Concordance of c-kit mutational status in matched primary and metastatic cutaneous canine mast cell tumors at baseline

BackgroundMutation analysis of proto-oncogene c-kit (c-kit) is advisable before starting treatment with tyrosine kinase inhibitors in dogs with mast cell tumor (MCT), including those with metastatic disease. Testing is usually performed on primary tumors, assuming that c-kit mutation status does not change in metastasis.Hypothesis/ObjectivesTo give an insight into the mutational processes and to make a recommendation on the use of c-kit mutational analysis in the clinical setting.AnimalsTwenty-one client-owned dogs with metastatic MCT.MethodsDogs undergoing resection or biopsy for both primary and matched metastatic MCT were prospectively enrolled. Total RNA or DNA was extracted from primary MCT and corresponding metastases. Exons 8, 9, and 11 were amplified by PCR and sequenced. Genetic features between primary MCT and metastases were compared. Their correlation with clinicopathologic features was investigated.ResultsConcordance (mutated or wild-type) of mutational status, evaluable in 21 primary and matched metastatic (20 nodal and 1 splenic) MCTs, was 100%. Three new c-kit mutations were identified. No significant correlation was detected between c-kit mutation and clinicopathologic features.Conclusions and Clinical ImportanceProto-oncogene c-kit mutational status is conserved between any primary and its matched secondary tumor, suggesting that both can be used for c-kit mutational testing. Targeted therapies might be also used to treat metastatic disease

Supersymmetric gyratons in five dimensions

We obtain the gravitational and electromagnetic field of a spinning radiation beam-pulse (a gyraton) in minimal five-dimensional gauged supergravity and show under which conditions the solution preserves part of the supersymmetry. The configurations represent generalizations of Lobatchevski waves on AdS with nonzero angular momentum, and possess a Siklos-Virasoro reparametrization invariance. We compute the holographic stress-energy tensor of the solutions and show that it transforms without anomaly under these reparametrizations. Furthermore, we present supersymmetric gyratons both in gauged and ungauged five-dimensional supergravity coupled to an arbitrary number of vector supermultiplets, which include gyratons on domain walls.Comment: 25 pages, no figures, uses JHEP3.cls. Final version to appear in CQ

Biological effects of EF24, a curcumin derivative, alone or combined with mitotane in adrenocortical tumor cell lines

Background: Curcumin has numerous properties and is used in many preclinical conditions, including cancer. It has low bioavailability, while its derivative EF24 shows enhanced solubility. However, its effects have never been explored in adrenocortical tumor cell models. The efficacy of EF24 alone or combined with mitotane (reference drug for adrenocortical cancer) was evaluated in two adrenocortical tumor cell lines, SW13 and H295R. Method and Results: EF24 reduced cell viability with an IC50 (half maximal inhibitory concentration) of 6.5 \ub1 2.4 \ub5M and 4.9 \ub1 2.8 \ub5M for SW13 and H295R cells, respectively. Combination index (EF24 associated with mitotane) suggested an additivity effect in both cell lines. Cell cycle analysis revealed an increase in subG0/G1 phase, while motility assay showed a decrease in migratory cell capacity, and similarly, clonogenic assay indicated that EF24 could reduce colony numbers. Furthermore, Wnt/\u3b2-catenin, NF-\u3baB, MAPK, and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with EF24 alone or combined with mitotane. In addition, intracellular reactive oxygen species levels increased in both cell lines. Conclusion: This work analyzed EF24 in adrenocortical tumor cell lines for the first time. These results suggest that EF24 could potentially impact on adrenocortical tumors, laying the foundation for further research in animal models

The transcriptional regulator ZNF398 mediates pluripotency and epithelial character downstream of TGF-beta in human PSCs

Human pluripotent stem cells (hPSCs) have the capacity to give rise to all differentiated cells of the adult. TGF-beta is used routinely for expansion of conventional hPSCs as flat epithelial colonies expressing the transcription factors POU5F1/OCT4, NANOG, SOX2. Here we report a global analysis of the transcriptional programme controlled by TGF-beta followed by an unbiased gain-of-function screening in multiple hPSC lines to identify factors mediating TGF-beta activity. We identify a quartet of transcriptional regulators promoting hPSC self-renewal including ZNF398, a human-specific mediator of pluripotency and epithelial character in hPSCs. Mechanistically, ZNF398 binds active promoters and enhancers together with SMAD3 and the histone acetyltransferase EP300, enabling transcription of TGF-beta targets. In the context of somatic cell reprogramming, inhibition of ZNF398 abolishes activation of pluripotency and epithelial genes and colony formation. Our findings have clear implications for the generation of bona fide hPSCs for regenerative medicine

Anticancer Effects of Wild Mountain Mentha longifolia Extract in Adrenocortical Tumor Cell Models

