Patients with chronic hepatitis B virus (HBV) infection who develop antiviral resistance lose benefits of therapy and may be predisposed to further resistance. Entecavir (ETV) resistance (ETVr) ...results from HBV reverse transcriptase substitutions at positions T184, S202, or M250, which emerge in the presence of lamivudine (LVD) resistance substitutions M204I/V ± L180M. Here, we summarize results from comprehensive resistance monitoring of patients with HBV who were continuously treated with ETV for up to 5 years. Monitoring included genotypic analysis of isolates from all patients at baseline and when HBV DNA was detectable by polymerase chain reaction (≥300 copies/mL) from Years 1 through 5. In addition, genotyping was performed on isolates from patients experiencing virologic breakthrough (≥1 log10 rise in HBV DNA). In vitro phenotypic ETV susceptibility was determined for virologic breakthrough isolates, and for HBV containing novel substitutions emerging during treatment. The results over 5 years of therapy showed that in nucleoside‐naïve patients, the cumulative probability of genotypic ETVr and genotypic ETVr associated with virologic breakthrough was 1.2% and 0.8%, respectively. In contrast, a reduced barrier to resistance was observed in LVD‐refractory patients, as the LVD resistance substitutions, a partial requirement for ETVr, preexist, resulting in a 5‐year cumulative probability of genotypic ETVr and genotypic ETVr associated with breakthrough of 51% and 43%, respectively. Importantly, only four patients who achieved <300 copies/mL HBV DNA subsequently developed ETVr. Conclusion: Long‐term monitoring showed low rates of resistance in nucleoside‐naïve patients during 5 years of ETV therapy, corresponding with potent viral suppression and a high genetic barrier to resistance. These findings support ETV as a primary therapy that enables prolonged treatment with potent viral suppression and minimal resistance. (HEPATOLOGY 2009.)
Peatlands represent large terrestrial carbon banks. Given that most peat accumulates in boreal regions, where low temperatures and water saturation preserve organic matter, the existence of peat in ...(sub)tropical regions remains enigmatic. Here we examined peat and plant chemistry across a latitudinal transect from the Arctic to the tropics. Near-surface low-latitude peat has lower carbohydrate and greater aromatic content than near-surface high-latitude peat, creating a reduced oxidation state and resulting recalcitrance. This recalcitrance allows peat to persist in the (sub)tropics despite warm temperatures. Because we observed similar declines in carbohydrate content with depth in high-latitude peat, our data explain recent field-scale deep peat warming experiments in which catotelm (deeper) peat remained stable despite temperature increases up to 9 °C. We suggest that high-latitude deep peat reservoirs may be stabilized in the face of climate change by their ultimately lower carbohydrate and higher aromatic composition, similar to tropical peats.
Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on ...the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70-0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence for plausible epigenetic mechanisms influencing NMR.
The Poly (ADP-ribose) polymerase (PARP) family has many essential functions in cellular processes, including the regulation of transcription, apoptosis and the DNA damage response. PARP1 possesses ...Poly (ADP-ribose) activity and when activated by DNA damage, adds branched PAR chains to facilitate the recruitment of other repair proteins to promote the repair of DNA single-strand breaks. PARP inhibitors (PARPi) were the first approved cancer drugs that specifically targeted the DNA damage response in BRCA1/2 mutated breast and ovarian cancers. Since then, there has been significant advances in our understanding of the mechanisms behind sensitization of tumors to PARP inhibitors and expansion of the use of PARPi to treat several other cancer types. Here, we review the recent advances in the proposed mechanisms of action of PARPi, biomarkers of the tumor response to PARPi, clinical advances in PARPi therapy, including the potential of combination therapies and mechanisms of tumor resistance.
Intergroup contact is widely recognized as one of the most validated methods of improving attitudes toward out-groups. Yet what is intergroup contact “good for” beyond this function? To answer this ...question we take a panoramic view of the literature, beginning with the recognition that contact is multifaceted in both form (e.g., face-to-face, indirect, simulated) and outcome (e.g., attitudes, cognition, behavior). Taking this highly inclusive view of what contact is and what contact does suggests that it plays a fundamental role in the shaping of human cognition. An increasingly diverse body of research demonstrates that contact exerts a generalizing reaction across target out-groups, making respondents less inward looking and more open to experiences. Contact shapes ideology regarding how the world ought to operate (i.e., ideologies about social hierarchy or regulation); over time, it can promote new ways of problem-solving, enhance cognitive flexibility, and foster creativity. For these reasons, we believe that contact is a key liberalizing agent that shapes human cognition and experience; consequently, contact theory should now share the stage with other prominent theories (e.g., cognitive dissonance) that speak to a broader understanding of human nature.
Background: Adolescence has been identified as a critical period with regard to the initiation and early escalation of alcohol use. Moreover, research on familial risk and protective processes ...provides independent support for multiple domains of parental influence on adolescent drinking; including parents’ own drinking behaviors, as well as the practices they employ to socialize their children. Despite this prevalence of findings, whether and how these distinct associations are related to one another is still not entirely clear.
