Somatic mutation but not aneuploidy differentiates lung cancer in never-smokers and smokers.

Lung cancer in never-smokers disproportionately affects older women. To understand the mutational landscape of this cohort, we performed detailed genome characterization of 73 lung adenocarcinomas from participants of the Women’s Health Initiative (WHI). We find enrichment of EGFR mutations in never-/light-smokers and KRAS mutations in heavy smokers as expected, but we also show that the specific variants of these genes differ by smoking status, with important therapeutic implications. Mutational signature analysis revealed signatures of clock, APOBEC, and DNA repair deficiency in never-/light-smokers; however, the mutational load of these signatures did not differ significantly from those found in smokers. Last, tumors from both smokers and never-/light-smokers shared copy number subtypes, with no significant differences in aneuploidy. Thus, the genomic landscape of lung cancer in never-/light-smokers and smokers is predominantly differentiated by somatic mutations and not copy number alterations.

A Co-Association of Streptococcus mutans and Veillonella parvula/dispar in Root Caries Patients and In Vitro Biofilms.

Root caries in geriatric patients is a growing problem as more people are maintaining their natural teeth into advanced age. We determined the levels of various bacterial species previously implicated in root caries disease or health using quantitative real-time PCR in a pilot study of 7 patients with 1 to 4 root caries lesions per person. Levels of 12 different species on diseased roots compared to healthy (contralateral control) roots were measured. Four species were found at significantly higher levels on diseased roots (Streptococcus mutans, Veillonella parvula/dispar, Actinomyces naeslundii/viscosus, and Capnocytophaga granulosa) compared across all plaque samples. The level of colonization by these species varied dramatically (up to 1,000-fold) between patients, indicating different patients have different bacteria contributing to root caries disease. Neither of the two species previously reported to correlate with healthy roots (C. granulosa and Delftia acidovorans) showed statistically significant protective roles in our population, although D. acidovorans showed a trend toward higher levels on healthy teeth (P = 0.08). There was a significant positive correlation between higher levels of S. mutans and V. parvula/dispar on the same diseased teeth. In vitro mixed biofilm studies demonstrated that co-culturing S. mutans and V. parvula leads to a 50 to 150% increase in sucrose-dependent biofilm mass compared to S. mutans alone, depending on the growth conditions, while V. parvula alone did not form in vitro biofilms. The presence of V. parvula also decreased the acidification of S. mutans biofilms when grown in artificial saliva and enhanced the health of mixed biofilms.

Human MYD88L265P is insufficient by itself to drive neoplastic transformation in mature mouse B cells.

MYD88 L265P is the most common mutation in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) and one of the most frequent in poor-prognosis subtypes of diffuse large B-cell lymphoma (DLBCL). Although inhibition of the mutated MYD88 pathway has an adverse impact on LPL/WM and DLBCL cell survival, its role in lymphoma initiation remains to be clarified. We show that in mice, human MYD88L265P promotes development of a non-clonal, low-grade B-cell lymphoproliferative disorder with several clinicopathologic features that resemble human LPL/WM, including expansion of lymphoplasmacytoid cells, increased serum immunoglobulin M (IgM) concentration, rouleaux formation, increased number of mast cells in the bone marrow, and proinflammatory signaling that progresses sporadically to clonal, high-grade DLBCL. Murine findings regarding differences in the pattern of MYD88 staining and immune infiltrates in the bone marrows of MYD88 wild-type (MYD88WT) and MYD88L265P mice are recapitulated in the human setting, which provides insight into LPL/WM pathogenesis. Furthermore, histologic transformation to DLBCL is associated with acquisition of secondary genetic lesions frequently seen in de novo human DLBCL as well as LPL/WM-transformed cases. These findings indicate that, although the MYD88L265P mutation might be indispensable for the LPL/WM phenotype, it is insufficient by itself to drive malignant transformation in B cells and relies on other, potentially targetable cooperating genetic events for full development of lymphoma.

Dopaminergic control of anxiety in young and aged zebrafish.

Changes in the expression of the dopamine transporter (DAT), or the sensitivity of dopamine receptors, are associated with aging and substance abuse and may underlie some of the symptoms common to both conditions. In this study, we explored the role of the dopaminergic system in the anxiogenic effects of aging and acute cocaine exposure by comparing the behavioral phenotypes of wild type (WT) and DAT knockout zebrafish (DAT-KO) of different ages. To determine the involvement of specific dopamine receptors in anxiety states, antagonists to D1 (SCH23390) and D2/D3 (sulpiride) were employed. We established that DAT-KO results in a chronic anxiety-like state, seen as an increase in bottom-dwelling and thigmotaxis. Similar effects were produced by aging and acute cocaine administration, both leading to reduction in DAT mRNA abundance (qPCR). Inhibition of D1 activity counteracted the anxiety-like effects associated with DAT deficit, independent of its origin. Inhibition of D2/D3 receptors reduced anxiety in young DAT-KO, and enhanced the anxiogenic effects of cocaine in WT, but did not affect aged WT or DAT-KO fish. These findings provide new evidence that the dopaminergic system plays a critical role in anxiety-like states, and suggest that adult zebrafish provide a sensitive diurnal vertebrate model for elucidating the molecular mechanisms of anxiety and a platform for anxiolytic drug screens.