A multi-center cooperative clinical trial was undertaken to evaluate the safety and efficacy of weekly taxol (TXL) therapy combined with short-premedication as a pretreatment in an effort to ...determine if TXL can be used in ambulatory treatment. TXL was administered at 60 mg/m2 to patients with advanced recurrent breast cancer once a week without a rest or with a rest for 1 week after treatment for 3 weeks. A total of 36 patients were finally enrolled. The site of recurrence was the local region in 8 patients, lung/pleura in 24, liver in 9, bone in 16, lymph nodes in 15, epicardium in 2, and brain metastasis in 2. The response was CR in 2, PR in 12, NC in 9, PD in 8, and NE in 5, with a response rate of 45.2%. Grade 4 anorexia was reported as non-hematotoxicity. All other adverse reactions, such as myalgia/arthralgia and peripheral neuropathy, were mild (grade 1 or 2). Hematotoxic effects observed in this study included only grade 3 leukopenia in 5 patients, neutropenia in 4, and decreases in hemoglobin in 1.
Despite the morphological diversity of animals, their basic anatomical patterns-the body plans in each animal phylum-have remained highly conserved over hundreds of millions of evolutionary years. ...This is attributed to conservation of the body plan-establishing developmental period (the phylotypic period) in each lineage. However, the evolutionary mechanism behind this phylotypic period conservation remains under debate. A variety of hypotheses based on the concept of modern synthesis have been proposed, such as negative selection in the phylotypic period through its vulnerability to embryonic lethality. Here we tested a new hypothesis that the phylotypic period is developmentally stable; it has less potential to produce phenotypic variations than the other stages, and this has most likely led to the evolutionary conservation of body plans.
By analyzing the embryos of inbred Japanese medaka embryos raised under the same laboratory conditions and measuring the whole embryonic transcriptome as a phenotype, we found that the phylotypic period has greater developmental stability than other stages. Comparison of phenotypic differences between two wild medaka populations indicated that the phylotypic period and its genes in this period remained less variational, even after environmental and mutational modifications accumulated during intraspecies evolution. Genes with stable expression levels were enriched with those involved in cell-cell signalling and morphological specification such as Wnt and Hox, implying possible involvement in body plan development of these genes.
This study demonstrated the correspondence between the developmental stage with low potential to produce phenotypic variations and that with low diversity in micro- and macroevolution, namely the phylotypic period. Whereas modern synthesis explains evolution as a process of shaping of phenotypic variations caused by mutations, our results highlight the possibility that phenotypic variations are readily limited by the intrinsic nature of organisms, namely developmental stability, thus biasing evolutionary outcomes.
Phenotypic evolution is mainly explained by selection for phenotypic variation arising from factors including mutation and environmental noise. Recent theoretical and experimental studies have ...suggested that phenotypes with greater developmental stability tend to have a constant phenotype and gene expression level within a particular genetic and environmental condition, and this positively correlates with stronger evolutionary conservation, even after the accumulation of genetic changes. This could reflect a novel mechanism that contributes to evolutionary conservation; however, it remains unclear whether developmental stability is the cause, or whether at least it contributes to their evolutionary conservation. Here, using Japanese medaka lines, we tested experimentally whether developmental stages and gene expression levels with greater stability led to their evolutionary conservation.
We first measured the stability of each gene expression level and developmental stage (defined here as the whole embryonic transcriptome) in the inbred F0 medaka population. We then measured their evolutionary conservation in the F3 generation by crossing the F0 line with the distantly related Japanese medaka line (Teradomori), followed by two rounds of intra-generational crossings. The results indicated that the genes and developmental stages that had smaller variations in the F0 generation showed lower diversity in the hybrid F3 generation, which implies a causal relationship between stability and evolutionary conservation.
These findings suggest that the stability in phenotypes, including the developmental stages and gene expression levels, leads to their evolutionary conservation; this most likely occurs due to their low potential to generate phenotypic variation. In addition, since the highly stable developmental stages match with the body-plan-establishment stage, it also implies that the developmental stability potentially contributed to the strict conservation of animal body plan.
