Recently, the role of transcriptional repression through epigenetic modulation in carcinogenesis has been clinically validated with several inhibitors of histone deacetylases and DNA ...methyltransferases. It has long been recognized that epigenetic alterations of tumor suppressor genes was one of the contributing factors in carcinogenesis. Inhibitors of histone deacetylase (HDAC) de-repress genes that subsequently result in growth inhibition, differentiation and apoptosis of cancer cells. Vorinostat (SAHA), romidepsin (depsipeptide, FK-228), belinostat (PXD101) and LAQ824/LBH589 have demonstrated therapeutic benefit as monotherapy in cutaneous T-cell lymphoma (CTCL) and have also demonstrated some therapeutic benefit in other malignancies. The approval of the HDAC inhibitor vorinostat (Zolinza™) was based on the inherent sensitivity of this type of lymphoma to alterations in acetylation patterns that resulted in the induction of repressed apoptotic pathways. However, the full potential of these inhibitors (epigenetic modulators) is still on the horizon, as the true breadth of their utility as anti-cancer agents will be determined by the careful analysis of gene expression changes generated by these inhibitors and then combined with conventional chemotherapy to synergistically improve response and toxicity for an overall enhanced therapeutic benefit to the patient. The question that must be considered is whether the current HDACIs are being utilized to their fullest potential in clinical trials based on their mechanism-based alterations in disease processes.
BACKGROUND: In order to assess the role of binucleate giant oocytes for generating digynic triploidy, we studied their frequency, maturation patterns and chromosomal complements at metaphase II (MII) ...or after fertilization. METHODS: Uncleaved, giant zygotes were incubated with podophyllotoxin and vinblastine, treated with hypotonic solution and fixed by a gradual fixation method. Giant MII oocytes were directly subjected to hypotonic treatment. The chromosomes were stained with Giemsa. RESULTS: A total of 7065 oocytes were collected during the study period, of which 18 (0.26%) were classified as giant cells. When considering only those patients in whom giant cells were identified (among other normal sized cells) a giant cell frequency of 18/237 (7.6%) was found. Nine cells underwent a union of the nuclei during maturation to MII and four of them became fertilized showing two pronuclei. Seven oocytes maintained the binucleate state to MII and one of them was fertilized showing three pronuclei. Ten unfertilized cells were available for cytogenetic analysis and proved to be diploid. All five giant zygotes revealed triploidy. CONCLUSIONS: The data suggest that giant oocytes may play an important, yet underestimated role in causing digynic triploidy. We recommend the exclusion of giant oocytes from IVF trials and that giant cells should be discarded, even if they carry the regular number of two pronuclei.
Tumor-derived circulating cell-free DNA (cfDNA) is present in the plasma of individuals with cancer. Assays aimed at detecting common cancer mutations in cfDNA are being developed for the detection ...of several cancer types. In breast cancer, however, such assays have failed to detect the disease at a sensitivity relevant for clinical use, in part due to the absence of multiple common mutations that can be co-detected in plasma. Unlike individual mutations that exist only in a subset of tumors, unique DNA methylation patterns are universally present in cells of a common type and therefore may be ideal biomarkers. Here we describe the detection and quantification of breast-derived cfDNA using a breast-specific DNA methylation signature.
We collected plasma from patients with localized breast cancer before and throughout treatment with neoadjuvant chemotherapy and surgery (N = 235 samples).
Pretreatment breast cfDNA was detected in patients with localized disease with a sensitivity of 80% at 97% specificity. High breast cfDNA levels were associated with aggressive molecular tumor profiles and metabolic activity of the disease. During neoadjuvant chemotherapy, breast cfDNA levels decreased dramatically. Importantly, the presence of breast cfDNA towards the end of the chemotherapy regimen reflected the existence of residual disease.
We propose that breast-specific cfDNA is a universal and powerful marker for the detection and monitoring of breast cancer.
•DNA derived from breast epithelial cells can be identified by DNA methylation.•Breast-derived DNA is elevated in the circulation of individuals with breast cancer.•Levels of breast-derived circulating DNA reflect response to treatment.•The presence of breast-derived circulating DNA is indicative of residual disease after treatment.
The global marine pharmaceutical pipeline consists of three Food and Drug Administration (FDA) approved drugs, one EU registered drug, 13 natural products (or derivatives thereof) in different phases ...of the clinical pipeline and a large number of marine chemicals in the preclinical pipeline. In the United States there are three FDA approved marine-derived drugs, namely cytarabine (Cytosar-U® , Depocyt® ), vidarabine (Vira-A® ) and ziconotide (Prialt® ). The current clinical pipeline includes 13 marine-derived compounds that are either in Phase I, Phase II or Phase III clinical trials. Several key Phase III studies are ongoing and there are seven marine-derived compounds now in Phase II trials. The preclinical pipeline continues to supply several hundred novel marine compounds every year and those continue to feed the clinical pipeline with potentially valuable compounds. From a global perspective the marine pharmaceutical pipeline remains very active, and now has sufficient momentum to deliver several additional compounds to the marketplace in the near future; this review provides a current view of the pipeline.
