BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation

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Early human dispersal at the western edge of the Eastern European plain: Data from Ukraine

The current state of research on Lower Palaeolithic sites in Ukraine within its 1991 borders is the focus of this paper. Over the last 10–15 years, many new sites have been discovered in different parts of the eastern European area of the country, reassessed some old materials. In the central European region of the country, in the Ukrainian Transcarpathia, important new stratified Lower Palaeolithic sites have also been found. The current Ukrainian Lower Palaeolithic records demonstrate hominin presence in mountainous areas (Carpathians, Crimea) and the valleys of all major rivers, namely the Dniester, Southern Buh, Dnieper and Severskiy Donets. The article presents a brief review of the main currently known Lower Palaeolithic assemblages. Available geological, geomorphological, biostratigraphical data and ESR dates allow defining their age between 1.2 and 0.4 Myг; sites correlate with few warm phases between MIS 35 and MIS 11. Earlier sites, very tentatively dated at around 2 Myг, gravitate towards the seashore and mountainous areas. Later sites witness steady, though not continuous, colonisation of East European plain fringe areas. The main regularities of geographical setting, chronology, morphological and technological characteristics of assemblages of the Lower Palaeolithic sites of the Western segment of the East European plain are characterised. Typologically, industries are mainly characterised as belonging to Mode I. Core-and-flake industries survives to the Holsteinian. Essential difficulties in lithic raw materials supply could probably be a reason for the rise of a peculiar pattern of technological behaviour that involved mainly bipolar knapping and widely applied trimming technique of shaping the working edges of tools. Some signals of probable population movements penetrated the territory of Ukraine by the Asia Minor “western” trajectory and by Caucasian “eastern” way are revealed.     

Cystine-knot peptides: emerging tools for cancer imaging and therapy

Cystine-knot miniproteins, also known as knottins, constitute a large family of structurally related peptides with diverse amino acid sequences and biological functions. Knottins have emerged as attractive candidates for drug development as they potentially fill a niche between small molecules and protein biologics, offering drug-like properties and the ability to bind to clinical targets with high affinity and selectivity. Due to their extremely high stability and unique structural features, knottins also demonstrate promise in addressing challenging drug development goals, including the potential for oral delivery and the ability to access intracellular drug targets. Several naturally-occurring knottins have recently received approval for treating chronic pain and irritable bowel syndrome, while others are under development for tumor imaging applications. To expand beyond nature’s repertoire, rational and combinatorial protein engineering methods are generating tumor-targeting knottins for use as cancer diagnostics and therapeutics.     

INHIBITION OF EHRLICH TUMOR GROWTH IN MICE BY ELECTRIC INTERFERENCE THERAPY (IN VIVO STUDIES)

A study of solid tumor growth retardation by employing extremely low frequency (ELF) electric fields has been carried out. ELF electric fields were generated in tumor tissue in mice by the interference of two high frequency sinusoidal waves with the beat frequency centered at the tumor core. The results indicated a pronounced decrease in tumor growth rate in animals exposed to a 5-Hz interferential frequency for 1 hr daily. The 1 hr/day treatment produced a greater retardation effect than the 1 hr/week treatment. This indicates that treatment duration at the applied field frequency appears to play an important role in tumor growth delay. The dielectric properties of the tumor cells showed higher permittivity and conductivity values than homologous normal tissue. The permittivity of tumor cells treated daily with 5 Hz reaches nearly the same value as control tissue. Moreover, histological studies show that tumor tissues treated daily with the same frequency undergo partial regression and shrinkage of the aggregates of neoplastic cells leaving very little of them. We conclude that this new interferential technique is promising for tumor treatment in which a resonating electric field affects cell-to-cell communication.     

Development of a human three-dimensional organotypic skin-melanoma spheroid model for in vitro drug testing

Despite remarkable efforts, metastatic melanoma (MM) still presents with significant mortality. Recently, mono-chemotherapies are increasingly replenished by more cancer-specific combination therapies involving death ligands and drugs interfering with cell signaling. Still, MM remains a fatal disease because tumors rapidly develop resistance to novel therapies thereby regaining tumorigenic capacity. Although genetically engineered mouse models for MM have been developed, at present no model is available that reliably mimics the human disease and is suitable for studying mechanisms of therapeutic obstacles including cell death resistance. To improve the increasing requests on new therapeutic alternatives, reliable human screening models are demanded that translate the findings from basic cellular research into clinical applications. By developing an organotypic full skin equivalent, harboring melanoma tumor spheroids of defined sizes we have invented a cell-based model that recapitulates both the 3D organization and multicellular complexity of an organ/tumor in vivo but at the same time accommodates systematic experimental intervention. By extending our previous findings on melanoma cell sensitization toward TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) by co-application of sublethal doses of ultraviolet-B radiation (UVB) or cisplatin, we show significant differences in the therapeutical outcome to exist between regular two-dimensional (2D) and complex in vivo-like 3D models. Of note, while both treatment combinations killed the same cancer cell lines in 2D culture, skin equivalent-embedded melanoma spheroids are potently killed by TRAIL+cisplatin treatment but remain almost unaffected by the TRAIL+UVB combination. Consequently, we have established an organotypic human skin-melanoma model that will facilitate efforts to improve therapeutic outcomes for malignant melanoma by providing a platform for the investigation of cytotoxic treatments and tailored therapies in a more physiological setting.     

