Epigenetic modifications play a key role in the patho-physiology of many tumors and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. ...DNA methyltransferase (DNMT) inhibitors represent a promising class of epigenetic modulators. Research performed yielded promising anti-tumorigenic activity for these agents in vitro and in vivo against a variety of hematologic and solid tumors. These epigenetic modulators cause cell cycle and growth arrest, differentiation and apoptosis. Rationale for combining these agents with cytotoxic therapy or radiation is straightforward since the use of DNMT inhibitor offers greatly improved access for cytotoxic agents or radiation for targeting DNA-protein complex. The positive results obtained with these combined approaches in preclinical cancer models demonstrate the potential impact DNMT inhibitors may have in treatments of different cancer types. Therefore, as the emerging interest in use of DNMT inhibitors as a potential chemo- or radiation sensitizers is constantly increasing, further clinical investigations are inevitable in order to finalize and confirm the consistency of current observations.The present article will provide a brief review of the biological significance and rationale for the clinical potential of DNMT inhibitors in combination with other chemotherapeutics or ionizing radiation. The molecular basis and mechanisms of action for these combined treatments will be discussed herein.
El presente artículo es un ejercicio de aproximación al estudio del texto poético desde la teoría queer. El universo de análisis se centra en la poesía lesbiana cuir contemporánea organizada por la ...Justa Poética, slam de poesía oral en la Ciudad Autónoma de Buenos Aires, Argentina. El artículo fue desarrollado a través de una investigación que parte de las teorías feministas y queer como herramientas teóricas para investigar la construcción de la subjetividad en el texto poético, entendiéndolo como una tecnología de género. El corpus analizado abre un vasto camino para pensar la construcción de una subjetividad lesbiana cuir en la poesía contemporánea, que se aleja del devenir mujer normativo y rompe con categorías del binarismo sexo-genérico varón/mujer, así como con ciertos discursos jerárquicos de normalización del cuerpo lesbiano.
We reported previously that the disruption of c-Myc through mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibition blocks the expression of the ...transformed phenotype in the embryonal rhabdomyosarcoma (ERMS) cell line (RD), thereby inducing myogenic differentiation in vitro. In this article, we investigate whether MEK/ERK inhibition, by the MEK/ERK inhibitor U0126, affects c-Myc protein level and growth of RMS tumor in an in vivo xenograft model. U0126 significantly reduced RMS tumor growth in RD cell line-xenotransplanted mice. Immunobiochemical and immunohistochemical analysis showed (a) phospho-active ERK levels were reduced by U0126 therapy and unaltered in normal tissues, (b) phospho-Myc and c-Myc was reduced commensurate with phospho-ERK inhibition, and (c) reduction in Ki-67 and endothelial (CD31) marker expression. These results indicate that MEK/ERK inhibition affects growth and angiogenic signals in tumor. The RD-M1 cultured xenograft tumor-derived cell line and the ERMS cell line TE671 responded to U0126 by arresting growth, down-regulating c-Myc, and initiating myogenesis. All these results suggest a tight correlation of MEK/ERK inhibition with c-Myc down-regulation and arrest of tumor growth. Thus, MEK inhibitors may be investigated for a signal transduction-based targeting of the c-Myc as a therapeutic strategy in ERMS.
Abstract
Food security during the Covid-19 pandemic is a condition in which all Bajo households have access to food both physically and economically for all their family members so that they are not ...at risk of losing both access during the Covid-19 pandemic. This study aims to determine the household food security of the Bajo community in the West Muna Regency during the Covid 19 pandemic. This research was carried out in March-May 2020 in Latawe Village, Napano Kusambi District, West Muna Regency. The research location was selected purposively considering that the village is a coastal village where most of the population living is Bajo people who work as fishermen as many as 180 families. Many as 64 families determined the number of research samples using the Slovin formula and sampling using a simple random sampling technique. Data analysis was carried out using a descriptive method to measure the food security of Bajo households during the Covid 19 pandemic, which was estimated using the share of food spending where if the percentage of food spending was <60% of total spending, the household was food-secure and if the share of food spending was 60% of total expenditures, are households that are food insecure. The results show that 46.88% of Bajo households are food secure, and 53.12% are food insecure.
