Interest in reconstructing demographic histories has motivated the development of methods to estimate locus-specific pairwise coalescence times from whole-genome sequencing data. Here we introduce a ...powerful new method, ASMC, that can estimate coalescence times using only SNP array data, and is orders of magnitude faster than previous approaches. We applied ASMC to detect recent positive selection in 113,851 phased British samples from the UK Biobank, and detected 12 genome-wide significant signals, including 6 novel loci. We also applied ASMC to sequencing data from 498 Dutch individuals to detect background selection at deeper time scales. We detected strong heritability enrichment in regions of high background selection in an analysis of 20 independent diseases and complex traits using stratified linkage disequilibrium score regression, conditioned on a broad set of functional annotations (including other background selection annotations). These results underscore the widespread effects of background selection on the genetic architecture of complex traits.
Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive ...gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial-mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited β-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.
An inverse association between alcoholic beverage intake and risk of renal cell cancer has been suggested in recent studies.
We examined the association between alcoholic beverages and renal cell ...cancer risk in a meta-analysis. We identified relevant studies by searching the database of PubMed, EMBASE, and MEDLINE published through August 2011. We combined the study-specific relative risks (RRs) using a random-effects model.
A total of 20 case-control studies, 3 cohort studies, and 1 pooled analysis of cohort studies were included in the meta-analysis. We observed that alcoholic beverage intake was associated with a lower risk of renal cell cancer in combined analysis of case-control and cohort studies; for total alcoholic beverage intake, combined RRs (95% confidence intervals) comparing top with bottom categories were 0.76 (0.68-0.85) in case-control studies, and 0.71 (0.63-0.78) in cohort studies (P for difference by study design=0.02). The inverse associations were observed for both men and women and for each specific type alcoholic beverage (beer, wine, and liquor). Also, we found that one drink per day of alcoholic beverage conferred the reduction in renal cell cancer risk, but further drinking above that level did not add benefit.
The findings from our meta-analysis support the hypothesis that alcoholic beverage intake is inversely associated with a lower risk of renal cell cancer, with moderate consumption conferring the protection and higher consumption conferring no additional benefits.
Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage that eventually leads to a ...complex process involving degradation of various components of the cartilage matrix, chief among them are the cartilage-specific type II collagen (CII) and aggrecan. While the loss of aggrecan is thought to be an early and reversible process, degradation of CII is considered to be irreversible and a key step in the loss of structural and functional integrity of cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. It is the major collagenase in OA cartilage and has the highest activity against CII. However, the clinical utility of broad-spectrum MMP inhibitors developed for treatment of OA has been restricted by dose- and duration-dependent musculoskeletal side effects in humans. Consequently, selectively inhibiting the MMP-13 would seem to be an attractive therapeutic objective. This review mainly focuses on selective MMP-13 inhibitors development in terms of OA since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, non-zinc-binding groups. In addition, dual inhibitors of MMP-13 and aggrecanase are also reviewed. Special emphasis is placed on logistic concerns for lead compound search as well as the structure-activity relationship (SAR) in this field. Through these methods, new hope is emerging for the treatment of OA through selective inhibition of MMP-13.
Telomerase (TERT) activation is a fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven ...by oncogenes. The recently discovered, highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation of TERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. Although TERT is expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence of TERT promoter mutations may shed light on whether a particular tumor arose from a stem cell or more differentiated cell type. It is becoming clear that TERT mutations occur early during cellular transformation, and activate the TERT promoter by recruiting transcription factors that do not normally regulate TERT gene expression. This review highlights the fundamental and widespread role of TERT promoter mutations in tumorigenesis, including recent progress on their mechanism of transcriptional activation. These somatic promoter mutations, along with germline variation in the TERT locus also appear to have significant value as biomarkers of patient outcome. Understanding the precise molecular mechanism of TERT activation by promoter mutation and germline variation may inspire novel cancer cell-specific targeted therapies for a large number of cancer patients.
The risk and prognosis of ovarian cancer have not been well established in women with endometriosis. Thus, we investigated the impact of endometriosis on the risk and prognosis for ovarian cancer, ...and evaluated clinicopathologic characteristics of endometriosis-associated ovarian cancer (EAOC) in comparison with non-EAOC.
After we searched an electronic search to identify relevant studies published online between January 1990 and December 2012, we found 20 case-control and 15 cohort studies including 444,255 patients from 1,625 potentially relevant studies. In the meta-analysis, ovarian cancer risk by endometriosis and clinicopathologic characteristics were evaluated using risk ratio (RR) or standard incidence ratio (SIR), and prognosis was investigated using hazard ratio (HR) with 95% confidence interval (CI). Heterogeneity was evaluated using Higgins I(2) to select fixed-effect (I(2) ≤50%) or random effects models (I(2)>50%), and found no publication bias using funnel plots with Egger's test (P>0.05). Furthermore, we performed subgroup analyses based on study design, assessment of endometriosis, histology, disease status, quality of study and adjustment for potential confounding factors to minimise bias.
