152 research outputs found
5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine
Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging. We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3–4 toxicities in breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II–IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3–4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1–37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values < 0.86 or >2.10 ng/mL/106 cells/min) increased the risk of G3–4 adverse events (OR = 10.40 [95% IC: 1.48–7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate as a predictor of G3–4 toxicity occurrence (OR = 10.9 [95% IC 1.2–96.2], P = 0.03). The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity
Chiral properties of hematite ({\alpha}-Fe2O3) inferred from resonant Bragg diffraction using circularly polarized x-rays
Chiral properties of the two phases - collinear motif (below Morin transition
temperature, TM=250 K) and canted motif (above TM) - of magnetically ordered
hematite ({\alpha}-Fe2O3) have been identified in single crystal resonant x-ray
Bragg diffraction, using circular polarized incident x-rays tuned near the iron
K-edge. Magneto-electric multipoles, including an anapole, fully characterize
the high-temperature canted phase, whereas the low-temperature collinear phase
supports both parity-odd and parity-even multipoles that are time-odd. Orbital
angular momentum accompanies the collinear motif, while it is conspicuously
absent with the canted motif. Intensities have been successfully confronted
with analytic expressions derived from an atomic model fully compliant with
chemical and magnetic structures. Values of Fe atomic multipoles previously
derived from independent experimental data, are shown to be completely
trustworthy
Disentangling multipole resonances through a full x-ray polarization analysis
Complete polarization analysis applied to resonant x-ray scattering at the Cr
K-edge in K2CrO4 shows that incident linearly polarized x-rays can be converted
into circularly polarized x-rays by diffraction at the Cr pre-edge (E = 5994
eV). The physical mechanism behind this phenomenon is a subtle interference
effect between purely dipole (E1-E1) and purely quadrupole (E2-E2) transitions,
leading to a phase shift between the respective scattering amplitudes. This
effect may be exploited to disentangle two close-lying resonances that appear
as a single peak in a conventional energy scan, in this way allowing to single
out and identify the different multipole order parameters involved.Comment: 6 pages, 6 figure
On the role of intrinsic disorder in the structural phase transition of magnetoelectric EuTiO3
Up to now the crystallographic structure of the magnetoelectric perovskite
EuTiO3 was considered to remain cubic down to low temperature. Here we present
high resolution synchrotron X-ray powder diffraction data showing the existence
of a structural phase transition, from cubic Pm-3m to tetragonal I4/mcm,
involving TiO6 octahedra tilting, in analogy to the case of SrTiO3. The
temperature evolution of the tilting angle indicates a second-order phase
transition with an estimated Tc=235K. This critical temperature is well below
the recent anomaly reported by specific heat measurement at TA\sim282K. By
performing atomic pair distribution function analysis on diffraction data we
provide evidence of a mismatch between the local (short-range) and the average
crystallographic structures in this material. Below the estimated Tc, the
average model symmetry is fully compatible with the local environment
distortion but the former is characterized by a reduced value of the tilting
angle compared to the latter. At T=240K data show the presence of local
octahedra tilting identical to the low temperature one, while the average
crystallographic structure remains cubic. On this basis, we propose intrinsic
lattice disorder to be of fundamental importance in the understanding of EuTiO3
properties.Comment: 13 pages, 8 figures, 2 table
A new insight into MYC action: control of RNA polymerase II methylation and transcription termination
MYC oncoprotein deregulation is a common catastrophic event in human cancer and limiting its activity restrains tumor development and maintenance, as clearly shown via Omomyc, an MYC-interfering 90 amino acid mini-protein. MYC is a multifunctional transcription factor that regulates many aspects of transcription by RNA polymerase II (RNAPII), such as transcription activation, pause release, and elongation. MYC directly associates with Protein Arginine Methyltransferase 5 (PRMT5), a protein that methylates a variety of targets, including RNAPII at the arginine residue R1810 (R1810me2s), crucial for proper transcription termination and splicing of transcripts. Therefore, we asked whether MYC controls termination as well, by affecting R1810me2S. We show that MYC overexpression strongly increases R1810me2s, while Omomyc, an MYC shRNA, or a PRMT5 inhibitor and siRNA counteract this phenomenon. Omomyc also impairs Serine 2 phosphorylation in the RNAPII carboxyterminal domain, a modification that sustains transcription elongation. ChIP-seq experiments show that Omomyc replaces MYC and reshapes RNAPII distribution, increasing occupancy at promoter and termination sites. It is unclear how this may affect gene expression. Transcriptomic analysis shows that transcripts pivotal to key signaling pathways are both up- or down-regulated by Omomyc, whereas genes directly controlled by MYC and belonging to a specific signature are strongly down-regulated. Overall, our data point to an MYC/PRMT5/RNAPII axis that controls termination via RNAPII symmetrical dimethylation and contributes to rewiring the expression of genes altered by MYC overexpression in cancer cells. It remains to be clarified which role this may have in tumor development
Melting of chiral order in terbium manganate (TbMnO3) observed with resonant x-ray Bragg diffraction
Resonant Bragg diffraction of soft, circularly polarized x-rays has been used
to observe directly the temperature dependence of chiral-order melting in a
motif of Mn ions in terbium manganate. The underlying mechanism uses the b-axis
component of a cycloid, which vanishes outside the polar phase. Melting is
witnessed by the first and second harmonics of a cycloid, and we explain why
the observed temperature dependence is different in the two harmonics. Our
direct observation of melting is supported by a solid foundation of evidence,
derived from extensive studies of the azimuthal-angle dependence of intensities
with both linear and circular polarization
Standard of care and promising new agents for the treatment of mesenchymal triple-negative breast cancer
The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of expression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes involved in proliferation and an immune-suppressive microenvironment. Several molecular alterations along different pathways activated during carcinogenesis and tumor progression have been outlined and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mes-enchymal transition process could lead to the overcoming of immune-resistance. This paper reviews the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order to restore immunocompetence in mesenchymal breast cancer patients
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