The growth and mortality rates of Myctophum affine larvae were analysed based on samples collected during the austral summer and winter of 2002 from south‐eastern Brazilian waters. The larvae ranged ...in size from 2·75 to 14·00 mm standard length (LS). Daily increment counts from 82 sagittal otoliths showed that the age of M. affine ranged from 2 to 28 days. Three models were applied to estimate the growth rate: linear regression, exponential model and Laird–Gompertz model. The exponential model best fitted the data, and L0 values from exponential and Laird–Gompertz models were close to the smallest larva reported in the literature (c. 2·5 mm LS). The average growth rate (0·33 mm day−1) was intermediate among lanternfishes. The mortality rate (12%) during the larval period was below average compared with other marine fish species but similar to some epipelagic fishes that occur in the area.
Expression of c-myc proto-oncogene is inappropriate in a wide range of human tumors, and is a downstream target of Ras/Raf/ERK pathway, which promotes c-Myc stability by enhancing c-Myc expression ...and activity. The aim of this study was to investigate whether the oncogenic phenotype in the human muscle-derived Rhabdomyosarcoma (RD) cell line and in non muscle-derived human tumor cell lines (SW403, IGR39 and PC3) can be blocked by disrupting the c-Myc pathway either by means of pharmacological MEK/ERK inhibition or by direct inactivation of the c-Myc protein.
We demonstrate that, in all the tumor cell lines used, the MEK/ERK inhibitor U0126 rapidly induces c-Myc de-phosphorylation, which is followed by a marked reduction in its expression level, by inhibition of proliferation and by reversion of anchorage-independent growth. These data suggest that the targeting of pathways controlling c-Myc expression or stability reverses deregulated growth of different tumor-derived cell lines. Indeed, in RD cells, we found a marked down-regulation of cyclins E2, A and B and CDK2, all of which are known to be targets of c-Myc. Moreover, ectopic MadMyc chimera, a c-Myc function antagonist, causes dramatic growth arrest, CDK and cyclin modulation as well as inhibition of anchorage-independent growth in RD cells, as occurs in U0126-treated cells. In particular, we found that the mere inhibition of c-Myc by MadMyc chimera rescues the myogenic program, MHC expression and the acquisition of the myogenic-like phenotype in RD cells.
Our data provide evidence of the key role played by the MEK/ERK pathway in the growth arrest and transformation phenotype of Rhabdomyosarcoma and of non muscle-derived tumor cell lines. In fact, MEK/ERK inhibitor, U0126, induces growth arrest, anchorage-dependent growth of these cell lines. In addition, the results of this study demonstrate that the direct inactivation of c-Myc by Mad/Myc chimera rescues myogenic program and leads to the reversal of the Rhabdomyosarcoma phenotype. In conclusion these data strongly suggest that the targeting of c-Myc by means of the MEK inhibitor can be tested as a promising strategy in anti-cancer therapy.
Decomposition of Additive Random Fields Zani, M.; Khartov, A. A.
Vestnik, St. Petersburg University. Mathematics,
2020/1, Letnik:
53, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We consider in this work an additive random field on 0, 1
d
, which is a sum of
d
uncorrelated random processes. We assume that the processes have zero mean and the same continuous covariance ...function. There is a significant interest in the study of random fields of this type. For example, they arise in the theory of intersections and self-intersections of Brownian processes, in the problems concerning small ball probabilities, and in the finite-rank approximation problems with arbitrarily large parametric dimension
d
. In problems of the last kind, the spectral characteristics of the covariance operator play a key role. For a given additive random field, the dependence of eigenvalues of its covariance operator on eigenvalues of the covariance operator of the marginal processes is quite simple, provided that the identical 1 is an eigenvector of the latter operator. In the opposite case, the dependence is complex, and, therefore, it is hard to study these random fields. Here, summands of the decomposition of the random field into the sum of its integral and its centered version are orthogonal in
L
2
(0, 1
d
), but, in general, they are correlated. In the present paper, we propose another interesting decomposition for random fields (it was discovered by the authors while resolving finite-rank approximation problems in the average-case setting). In the obtained decomposition, the summands are orthogonal in
L
2
(0, 1
d
) and are uncorrelated. Moreover, for large
d
, they are respectively close to the integral and to the centered version of the random field with small relative mean square errors.