Endometriosis increased ovarian cancer risk in case-control or two-arm cohort studies (RR, 1.265; 95% CI, 1.214-1.318) and single-arm cohort studies (SIR, 1.797; 95% CI, 1.276-2.531), which were similar in subgroup analyses. Although progression-free survival was not different between EAOC and non-EAOC (HR, 1.023; 95% CI, 0.712-1.470), EAOC was associated with better overall survival than non-EAOC in crude analyses (HR, 0.778; 95% CI, 0.655-0.925). However, progression-free survival and overall survival were not different between the two groups in subgroup analyses. Stage I-II disease, grade 1 disease and nulliparity were more common in EAOC (RRs, 1.959, 1.319 and 1.327; 95% CIs, 1.367-2.807, 1.149-1.514 and 1.245-1.415), whereas probability of optimal debulking surgery was not different between the two groups (RR, 1.403; 95% CI, 0.915-2.152). Furthermore, endometrioid and clear cell carcinomas were more common in EAOC (RRs, 1.759 and 2.606; 95% CIs, 1.551-1.995 and 2.225-3.053), whereas serous carcinoma was less frequent in EAOC than in non-EAOC (RR, 0.733; 95% CI, 0.617-0.871), and there was no difference in the risk of mucinous carcinoma between the two groups (RR, 0.805; 95% CI, 0.584-1.109). These clinicopathologic characteristics were also similar in subgroup analyses.
Endometriosis is strongly associated with the increased risk of ovarian cancer, and EAOC shows favourable characteristics including early-stage disease, low-grade disease and a specific histology such as endometrioid or clear cell carcinoma. However, endometriosis may not affect disease progression after the onset of ovarian cancer.
Fine-scale rates of meiotic recombination vary by orders of magnitude across the genome and differ between species and even populations. Studying cross-population differences has been stymied by the ...confounding effects of demographic history. To address this problem, we developed a demography-aware method to infer fine-scale recombination rates and applied it to 26 diverse human populations, inferring population-specific recombination maps. These maps recapitulate many aspects of the history of these populations including signatures of the trans-Atlantic slave trade and the Iberian colonization of the Americas. We also investigated modulators of the local recombination rate, finding further evidence that Polycomb group proteins and the trimethylation of H3K27 elevate recombination rates. Further differences in the recombination landscape across the genome and between populations are driven by variation in the gene that encodes the DNA binding protein PRDM9, and we quantify the weak effect of meiotic drive acting to remove its binding sites.
•Climate change increased bloom areas by 414% during the last two decades in taihu.•Nutrient targets under different climate scenarios for lake taihu was estimated.•More than 46.3% phosphorus ...reduction could ensure low risk of large blooms.•Continuous variable bayesian modelling framework was useful for bloom predictions.
Although nutrient reduction has been used for lake eutrophication mitigation worldwide, the use of this practice alone has been shown to be less effective in combatting cyanobacterial blooms, primarily because of climate change. In addition, quantifying the climate change contribution to cyanobacterial blooms is difficult, further complicating efforts to set nutrient reduction goals for mitigating blooms in freshwater lakes. This study employed a continuous variable Bayesian modeling framework to develop a model to predict spring cyanobacterial bloom areas and frequencies (the responses) using nutrient levels and climatic factors as predictors. Our results suggested that both spring climatic factors (e.g., increasing temperature and decreasing wind speed) and nutrients (e.g., total phosphorus) played vital roles in spring blooms in Lake Taihu, with climatic factors being the primary drivers for both bloom areas and frequencies. Climate change in spring had a 90% probability of increasing the bloom area from 35 km2 to 180 km2 during our study period, while nutrient reduction limited the bloom area to 170 km2, which helped mitigate expansion of cyanobacterial blooms. For lake management, to ensure a 90% probability of the mean spring bloom areas remaining under 154 km2 (the 75th percentile of the bloom areas in spring), the total phosphorus should be maintained below 0.073 mg·L−1 under current climatic conditions, which is a 46.3% reduction from the current level. Our modeling approach is an effective method for deriving dynamic nutrient thresholds for lake management under different climatic scenarios and management goals.
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Multiferroic Nd/Sm-doped BiFeO3 ceramics synthesized at 700 °C by spark plasma sintering in conjunction with sol-gel precursor powders are investigated by X-ray diffraction, scanning electron ...microscopy, dielectric, ferroelectric and magnetic measurements. With the doping content of Nd/Sm beyond 10 mol%, the crystal structure changes from R3c to coexistence of Pbam and R3c. It is also revealed that the grain size for all samples greatly decreases and the dielectric, ferroelectric and magnetic properties are obviously improved with Nd/Sm doping. The optimized remanent polarization are about 1.451 μC/cm2 and 3.448 μC/cm2 for the 10 mol% Nd-doped and 15 mol% Sm-doped BiFeO3 ceramics, respectively. Because of the reduced concentration of oxygen vacancies, the leakage current density of Nd/Sm-doped ceramics decreases more than two orders of magnitude compared to the pure BiFeO3 sample. The maximum remanent magnetization for the Sm-doped ceramics is approximately 0.279 emu/g, which is higher than that for the Nd-doped samples (0.263 emu/g).
A key step in implementing Bayesian networks (BNs) is the discretization of continuous variables. There are several mathematical methods for constructing discrete distributions, the implications of ...which on the resulting model has not been discussed in literature. Discretization invariably results in loss of information, and both the discretization method and the number of intervals determines the level of such loss. We designed an experiment to evaluate the impact of commonly used discretization methods and number of intervals on the developed BNs. The conditional probability tables, model predictions, and management recommendations were compared and shown to be different among models. However, none of the models did uniformly well in all comparison criteria. As we cannot justify using one discretization method against others, we recommend caution when discretization is used, and a verification process that includes evaluating alternative methods to ensure that the conclusions are not an artifact of the discretization approach.
•An experiment was designed to evaluate the impact of commonly used discretization methods and number of intervals on the developed Bayesian Networks (BNs).•The conditional probability tables, and hence, model predictions and management recommendations differed among models.•None of the models did uniformly well in all comparison criteria.•It is suggested that discretization be used with caution or be avoided, when possible, and the BN models be modified to accommodate continuous variables.•A verification process is recommended that includes evaluating alternative methods to ensure that the conclusions are not an artifact of the discretization approach.
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