Resolution, conflict and rate shifts: insights from a densely sampled plastome phylogeny for Rhododendron (Ericaceae).

BACKGROUND AND AIMS: Rhododendron is a species-rich and taxonomically challenging genus due to recent adaptive radiation and frequent hybridization. A well-resolved phylogenetic tree would help to understand the diverse history of Rhododendron in the Himalaya-Hengduan Mountains where the genus is most diverse. METHODS: We reconstructed the phylogeny based on plastid genomes with broad taxon sampling, covering 161 species representing all eight subgenera and all 12 sections, including ~45 % of the Rhododendron species native to the Himalaya-Hengduan Mountains. We compared this phylogeny with nuclear phylogenies to elucidate reticulate evolutionary events and clarify relationships at all levels within the genus. We also estimated the timing and diversification history of Rhododendron, especially the two species-rich subgenera Rhododendron and Hymenanthes that comprise >90 % of Rhododendron species in the Himalaya-Hengduan Mountains. KEY RESULTS: The full plastid dataset produced a well-resolved and supported phylogeny of Rhododendron. We identified 13 clades that were almost always monophyletic across all published phylogenies. The conflicts between nuclear and plastid phylogenies suggested strongly that reticulation events may have occurred in the deep lineage history of the genus. Within Rhododendron, subgenus Therorhodion diverged first at 56 Mya, then a burst of diversification occurred from 23.8 to 17.6 Mya, generating ten lineages among the component 12 clades of core Rhododendron. Diversification in subgenus Rhododendron accelerated c. 16.6 Mya and then became fairly continuous. Conversely, Hymenanthes diversification was slow at first, then accelerated very rapidly around 5 Mya. In the Himalaya-Hengduan Mountains, subgenus Rhododendron contained one major clade adapted to high altitudes and another to low altitudes, whereas most clades in Hymenanthes contained both low- and high-altitude species, indicating greater ecological plasticity during its diversification. CONCLUSIONS: The 13 clades proposed here may help to identify specific ancient hybridization events. This study will help to establish a stable and reliable taxonomic framework for Rhododendron, and provides insight into what drove its diversification and ecological adaption. Denser sampling of taxa, examining both organelle and nuclear genomes, is needed to better understand the divergence and diversification history of Rhododendron.

Measuring Survival Benefit in Health Technology Assessment in the Presence of Nonproportional Hazards.

BACKGROUND: Proportional hazards (PH) is an assumption often made by researchers, despite evidence of nonproportionality in a significant proportion of clinical trials. In the presence of non-PH, the interpretation of hazard ratios, medians, and landmark survival as summary measures of treatment effect can become problematic. Several recent studies have recommended restricted mean survival time (RMST) as an alternative metric for survival analysis, particularly where non-PH may apply. OBJECTIVES: To determine the current approaches of health technology assessment (HTA) agencies to value assessment in the presence of non-PH, and the extent to which RMST is accepted as an alternative measure of treatment benefit. METHODS: Methodological guidelines published by 10 HTA agencies were reviewed to establish recommended approaches for presenting survival benefit from clinical trials. Published HTA reports for 23 oncology agents approved by the US Food and Drug Administration and the European Medicines Agency since 2014 were reviewed to determine how guidelines are implemented in practice and identify instances where the PH assumption was tested and RMST analyses reported. RESULTS: Testing for non-PH is not widely incorporated into HTA except by the UK National Institute for Health and Care Excellence. RMST is used infrequently but has been used in a number of countries, particularly by agencies that focus on cost effectiveness. CONCLUSIONS: HTA agencies vary in their approaches to non-PH. Most do not routinely check the PH assumption. RMST has played a role in assessing clinical benefit within HTA, although not consistently within countries (across drugs) or across countries (for the same drug).

Positive impact of the negative lymph node count on the survival rate of stage III colon cancer with pN1 and right-side disease.

Background: We aimed to investigate the role of the negative lymph node count (NLN) as a predictor of prognosis in patients with stage III colon cancer. Methods: We conducted a retrospective study on patients who were diagnosed with stage III colon cancer at Sun Yat-sen University Cancer Center. According to the number of negative lymph nodes, all patients were divided into the low or high NLN group. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method and log-rank test between the two groups. Univariate and multivariate Cox proportional hazards models were used to evaluate the risk factors for survival. Results: The time-dependent receiver operating characteristic (ROC) curve showed that the optimal cutoff value of NLN was nine. In total, 167 and 298 patients were distributed into the low and high NLN groups, respectively. Patients in the high NLN group tended to present with a greater proportion of right-side colon cancer and pN1 stage disease, superior DFS (P < 0.001) and OS (P = 0.001) than those in the low NLN group. Multivariable analyses confirmed increased NLN as a positive prognostic variable, independent of other potential confounding factors. Subgroup analysis showed that in patients with a right-side location, those with 9 or fewer negative lymph nodes had a 5-year OS rate of 35.4% versus 77.1% in those with more than 9 negative lymph nodes evaluated (P < 0.001). For patients with stage pN1, those with NLN ≤9 exhibited an inferior 5-year OS rate than those with NLN > 9 (71.1% vs 84.8%, respectively; P = 0.009). There was no association between the number of negative lymph nodes identified and survival for patients with stage pN2 and left-side disease. Conclusion: NLN is an important prognostic factor for stage III colon cancer patients with right-side and stage pN1 disease other than for patients with stage pN2 and left-side disease, which can be partly explained in terms of inflammation and immunity.

p53R2 as a novel prognostic biomarker in nasopharyngeal carcinoma.

BACKGROUND: p53R2 is a target of p53 gene, which is essential for DNA repair, mitochondrial DNA synthesis, protection against oxidative stress, chromosomal instability, chronic inflammation and tumorigenesis. This study is aimed to investigate the expression of ribonucleotide reductase (RR) subunit p53R2 in nasopharyngeal carcinoma and its significance in the prognosis. METHODS: The expression levels of p53R2 in 201 patients with NPC were examined by immunohistochemical assay. The correlations of p53R2 expression and clinicopathological features of nasopharyngeal carcinoma patient were analysed by chi-square test. The Kaplan-Meier survival analysis and Cox multivariate regression model were used to analyze the prognostic significance of the patients with NPC. RESULTS: Immunohistochemical results showed that p53R2 was positively expressed in 92.5% (186/201) of nasopharyngeal carcinoma and the high expression rate was 38.3% (77/201). Further analysis observed that the negative correlation between expression of p53R2 and pT status had statistical significance (P < 0.05). Kaplan-Meier survival analysis found that the mean survival time of patients with high expression of p53R2 was 143.32 months, while the patients with low expression level of p53R2 was 121.63 months (P < 0.05). Cox regression analysis suggested that p53R2 protein expression could be used as an independent prognostic factor for nasopharyngeal carcinoma (P < 0.05). CONCLUSIONS: This study drew a conclusion that p53R2 could be used as a prognostic biomarker indicative of the favorable outcome for patients with nasopharyngeal carcinoma.