This association was explained by depression symptoms among male and female nonusers. Among male VHA users an association between TBI and suicidal ideation remained when accounting for depression symptoms, OR = 2.50, 95% CI [1.33, 4.71]. Our findings offered evidence of an association between TBI and suicidal ideation among male OEF/OIF VHA users.     

Management of bisphosphonate‐related osteonecrosis of the jaw: a literature review

Osteonecrosis of the jaw (ONJ) is a serious side effect of bisphosphonate use in patients with osteoporosis, Paget's disease, hypercalcemia of malignancy, metastatic bone disease and multiple myeloma, although recently this complication has also been reported in patients under non‐bisphosphonate medication, such as denosumab and bevacizumab. The occurrence of ONJ is higher in oncology patients treated with high‐dose iv bisphosphonates than in osteoporosis patients treated with oral bisphosphonates. Although multiple hypotheses have been proposed, the exact pathogenic mechanism of ONJ still remains unclear. As treatment protocols based on randomized controlled trials (RCTs) do not exist, we critically reviewed the existing data concerning the management of bisphosphonate‐related osteonecrosis of the jaw, including the most recent data for the use of teriparatide and hyperbaric oxygen.     

Long-term protection of hematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O6-alkylguanine-DNA-alkyltransferase

A human O6-alkylguanine-DNA-alkyltransferase (ATase) cDNA-containing retrovirus was used to infect murine long-term primary bone marrow cultures. High levels of ATase expression were obtained, and colony- forming cells of the granulocyte-macrophage lineage from the cultures transduced with the human ATase retrovirus were three times more resistant to the alkylating agent, N-methyl-N-nitrosourea (MNU), than control cultures. Furthermore, expression of the human ATase protected long-term hematopoiesis, measured as the output of progenitor cells to the nonadherent fraction of the culture, against the cytotoxic effects of repeated exposures to MNU. These results clearly show that a human ATase cDNA-containing retrovirus can be used to infect long-term primary bone marrow cultures and that this attenuates their sensitivity to nitrosoureas.