Methods: The present study used data from 4,731 adolescents and their parents to test the nature of associations between (a) parents’ frequencies of alcohol use and intoxication, and lifetime alcohol‐related problems, (b) adolescents’ perceptions of the parenting that they receive, and (c) adolescents’ prevalence of alcohol use and intoxication at 14 and 17½ years of age. As such, multiple mediation modeling was used to assess whether parental alcohol use behaviors influence adolescent alcohol use directly, or if they operate through indirect associations with various aspects of parenting that subsequently influence adolescent use.
Results: Examination of simple associations demonstrated that maternal and paternal alcohol use behaviors were positively linked with adolescent use behaviors at 14 and 17½ years of age. Likewise, several parenting behaviors were independently associated with both parental and adolescent drinking. Examined collectively, multivariate path analyses indicated that associations between parents’ and adolescents’ alcohol‐related behaviors were mediated, in part, by adolescents’ perceptions of the parenting that they received, especially at 14 years of age. Furthermore, perceived parental monitoring and discipline had unique mediating capabilities, net the effects of all other parenting behaviors.
Conclusions: This study demonstrates that parenting is an important mediator of the association between parental and adolescent drinking practices. An important area for future research will be to study how adolescents can avoid alcohol‐related problems despite being reared within a risk laden parenting environment and/or having parents who drink frequently.
Background
Adolescent alcohol abuse is associated with adverse outcomes in early adulthood, but differences in familial status and structure and household and community environments correlate with ...both adolescent drinking and adverse adult outcomes and may explain their association. We studied drinking‐discordant twin pairs to evaluate such confounds to ask: Will between‐family associations replicate in within‐family comparisons?
Methods
With longitudinal data from >3,000 Finnish twins, we associated drinking problems at age 18½ with 13 outcomes assessed at age 25; included were sustained substance abuse, poor health, physical symptoms, early coital debut, multiple sexual partners, life dissatisfaction, truncated education, and financial problems. We assessed associations among twins as individuals with linear regression adjusted for correlated observations; within‐family analyses of discordant twin pairs followed, comparing paired means for adult outcomes among co‐twins discordant for adolescent problem drinking. Defining discordance by extreme scores on self‐reported problem drinking at age 18½ permitted parallel analyses of twins as individuals and discordant twin pairs. Alternate definitions of pair‐wise discordance and difference score correlations across the entire twin sample yielded supplementary analyses.
Results
All individual associations were highly significant for all definitions of discordance we employed. Depending on definitions of discordance, 11 to 13 comparisons of all drinking‐discordant twin pairs and 3 to 6 comparisons of discordant monozygotic (MZ) twin pairs replicated between‐family associations. For most outcomes, effect size attenuated from individual‐level analysis to that within discordant MZ twin pairs providing evidence of partial confounding in associations reported in earlier research. The exception was the General Health Questionnaire (GHQ); at age 25, GHQ‐12 had equivalent associations with age 18½ Rutgers Alcohol Problem Index across all comparisons.
Conclusions
Our analyses control for shared family background, and, partly or fully, for shared genes, to yield within‐family replications and more compelling evidence than previously available that adolescent alcohol abuse disrupts transitions into early adulthood.
Background
Malignant peripheral nerve sheath tumors (MPNST) are a rare form of soft tissue sarcoma with few studies reporting on patient outcomes and prognostic variables.
Methods
A retrospective ...review of 175 patients diagnosed with MPNST from 1985 to 2010 was performed. Patient, tumor, and treatment characteristics were evaluated to identify prognostic variables.
Results
The median age of our study population was 44 years, and 51% were female. Median tumor size was 6 cm, and 61% of patients had high-grade tumors. Tumors were most commonly located on the extremities (45%), then trunk (34%) and head/neck (19%). The majority of patients underwent surgical resection (95%) and adjuvant treatment with chemotherapy (6%), radiation (42%) or both (22%). Margin status was R0 in 69%, R1 in 2%, R2 in 9%, and unknown in 20%. The local recurrence rate was 22%, and 5- and 10-year disease-specific survival (DSS) were 60% and 45%, respectively. On univariate analysis, no predictors for local recurrence were identified. Tumor size ≥5 cm, high tumor grade, tumor location, presence of neurofibromatosis type 1, local recurrence, and adjuvant chemotherapy were all associated with DSS. On multivariate analysis, size ≥5 cm hazard ratio (HR) = 6.1, 95% confidence interval (CI) 1.5–25.0, local recurrence (HR = 4.4, 95% CI 1.7–11.4), high tumor grade (HR = 3.8, 95% CI 1.1–13.2), and truncal location (HR = 3.7, 95% CI 1.1–12.7) were poor prognostic indicators for DSS.
Conclusions
High tumor grade and tumor size ≥5 cm predict adverse DSS for MPNST. In the context of a multidisciplinary treatment regimen, local recurrence and survival outcomes at 5 and 10 years were better than previously reported for MPNST.
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