Skp-cullin-F box E3 ligase component FBXL2 ubiquitinates Aurora B to inhibit tumorigenesis

Aurora B kinase is an integral regulator of cytokinesis, as it stabilizes the intercellular canal within the midbody to ensure proper chromosomal segregation during cell division. Here we identified that the ubiquitin E3 ligase complex SCF^FBXL2 mediates Aurora B ubiquitination and degradation within the midbody, which is sufficient to induce mitotic arrest and apoptosis. Three molecular acceptor sites (K¹⁰², K¹⁰³ and K²⁰⁷) within Aurora B protein were identified as important sites for its ubiquitination. A triple Lys mutant of Aurora B (K¹⁰²/¹⁰³/^207R) exhibited optimal resistance to SCF^FBXL2-directed polyubiquitination, and overexpression of this variant resulted in a significant delay in anaphase onset, resulting in apoptosis. A unique small molecule F-box/LRR-repeat protein 2 (FBXL2) activator, BC-1258, stabilized and increased levels of FBXL2 protein that promoted Aurora B degradation, resulting in tetraploidy, mitotic arrest and apoptosis of tumorigenic cells, and profoundly inhibiting tumor formation in athymic nude mice. These findings uncover a new proteolytic mechanism targeting a key regulator of cell replication that may serve as a basis for chemotherapeutic intervention in neoplasia.     

Transforming growth factors (TGFs): Properties and possible mechanisms of action

Transforming growth factors (TGFs) are growth-promoting polypeptides that cause phenotypic transformation and anchorage-independent growth of normal cells. They have been isolated from several human and animal carcinoma and sarcoma cells. One TGF is sarcoma growth factor (SGF) which is released hy murine sarcoma virus-transformed cells. The TGFs interact with epidermal growth factor (EGF) cell membrane receptors. TGFs are not detectable in culture fluids from cells which contain high numbers of free EGF cell membrane receptors. SGF acts as a tumor promoter in cell culture systems and its effect on the transformed phenotype is blocked by retinoids (vitamin A and synthetic analogs). The production of TGFs by transformed cells and the responses of normal cells to the addition of TGFs to the culture medium raise the possibility that cells “autostimulate” their own growth by releasing factors that rebind at the cell surface. The term “autocrine secretion” has been proposed for this type of situation where a cell secretes a hormone-like substance for which it has external cell membrane receptors. The autocrine concept may provide a partial explanation for some aspects of tumor cell progression.     

Anti‐Tumor‐Initiating Effects of Spiro‐biflavonoids from Abies sachalinensis

Cancer chemoprevention, the prevention of cancer by ingestion of chemical agents that reduce the risk of carcinogenesis, is one of the potent ways to reduce morbidity and mortality. We have been searching for cancer chemopreventive agents from the leaves and barks of coniferous trees that have been treated as waste in the forestry industry. We have previously reported the isolation of spiro‐biflavonoids, named as abiesinols, and a neolignan from the MeOH extract of the bark of Abies sachalinensis. These compounds were tested for their inhibitory effects on the activation of (±)‐(E)‐methyl‐2‐[(E)‐hydroxyimino]‐5‐nitro‐6‐methoxyhex‐3‐enamide (NOR 1), a nitric oxide (NO) donor, as a primary screening test for anti‐tumor initiators. All compounds tested exhibited potent inhibitory effects on NOR 1 activation. Furthermore, abiesinol A, bearing a spiro‐biflavonoid skeleton, showed remarkable anti‐tumor‐initiating activity in the in vivo two‐stage mouse skin carcinogenesis test using peroxynitrite (ONOO^?; PN) as the initiator and 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) as the promoter.     

Synthesis of diethylamino-curcumin mimics with substituted triazolyl groups and their sensitization effect of TRAIL against brain cancer cells

A newly designed curcumin mimic library (11a–11k) with 2-ethylamino groups in a chalcone structure and variously substituted triazole groups as side chains was synthesized using the Huisgen 1,3-cycloaddition reaction between various alkynes (a–k) and an intermediate (10), with CuSO₄ and sodium ascorbate in a solution mixture of chloroform, ethanol, and water (5:3:1) at room temperature for 5 h. In the lactate dehydrogenase (LDH) release assay involving co-treatment with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and/or synthetic curcumin derivatives using TRAIL-resistant human CRT-MG astroglioma cells, the novel curcumin mimic library was found to effectively stimulate the cytotoxicity of TRAIL, causing mild cytotoxicity when administered alone. In particular, 11a and 11j are promising candidates for TRAIL-sensitizers with potential use in combination chemotherapy for brain tumors.     

NK cells: An attractive candidate for cancer therapy

Natural killer (NK) cells have significant capability in tumor immune-surveillance. The ability of lyse transformed cells immediately in an antigen-independent manner make them an attractive candidate for cancer cell therapy. Despite employment of NK cells in cancer immunotherapy, clinical trials are faced with serious limitations such as trouble with the penetration of NK cells in tumor sites, limited in vivo persistence, and tumor microenvironment interference. Taken together, the NK-cell cancer therapy is still infant scenario that has a long way to be translated in clinic. Current article first reviews characteristic features of NK lymphocytes. Then, it discusses about important disruptive barriers and motivator in the developmental stages of NK cells like as tumor microenvironment. Finally, some revolutionary approaches are highlighted utilizing of NK cells in cancer therapy.