8 research outputs found
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
Salvage Chemotherapy with Cisplatin, Ifosfamide, and Paclitaxel in Aggressive Variant of Metastatic Castration-Resistant Prostate Cancer
Significant progress has been achieved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, results in patients with aggressive variant prostate cancer (AVPC) have been disappointing. Here, we report retrospectively collected data from intensively pretreated AVPC patients (n = 17; 88.2% visceral metastases; 82% elevation of neuroendocrine markers) treated with salvage chemotherapy consisting of cisplatin, ifosfamide, and paclitaxel (TIP). At the interim analysis, 60% of patients showed radiographic response or stable disease (PFS = 2.5 months; OS = 6 months). In men who responded to chemotherapy, an OS > 15 months was observed. Preclinical analyses confirmed the high activity of the TIP regimen, especially in docetaxel-resistant prostate cancer cells. This effect was primarily mediated by increased cisplatin sensitivity in the emergence of taxane resistance. Proteomic and functional analyses identified a lower DNA repair capacity and cell cycle machinery deficiency to be causative. In contrast, paclitaxel showed inconsistent effects, partially antagonizing cisplatin and ifosfamide in some AVPC models. Consequently, paclitaxel has been excluded from the TIP combination for future patients. In summary, we report for the first time the promising efficacy of TIP as salvage therapy in AVPC. Our preclinical data indicate a pivotal role for cisplatin in overcoming docetaxel resistance
Study of Structure–Activity Relationships of the Marine Alkaloid Fascaplysin and Its Derivatives as Potent Anticancer Agents
Marine alkaloid fascaplysin and its derivatives are known to exhibit promising anticancer properties in vitro and in vivo. However, toxicity of these molecules to non-cancer cells was identified as a main limitation for their clinical use. Here, for the very first time, we synthesized a library of fascaplysin derivatives covering all possible substituent introduction sites, i.e., cycles A, C and E of the 12H-pyrido[1-2-a:3,4-b’]diindole system. Their selectivity towards human prostate cancer versus non-cancer cells, as well as the effects on cellular metabolism, membrane integrity, cell cycle progression, apoptosis induction and their ability to intercalate into DNA were investigated. A pronounced selectivity for cancer cells was observed for the family of di- and trisubstituted halogen derivatives (modification of cycles A and E), while a modification of cycle C resulted in a stronger activity in therapy-resistant PC-3 cells. Among others, 3,10-dibromofascaplysin exhibited the highest selectivity, presumably due to the cytostatic effects executed via the targeting of cellular metabolism. Moreover, an introduction of radical substituents at C-9, C-10 or C-10 plus C-3 resulted in a notable reduction in DNA intercalating activity and improved selectivity. Taken together, our research contributes to understanding the structure–activity relationships of fascaplysin alkaloids and defines further directions of the structural optimization
Rhizochalinin Exhibits Anticancer Activity and Synergizes with EGFR Inhibitors in Glioblastoma In Vitro Models
Rhizochalinin (Rhiz) is a recently
discovered cytotoxic
sphingolipid
synthesized from the marine natural compound rhizochalin. Previously,
Rhiz demonstrated high in vitro and in vivo efficacy in various cancer
models. Here, we report Rhiz to be highly active in human glioblastoma
cell lines as well as in patient-derived glioma-stem like neurosphere
models. Rhiz counteracted glioblastoma cell proliferation by inducing
apoptosis, G2/M-phase cell cycle arrest, and inhibition of autophagy.
Proteomic profiling followed by bioinformatic analysis suggested suppression
of the Akt pathway as one of the major biological effects of Rhiz.
Suppression of Akt as well as IGF-1R and MEK1/2 kinase was confirmed
in Rhiz-treated GBM cells. In addition, Rhiz pretreatment resulted
in a more pronounced inhibitory effect of γ-irradiation on the
growth of patient-derived glioma-spheres, an effect to which the Akt
inhibition may also contribute decisively. In contrast, EGFR upregulation,
observed in all GBM neurospheres under Rhiz treatment, was postulated
to be a possible sign of incipient resistance. In line with this,
combinational therapy with EGFR-targeted tyrosine kinase inhibitors
synergistically increased the efficacy of Rhiz resulting in dramatic
inhibition of GBM cell viability as well as a significant reduction
of neurosphere size in the case of combination with lapatinib. Preliminary
in vitro data generated using a parallel artificial membrane permeability
(PAMPA) assay suggested that Rhiz cannot cross the blood brain barrier
and therefore alternative drug delivery methods should be used in
the further in vivo studies. In conclusion, Rhiz is a promising new
candidate for the treatment of human glioblastoma, which should be
further developed in combination with EGFR inhibitors
Rhizochalinin Exhibits Anticancer Activity and Synergizes with EGFR Inhibitors in Glioblastoma In Vitro Models
Rhizochalinin (Rhiz) is a recently
discovered cytotoxic
sphingolipid
synthesized from the marine natural compound rhizochalin. Previously,
Rhiz demonstrated high in vitro and in vivo efficacy in various cancer
models. Here, we report Rhiz to be highly active in human glioblastoma
cell lines as well as in patient-derived glioma-stem like neurosphere
models. Rhiz counteracted glioblastoma cell proliferation by inducing
apoptosis, G2/M-phase cell cycle arrest, and inhibition of autophagy.
Proteomic profiling followed by bioinformatic analysis suggested suppression
of the Akt pathway as one of the major biological effects of Rhiz.
Suppression of Akt as well as IGF-1R and MEK1/2 kinase was confirmed
in Rhiz-treated GBM cells. In addition, Rhiz pretreatment resulted
in a more pronounced inhibitory effect of γ-irradiation on the
growth of patient-derived glioma-spheres, an effect to which the Akt
inhibition may also contribute decisively. In contrast, EGFR upregulation,
observed in all GBM neurospheres under Rhiz treatment, was postulated
to be a possible sign of incipient resistance. In line with this,
combinational therapy with EGFR-targeted tyrosine kinase inhibitors
synergistically increased the efficacy of Rhiz resulting in dramatic
inhibition of GBM cell viability as well as a significant reduction
of neurosphere size in the case of combination with lapatinib. Preliminary
in vitro data generated using a parallel artificial membrane permeability
(PAMPA) assay suggested that Rhiz cannot cross the blood brain barrier
and therefore alternative drug delivery methods should be used in
the further in vivo studies. In conclusion, Rhiz is a promising new
candidate for the treatment of human glioblastoma, which should be
further developed in combination with EGFR inhibitors
The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes
The male-specific region of the Y chromosome, the MSY, differentiates the sexes and comprises 95% of the chromosome's length. Here, we report that the MSY is a mosaic of heterochromatic sequences and three classes of euchromatic sequences: X-transposed, X-degenerate and ampliconic. These classes contain all 156 known transcription units, which include 78 protein-coding genes that collectively encode 27 distinct proteins. The X-transposed sequences exhibit 99% identity to the X chromosome. The X-degenerate sequences are remnants of ancient autosomes from which the modern X and Y chromosomes evolved. The ampliconic class includes large regions (about 30% of the MSY euchromatin) where sequence pairs show greater than 99.9% identity, which is maintained by frequent gene conversion (non-reciprocal transfer). The most prominent features here are eight massive palindromes, at least six of which contain testis gene