The addition of pembrolizumab to chemotherapy for metastatic lung cancer without
EGFR
or
ALK
mutations resulted in better progression-free and overall survival than chemotherapy alone. Immune-related ...adverse effects were more common with the combination.
Primitive cancers have so-called hot-spot mutations in
DICER1
that alter the function of
DICER1,
an enzyme that processes microRNA. Some of these cancers harbor a loss-of-function mutation in the ...other
DICER1
allele, suggesting a new mutational mechanism of oncogenesis.
Sex cord–stromal tumors and germ-cell tumors account for less than 10% of ovarian cancers.
1
Unlike epithelial ovarian cancers, both sex cord–stromal tumors and germ-cell tumors can also occur in the testicle; testicular germ-cell tumors are the most common cancer in boys and men of European descent between the ages of 15 and 34 years.
2
,
3
Other than a pathognomonic somatic mutation in
FOXL2
in adult granulosa-cell tumors,
4
–
6
little is known about the pathogenesis of ovarian sex cord–stromal tumors and germ-cell tumors. Recently, germline mutations in the microRNA processing gene
DICER1
have been reported in probands with pleuropulmonary blastoma or . . .
Approximately 99% of the plastics produced today are petroleum-based, and the packaging industry alone consumes over 38% of these plastics. In this review, we argue that renewable polyesters can ...provide a key milestone as renewable plastics in the route toward green packaging. This review describes different classes of polyesters with particular regard to their potential use as packaging materials. Some of the families of polyesters discussed include poly(ethylene terephthalate) and its renewable analogs, poly(lactic acid), poly(hydroxyalkanoates), and poly(epoxy anhydrides). The synthesis of polyesters is discussed from a green chemistry perspective. A structure-property correlation among the various polyesters is also discussed. The challenges that currently hinder the widespread adoption of polyesters as leading packaging materials are reviewed. The environmental footprint and end of life scenario of polyesters are discussed. Finally, future research directions are summarized as a possible roadmap towards the widespread adoption of renewable polyesters as sustainable packaging materials.
Approximately 99% of the plastics used in the packaging industry today are petroleum-based. However, the adoption of biobased plastics could help to greatly reduce the environmental footprint of packaging materials and help to conserve our non-renewable petroleum resources. This tutorial review provides an overview of renewable polyesters and their potential packaging materials.
Since it first secured a foothold in the southern United States in the 1930s from its native South America, the red imported fire ant Solenopsis invicta Buren has now spread to more than 20 countries ...and territories. We update the status of S. invicta in Australia, China and Taiwan and discuss the invasion threat posed to other countries in the region, including India, Japan, South Korea, Myanmar, Laos and Vietnam. An analysis of the manner of spread and responses by governments to the invasion reveals some important lessons: (a) S. invicta can be eradicated if detected early enough, (b) there has been a level of unpreparedness and under‐resourcing of quarantine agencies in some countries to deal with the pest, (c) strict controls on the movement of products likely to harbor S. invicta are essential in preventing or slowing the spread of the pest and has a major influence on the success or failure of eradication efforts and (d) a coordinated agency response is necessary to prevent treatment failure. Currently, cargo container traffic is the main mechanism for movement of S. invicta around the world and can only be addressed by international collaboration. Given the recent fire ant propagule pressure on Japan and South Korea via container traffic from China, it is likely that China may be a new bridgehead for the invasion of its neighbors in Asia and beyond.
We review the current invasion status of the red imported fire ant, Solenopsis invicta in Asia‐Pacific regions.
Tumor hypoxia is increasingly being recognized as a characteristic feature of solid tumors and significantly complicates many treatments based on radio-, chemo-, and phototherapies. While ...photodynamic therapy (PDT) is based on photosensitizer interactions with diffused oxygen, photothermal therapy (PTT) has emerged as a new phototherapy that is predicted to be independent of oxygen levels within tumors. It has been challenging to meaningfully compare these two modalities due to differences in contrast agents and irradiation parameters, and no comparative in vivo studies have been performed until now. Here, by making use of recently developed nanostructured self-quenched porphysome nanoparticles, we were able to directly compare PDT and PTT using matched light doses and matched porphyrin photosensitizer doses (with the photosensitizer being effective for either PTT or PDT based on the existence of nanostructure or not). Therefore, we demonstrated the nanostructure-driven conversion from the PDT singlet oxygen generating mechanism of porphyrin to a completely thermal mechanism, ideal for PTT enhancement. Using a novel hypoxia tumor model, we determined that nanostructured porphyrin PTT enhancers are advantageous to overcome hypoxic conditions to achieve effective ablation of solid tumors.
We propose a new method for determining the target genes of transcriptional enhancers in specific cells and tissues. It combines global trends across many samples and sample-specific information, and ...considers the joint effect of multiple enhancers. Our method outperforms existing methods when predicting the target genes of enhancers in unseen samples, as evaluated by independent experimental data. Requiring few types of input data, we are able to apply our method to reconstruct the enhancer-target networks in 935 samples of human primary cells, tissues and cell lines, which constitute by far the largest set of enhancer-target networks. The similarity of these networks from different samples closely follows their cell and tissue lineages. We discover three major co-regulation modes of enhancers and find defense-related genes often simultaneously regulated by multiple enhancers bound by different transcription factors. We also identify differentially methylated enhancers in hepatocellular carcinoma (HCC) and experimentally confirm their altered regulation of HCC-related genes.
