Therapeutic challenges in quadruple negative breast cancer

Recently, breast cancer (BC) continuously ranks first in the incidence rate of malignant neoplasms in womenworldwide. Quadruple negative BC (QNBC) is a recently identified subtype of triple negative BC (TNBC) presenting with negative androgen receptor expression. QNBC characterization and treatment is fraught with many challenges.There is cumulative evidence suggestingthat QNBC ishighly proliferative and immunogenic, rendering it anideal candidate for cytotoxic chemotherapy and immunotherapy. Several chemotherapeutic agents such as imatinib, cabozantinib, dasatinib, lucitanib,sunitinib, docetaxel, doxorubicin, and cyclophosphamidein QNBCpatients are highlighted. Some subtypes and related pathway proteins are preferentially expressed in QNBC and may act as effective therapeutic targets such as acyl-CoA synthetase4, S-phase kinase associated protein 2, immune checkpoint inhibitors, kinesin family member C1,and epidermal growth factor receptor. Several recent investigations comparing the therapeutic approach to QNBC and TNBC are briefly reviewed. Further more intensive and problem-oriented research in this topic of rising socio-medical importance is needed

The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence.

YTHDF2 binds and destabilizes N6-methyladenosine (m6A)-modified mRNA. The extent to which this branch of m6A RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of m6A in these upregulated genes. In summary, the m6A-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development

A Review on Antitumor and Antiviral Potential of Cranberries (Vaccinium Vitis-Idaea) Origin from Bulgaria

A major goal in antitumor and antiviral therapy is to find active ingredients that selectively suppress the proliferation of tumor cells or inhibit viral replication and proliferation. In this connection, the antitumor and antiviral activity of natural products with proven phytochemical properties and pharmacological significance are actively investigated. A promising candidate are Bulgarian cranberries from high mountain plant populations, which are a valuable natural source of food and have proven healing properties in urinary tract infections, eye diseases and cardiovascular disorders, as well as prevention of hypertension and diabetes. The active components of Vaccinium vitis-idaea L. are polyphenols and anthocyanins which belong to classes of plant components with high antioxidant, antimicrobial, cytotoxic and antiproliferative activity. Cranberries contain a high percentage and variety of vitamins (A,  E, C,  etc.) and a number of minerals (K, Ca, Mg, P, Na). In the world regions where endemic measles outbreaks occur, for secondary prevention and avoidance of complications including blindness, WHO recommends the use of high doses of vitamin A in children under 5 years of age. Bulgarian cranberries are a valuable source of vitamins A and C.The assessement of biological activity of the individual components and fractions in the composition of the Bulgarian cranberries may help to identify substances with antitumor and/or antiviral activity that could potentially be useful in future development of new therapeutic agents

Vaccinium Vitis-Idaea L., Origin from Bulgaria Indicate in Vitro Antitumor Еffect on Human Cervical and Breast Cancer Cells

Cancer is a socially significant disease. Along with efforts to understand the complex genetic/epigenetic factors that trigger a carcinogenesis, it is also necessary to analyze the potential natural active substances that may delay or even stop neoplastic transformation. Promising candidates are Bulgarian cranberries from high mountain plant populations, which are rich in phenolics and anthocyanins and have proven beneficial effects on human body.The present study aims to evaluate in vitro, antitumor activities of total extracts and purified nonanthocyanin and anthocyanins fractions of Vaccinium vitis-idaea L., picked in Bulgaria on human cervical (HeLa) and breast (MCF7) cancer cell lines, as well as to examine some of the apoptotic mechanisms underlying them.Materials and methods: Four methanol extracts and respective number of purified B- nonanthocyanin / C- anthocyanins fractions of Bulgarian lingonberry were used. Antitumor effect was established by Trypan Blue method, monitoring of morphological changes and МТТ cell viability assay. Assessment of apoptotic activity was performed using DNA fragmentation method.Results: The results from МТТ analyses showed that B- nonanthocyanin fractions of Bulgarian lingonberry have well expressed inhibitory effect on survival of tested tumor cells. The observed effect dependent of the dose administered and were stronger in relation with the high-mountain populations and HeLa cell line. The integrity of the extracted DNA from treated survival cells indicates possible apoptosis mechanisms under the action of biologically active ingredients from lingonberries.Conclusion: Survey of antitumor activities of Bulgarian lingonberries based on molecular methods, could contribute to establish the natural substances useful for human health in general and practical oncology

NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells

Summary: Spermatogonial stem cells (SSCs) sustain spermatogenesis and fertility throughout adult male life. The conserved RNA-binding protein NANOS2 is essential for the maintenance of SSCs, but its targets and mechanisms of function are not fully understood. Here, we generated a fully functional epitope-tagged Nanos2 mouse allele and applied the highly stringent cross-linking and analysis of cDNAs to define NANOS2 RNA occupancy in SSC lines. NANOS2 recognizes the AUKAAWU consensus motif, mostly found in the 3′ untranslated region of defined messenger RNAs (mRNAs). We find that NANOS2 is a regulator of key signaling and metabolic pathways whose dosage or activity are known to be critical for SSC maintenance. NANOS2 interacts with components of CCR4-NOT deadenylase complex in SSC lines, and consequently, NANOS2 binding reduces the half-lives of target transcripts. In summary, NANOS2 contributes to SSC maintenance through the regulation of target mRNA stability and key self-renewal pathways

Cd(II) and Pb(II) complexes of the polyether ionophorous antibiotic salinomycin

<p>Abstract</p> <p>Background</p> <p>The natural polyether ionophorous antibiotics are used for the treatment of coccidiosis in poultry and ruminants. They are effective agents against infections caused by Gram-positive microorganisms. On the other hand, it was found that some of these compounds selectively bind lead(II) ions in <it>in vivo </it>experiments, despite so far no Pb(II)-containing compounds of defined composition have been isolated and characterized. To assess the potential of polyether ionophores as possible antidotes in the agriculture, a detailed study on their <it>in vitro </it>complexation with toxic metal ions is required. In the present paper we report for the first time the preparation and the structure elucidation of salinomycin complexes with ions of cadmium(II) and lead(II).</p> <p>Results</p> <p>New metal(II) complexes of the polyether ionophorous antibiotic salinomycin with Cd(II) and Pb(II) ions were prepared and structurally characterized by IR, FAB-MS and NMR techniques. The spectroscopic information and elemental analysis data reveal that sodium salinomycin (SalNa) undergoes a reaction with heavy metal(II) ions to form [Cd(Sal)₂(H₂O)₂] (<b>1</b>) and [Pb(Sal)(NO₃)] (<b>2</b>), respectively. Abstraction of sodium ions from the cavity of the antibiotic is occurring during the complexation reaction. Salinomycin coordinates with cadmium(II) ions as a bidentate monoanionic ligand through the deprotonated carboxylic moiety and one of the hydroxyl groups to yield <b>1</b>. Two salinomycin anions occupy the equatorial plane of the Cd(II) center, while two water molecules take the axial positions of the inner coordination sphere of the metal(II) cation. Complex <b>2 </b>consists of monoanionic salinomycin acting in polydentate coordination mode in a molar ratio of 1: 1 to the metal ion with one nitrate ion for charge compensation.</p> <p>Conclusion</p> <p>The formation of the salinomycin heavy metal(II) complexes indicates a possible antidote activity of the ligand in case of chronic/acute intoxications likely to occur in the stock farming.</p

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance

Defective germline reprogramming rewires the spermatogonial transcriptome.

Defective germline reprogramming in Piwil4 (Miwi2)- and Dnmt3l-deficient mice results in the failure to reestablish transposon silencing, meiotic arrest and progressive loss of spermatogonia. Here we sought to understand the molecular basis for this spermatogonial dysfunction. Through a combination of imaging, conditional genetics and transcriptome analysis, we demonstrate that germ cell elimination in the respective mutants arises as a result of defective de novo genome methylation during reprogramming rather than because of a function for the respective factors within spermatogonia. In both Miwi2-/- and Dnmt3l-/- spermatogonia, the intracisternal-A particle (IAP) family of endogenous retroviruses is derepressed, but, in contrast to meiotic cells, DNA damage is not observed. Instead, we find that unmethylated IAP promoters rewire the spermatogonial transcriptome by driving expression of neighboring genes. Finally, spermatogonial numbers, proliferation and differentiation are altered in Miwi2-/- and Dnmt3l-/- mice. In summary, defective reprogramming deregulates the spermatogonial transcriptome and may underlie spermatogonial dysfunction