Recent advances in embryonic stem cell (ESC) derivation and genome editing offer efficient platforms for genetic screening. In this issue, Li et al. and Leeb et al., respectively, expand such ...applications by generating haploid rat ESCs for screening, mutagenesis, and CRISPR-Cas-mediated gene targeting and by developing a forward genetic screen for interrogating haploid mESCs.
DNA transposons and retroviruses are versatile tools in functional genomics and gene therapy. To facilitate their application, we conducted a genome-wide insertion site profiling of the piggyBac ...(PB), Tol2 and Sleeping Beauty (SB) transposons and the murine leukemia virus (MLV) in mouse embryonic stem cells (ESCs). PB and MLV preferred highly expressed genes, whereas Tol2 and SB preferred weakly expressed genes. However, correlations with DNase I hypersensitive sites were different for all vectors, indicating that chromatin accessibility is not the sole determinant. Therefore, we analysed various chromatin states. PB and MLV highly correlated with Cohesin, Mediator and ESC-specific transcription factors. Notably, CTCF sites were correlated with PB but not with MLV, suggesting MLV prefers smaller promoter-enhancer loops, whereas PB insertion encompasses larger chromatin loops termed topologically associating domains. Tol2 also correlated with Cohesin and CTCF. However, correlations with ESC-specific transcription factors were weaker, suggesting that Tol2 prefers transcriptionally weak chromatin loops. Consistently, Tol2 insertions were associated with bivalent histone modifications characteristic of silent and inducible loci. SB showed minimum preference to all chromatin states, suggesting the least adverse effect on adjacent genes. These results will be useful for vector selection for various applications.
Abstract The development of haematopoiesis involves the coordinated action of numerous genes, some of which are implicated in haematological malignancies. However, the biological function of many ...genes remains elusive and unknown functional genes are likely to remain to be uncovered. Here, we report a previously uncharacterised gene in haematopoiesis, identified by screening mutant embryonic stem cells. The gene, ‘ attenuated haematopoietic development ( Ahed )’, encodes a nuclear protein. Conditional knockout (cKO) of Ahed results in anaemia from embryonic day 14.5 onward, leading to prenatal demise. Transplantation experiments demonstrate the incapacity of Ahed -deficient haematopoietic cells to reconstitute haematopoiesis in vivo. Employing a tamoxifen-inducible cKO model, we further reveal that Ahed deletion impairs the intrinsic capacity of haematopoietic cells in adult mice. Ahed deletion affects various pathways, and published databases present cancer patients with somatic mutations in Ahed . Collectively, our findings underscore the fundamental roles of Ahed in lifelong haematopoiesis, implicating its association with malignancies.
Aims
Early tumor recurrence (ETR) after hepatic resection is a crucial predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify clinically ...significant serum microRNAs (miRNAs) involved in the ETR of HCC.
Methods
We compared expression profiles of circulating miRNAs from serum samples between five HCC patients with ETR (recurrence within 12 months after hepatectomy) and five HCC patients without recurrence using microarray analysis of miRNA. The identified miRNA associated with ETR was further verified in 121 HCC patients, 73 liver disease patients, and 15 health controls by real‐time quantitative reverse transcription–polymerase chain reaction (PCR).
Results
Of the approximately 2000 miRNAs analyzed, we identified 15 miRNAs for which expression levels correlated significantly with ETR. Of these miRNAs, we further investigated expression of miRNA‐1246 (miR‐1246). Quantitative PCR confirmed that miR‐1246 was upregulated in HCC with ETR, compared to the level in HCC without ETR (P < 0.001). Serum miR‐1246 showed a receiver operating characteristic curve area of 0.762, with 77.4% specificity and 54.1% sensitivity in discriminating HCC patients with ETR from HCC patients without ETR. Altered expression of miR‐1246 was associated with aggressive tumor characteristics, including tumor–node–metastasis classification (P = 0.0413), tumor differentiation (P = 0.0419), and portal vein invasion (P = 0.0394). Moreover, multivariate Cox regression analysis identified serum miR‐1246 level as an independent risk factor for overall survival (hazard ratio, 2.784; 95% confidence interval, 1.528–5.071; P = 0.0008).
Conclusion
Circulating miR‐1246 in serum has strong potential as a novel ETR and prognostic biomarker for HCC.
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