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•The serum vitamin D metabolome has expanded substantially in recent years.•Several metabolites can be quantitated simultaneously by LC/MS/MS.•New metabolites made by CYP11A1 such as ...20-hydroxyvitamin D3 have been detected.•Metabolites produced by CYP24A1 have been, or are likely to be detected in serum.•Measuring an increased range of vitamin D metabolites should be of clinical use.
Vitamin D, referring to the two forms, D2 from the diet and D3 primarily derived from phototransformation in the skin, is a prohormone important in human health. The most hormonally active form, 1α,25-dihydroxyvitamin D (1α,25(OH)2D), formed from vitamin D via 25-hydroxyvitamin D (25(OH)D), is not only important for regulating calcium metabolism, but has many pleiotropic effects including regulation of the immune system and has anti-cancer properties. The major circulating form of vitamin D is 25(OH)D and both D2 and D3 forms are routinely measured by LC/MS/MS to assess vitamin D status, due to their relatively long half-lives and much higher concentrations compared to 1α,25(OH)2D. Inactivation of both 25(OH)D and 1α,25(OH)2D is catalyzed by CYP24A1 and 25-hydroxyvitamin D3 3-epimerase. Initial products from these enzymes acting on 25(OH)D3 are 24R,25(OH)2D3 and 3-epi-25(OH)D3, respectively, and both of these can also be measured routinely in some clinical laboratories to further document vitamin D status. With advances in LC/MS/MS and its increased availability, and with the help of studies with recombinant vitamin D-metabolizing enzymes, many other vitamin D metabolites have now been detected and in some cases quantitated, in human serum. CYP11A1 which catalyzes the first step in steroidogenesis, has been found to also act on vitamins D3 and D2 hydroxylating both at C20, but with some secondary metabolites produced by subsequent hydroxylations at other positions on the side chain. The major vitamin D3 metabolite, 20S-hydroxyvitamin D3 (20S(OH)D3), shows biological activity, often similar to 1α,25(OH)2D3 but without calcemic effects. Using standards produced enzymatically by purified CYP11A1 and characterized by NMR, many of these new metabolites have been detected in human serum, with semi-quantitative measurement of 20S(OH)D3 indicating it is present at comparable concentrations to 24R,25(OH)2D3 and 3-epi-25(OH)D3. Recently, vitamin D-related hydroxylumisterols derived from lumisterol3, a previtamin D3 photoproduct, have also been measured in human serum and displayed biological activity in initial in vitro studies. With the current extensive knowledge on the reactions and pathways of metabolism of vitamin D, especially those catalyzed by CYP24A1, CYP27A1, CYP27B1, CYP3A4 and CYP11A1, it is likely that many other of the resulting hydroxyvitamin D metabolites will be measured in human serum in the future, some contributing to a more detailed understanding of vitamin D status in health and disease.
Next-generation sequencing of follicular lymphoma and diffuse-large B-cell lymphoma has revealed frequent somatic, heterozygous Y641 mutations in the histone methyltransferase EZH2. Heterozygosity ...and the presence of equal quantities of both mutant and wild-type mRNA and expressed protein suggest a dominant mode of action. Surprisingly, B-cell lymphoma cell lines and lymphoma samples harboring heterozygous EZH2Y641 mutations have increased levels of histone H3 Lys-27–specific trimethylation (H3K27me3). Expression of EZH2Y641F/N mutants in cells with EZH2WT resulted in an increase of H3K27me3 levels in vivo. Structural modeling of EZH2Y641 mutants suggests a “Tyr/Phe switch” model whereby structurally neutral, nontyrosine residues at position 641 would decrease affinity for unmethylated and monomethylated H3K27 substrates and potentially favor trimethylation. We demonstrate, using in vitro enzyme assays of reconstituted PRC2 complexes, that Y641 mutations result in a decrease in monomethylation and an increase in trimethylation activity of the enzyme relative to the wild-type enzyme. This represents the first example of a disease-associated gain-of-function mutation in a histone methyltransferase, whereby somatic EZH2 Y641 mutations in lymphoma act dominantly to increase, rather than decrease, histone methylation. The dominant mode of action suggests that allele-specific EZH2 inhibitors should be a future therapeutic strategy for this disease.
CDK12 (cyclin-dependent kinase 12) is a regulatory kinase with evolutionarily conserved roles in modulating transcription elongation. Recent tumor genome studies of breast and ovarian cancers ...highlighted recurrent CDK12 mutations, which have been shown to disrupt DNA repair in cell-based assays. In breast cancers, CDK12 is also frequently co-amplified with the HER2 (ERBB2) oncogene. The mechanisms underlying functions of CDK12 in general and in cancer remain poorly defined. Based on global analysis of mRNA transcripts in normal and breast cancer cell lines with and without CDK12 amplification, we demonstrate that CDK12 primarily regulates alternative last exon (ALE) splicing, a specialized subtype of alternative mRNA splicing, that is both gene- and cell type-specific. These are unusual properties for spliceosome regulatory factors, which typically regulate multiple forms of alternative splicing in a global manner. In breast cancer cells, regulation by CDK12 modulates ALE splicing of the DNA damage response activator ATM and a DNAJB6 isoform that influences cell invasion and tumorigenesis in xenografts. We found that there is a direct correlation between CDK12 levels, DNAJB6 isoform levels and the migration capacity and invasiveness of breast tumor cells. This suggests that CDK12 gene amplification can contribute to the pathogenesis of the cancer.
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