Hydrothermally converted biomass (hydrochar) is evaluated as a carbon‐rich soil amendment in addition to pyrogenic biochar. After assessing the suitability of hydrochar for use in agriculture, its ...environmental safety and comparing its chemistry with that of biochar, we describe a field trial established at Halle (Germany) under natural conditions for a temperate climate and without further external management practices. The main objective of our study was to analyse the stability and hence the C sequestration potential of composted chars over a period of 2 years. Four treatments (no amendment control, compost, co‐composted hydrochar and co‐composted biochar) in fourfold field replication were chosen to make a direct comparison of biochar and hydrochar under field conditions. The total organic carbon and total N increased in all treatments in comparison with the control but only in biochar‐amended treatments were N concentrations more stable. Composted biochar showed significantly more black carbon content in topsoil, sampled some months after application, compared with all other treatments. We show that hydrochar is less suitable for long‐term C sequestration in comparison with biochar but has potential for soil amelioration because it delivers essential nutrients. On the other hand, biochar is richer in polyaromatic C than hydrochar and therefore is more stable in the long term. We assessed biochar stability using the black carbon analysis of the different soil samples.
Opinions provided by leaders in marine natural products will address potential reasons and perceptions from academic and pharmaceutical communities regarding the development of marine natural ...products as viable therapeutic entities.
Marine pharmacology, the pharmacology of marine natural products, has been for some time more associated with marine natural products chemistry rather than mainstay pharmacology. However, in recent years a renaissance has occurred in this area of research, and has seen the US Food & Drug Administration (FDA) approval in 2004 of Prialt® (ziconotide, ω-conotoxin MVIIA) the synthetic equivalent of a conopeptide found in marine snails, used for the management of severe chronic pain. Furthermore Yondelis® (trabectedin, ET-743) an antitumor agent discovered in a marine colonial tunicate, and now produced synthetically, receiving Orphan Drug designation from the European Commission (EC) and FDA for soft tissue sarcomas and ovarian cancer and its registration in 2007 in the EU for the treatment of soft tissue sarcoma. The approval/marketing of so few marine natural products has come after many years of research primarily by the academic community and the sporadic involvement of major pharmaceutical companies. This commentary, through the opinions provided by several leaders in the marine natural products field, will examine the potential reasons and perceptions from both the academic and pharmaceutical communities regarding the development of marine natural products as viable therapeutic entities.
The Internet continues to be a popular venue for men who have sex with men (MSM) to seek sexual partners. Increased sexual risk behavior has been linked to MSM who use the Internet to seek partners. ...However, there has been little research on how new mobile-based social networking applications (“apps”) may affect sex-seeking and sexual risk behaviors of MSM. One hundred twenty-six MSM in New York City were recruited to complete an online survey on the use of the Internet and other technology for sex-seeking. The authors collected data on variables of interest including sexual sensation seeking, gay identity affirmation, internalized homophobia, Internet/app use, and sexual behavior with men met via the Internet and mobile apps. Results indicated that men who use both the Internet and mobile apps to seek partners were younger and reported higher incomes (p < .05) than men who used the Internet only. There were no significant differences between the groups with regard to race, sexual sensation seeking, gay identity affirmation, or internalized homophobia, indicating that the use of mobile-based apps for sex-seeking may be simply an example of evolving technologies. These findings may provide insight for the feasibility and planning of effective mobile app-based HIV/STI programs for MSM.
The genes
Phf5a and
Phf5b-ps are the first two members of a novel murine multigene family that is highly conserved during evolution and belongs to the superfamily of PHD-finger genes. The
Phf5 gene ...family contains an active locus on mouse chromosome 15, region E and several processed pseudogenes on different chromosomes. The active locus,
Phf5a, is expressed ubiquitously in pre- and postnatal murine tissues and encodes a protein of 110 amino acids. The protein is localized in the nucleus in a non-homogenous pattern as the nucleolar subcompartment is almost free of Phf5a. The molecular and biological functions of
Phf5a are unknown up-to-date, but the systematic deletion of its yeast homolog is lethal, pointing out that the protein is required for cell viability. Interpretation of our data and review of the literature suggest both basic and essential cellular functions of the Phf5a protein, possibly acting as a chromatin-associated protein.
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