We have investigated the electron spin diffusion length at room temperature in bulk n-doped germanium as a function of the doping concentration. To this purpose, we exploit a nonlocal spin ...injection/detection scheme where spins are optically injected at the direct gap of Ge and electrically detected by means of the inverse spin-Hall effect (ISHE). By optically generating a spin population in the conduction band of the semiconductor at different distances from the spin detector, we are able to directly determine the electron spin diffusion length Ls in the Ge substrate. We experimentally observe that Ls > 20 μm for lightly doped samples and, by taking into account the electron diffusion coefficient, we estimate electron spin lifetime values τs larger than 50 ns. In contrast, for heavily doped Ge substrates, the spin diffusion length decreases to a few micrometers, corresponding to τs ≈ 20 ns. These results can be exploited to refine spin transport models in germanium and reduce the experimental uncertainties associated with the evaluation of Ls from other spin injection/detection techniques.
Aim of the present study was to evaluate the accuracy which can be obtained with helical TomoTherapy
(HT, Accuray) systems in the case of multiple intracranial targets treatments. Set-up accuracy was ...measured, for different registration options and MegaVoltage CT (MVCT) slice thickness, by applying known misalignments to an ad-hoc developed phantom. End-to-end (E2E) tests were performed to assess the delivery accuracy in phantoms containing multiple targets by using radiochromic films: measured dose distribution centroids were compared with physical and calculated target positions on axial and coronal planes. A Gamma index analysis was carried out on planned and measured planar dose maps. The bone and tissue algorithm with the fine MVCT reconstruction grid gave the best results among the automatic options. The most accurate registration modality resulted to be the manual one with a sub-voxel accuracy shifts and a capability in the detection of rotations within 0.3°. For the E2E along the coronal plane (six targets), a mean deviation between measured dose distribution centroids and physical barycenters of 0.6 mm (range 0.1 mm-1.3 mm) was observed. Along the axial plane (five targets), a mean deviation of 1.2 mm (range 0.7 mm-2.1 mm) was found for the centroids shifts. Gamma index (5%, 1 mm, local) passing rates higher than 87.5% between planned and delivered dose distributions were measured. These results demonstrate that multiple brain lesion HT treatments are feasible with an accuracy at least comparable to frameless linac-based delivery, when a set-up capable to assure angular corrections and a reliable patient immobilization is employed.
We hypothesized that hormonal therapy favors the development of the hormone-resistant phenotype through epigenetic mechanisms. Human prostate cancer tissues and in vitro and in vivo models were used ...to verify this hypothesis. We demonstrated that tumor cells continuously treated with bicalutamide (BCLT) or cultured in androgen-depleted medium progressively acquire higher DNA methyltransferase (DNMT) activity and expression than cells cultured in standard condition. Increased DNMT expression and activity also paralleled the up-regulation of truncated AR isoforms, which favors the development of the hormone-resistant phenotype. After androgen stimulation with 10−12 m dihydrotestosterone, DNMT activity was significantly reduced in comparison with hormonal therapy. Consistent with these observations, the silencing of DNMT3a and DNMT3b significantly decreased the DNMT activity levels. These findings were also directly correlated with phosphatase and tensin homolog down-regulation and activation of ERK and phosphatidylinositol 3-kinases/AKT8 virus oncogene cellular homolog pathways. The use of a pan-DNMT inhibitor (5-Azacitidine) greatly reduced the development of the hormone-resistant phenotype induced by long-term BCLT treatment, and this finding correlated with low DNMT activity. The regulation of DNMT activity was, in some measure, dependent on the androgen receptor, as small interfering RNA treatment targeting the androgen receptor greatly decreased the modulation of DNMT activity under androgenic and antiandrogenic stimulation. These observations were correlated in vivo in patients, as demonstrated by immunohistochemistry. Patients treated by BCLT before surgery had higher DNMT3a and DNMT3b expression than patients who had not undergone this treatment. Our findings provide evidence of a relationship between the castration-resistant phenotype and DNMT expression and activity in human prostate cancer.
PDF