Mint [Mentha longifolia (L.) Hudson] is an aromatic plant that belongs to Lamiaceae family. It is traditionally used as herbal tea in Europe, Australia and North Africa and shows numerous pharmacological effects, such as spasmolytic, antioxidant, antimicrobial and anti-hemolytic. Recently, its antiproliferative role has been suggested in a small number of tumor cell models, but no data are available on adrenocortical carcinoma, a malignancy with a survival rate at 5 years of 20%\u201330% which frequently metastasize. This work aimed to study the effects of Mentha longifolia L. crude extract (ME) on two adrenocortical tumor cell models (H295R and SW13 cells). Chemical composition of ME was assessed by gas-chromatography/mass spectrometry and NMR spectroscopy analysis. Brine shrimp lethality assay showed ME effects at >0.5 \ub5g/\ub5l (p 0.5 \ub5g/\ub5l, p 0.5 \ub5g/\ub5l, p < 0.05), while Wright staining demonstrated the presence of both necrotic and apoptotic cells. Cell cycle analysis showed a strong increase in subG0/G1 phase, related to cell death. Furthermore, MAPK and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with ME alone or combined with mitotane. The crude methanolic extract of wild mountain mint can decrease cell viability, vitality and survival of adrenocortical tumor cell models, in particular of SW13 cells. These data show the potential anticancer effects of ME, still more work is needed to corroborate these findings

Black strings in AdS_5

We present non-extremal magnetic black string solutions in five-dimensional gauged supergravity. The conformal infinity is the product of time and S^1xS_h, where S_h denotes a compact Riemann surface of genus h. The construction is based on both analytical and numerical techniques. We compute the holographic stress tensor, the Euclidean action and the conserved charges of the solutions and show that the latter satisfy a Smarr-type formula. The phase structure is determined in the canonical ensemble, and it is shown that there is a first order phase transition from small to large black strings, which disappears above a certain critical magnetic charge that is obtained numerically. For another particular value of the magnetic charge, that corresponds to a twisting of the dual super Yang-Mills theory, the conformal anomalies coming from the background curvature and those arising from the coupling to external gauge fields exactly cancel. We also obtain supersymmetric solutions describing waves propagating on extremal BPS magnetic black strings, and show that they possess a Siklos-Virasoro reparametrization invariance.Comment: 40 pages, 7 figures, JHEP3. v2: minor corrections, 2 references added. v3: typos in holographic stress tensor corrected, 3 references adde

All null supersymmetric backgrounds of N=2, D=4 gauged supergravity coupled to abelian vector multiplets

The lightlike supersymmetric solutions of N=2, D=4 gauged supergravity coupled to an arbitrary number of abelian vector multiplets are classified using spinorial geometry techniques. The solutions fall into two classes, depending on whether the Killing spinor is constant or not. In both cases, we give explicit examples of supersymmetric backgrounds. Among these BPS solutions, which preserve one quarter of the supersymmetry, there are gravitational waves propagating on domain walls or on bubbles of nothing that asymptote to AdS_4. Furthermore, we obtain the additional constraints obeyed by half-supersymmetric vacua. These are divided into four categories, that include bubbles of nothing which are asymptotically AdS_4, pp-waves on domain walls, AdS_3 x R, and spacetimes conformal to AdS_3 times an interval.Comment: 55 pages, uses JHEP3.cls. v2: Minor errors corrected, small changes in introductio

Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models

Stabilization of G-quadruplex (G4) structures in promoters is a novel promising strategy to regulate gene expression at transcriptional and translational levels. c-KIT proto-oncogene encodes for a tyrosine kinase receptor. It is involved in several physiological processes, but it is also dysregulated in many diseases, including cancer. Two G-rich sequences able to fold into G4, have been identified in c-KIT proximal promoter, thus representing suitable targets for anticancer intervention. Herein, we screened an \u201cin house\u201d library of compounds for the recognition of these G4 elements and we identified three promising ligands. Their G4-binding properties were analyzed and related to their antiproliferative, transcriptional and post-transcriptional effects in MCF7 and HGC27 cell lines. Besides c-KIT, the transcriptional analysis covered a panel of oncogenes known to possess G4 in their promoters. From these studies, an anthraquinone derivative (AQ1) was found to efficiently downregulate c-KIT mRNA and protein in both cell lines. The targeted activity of AQ1 was confirmed using c-KIT\u2013dependent cell lines that present either c-KIT mutations or promoter engineered (i.e., \u3b1155, HMC1.2 and ROSA cells). Present results indicate AQ1 as a promising compound for the target therapy of c-KIT-dependent tumors, worth of further and in depth molecular investigations

Do a Few Weeks Matter? Late Preterm Infants and Breastfeeding Issues

The late preterm infant population is increasing globally. Many studies show that late preterm infants are at risk of experiencing challenges common to premature babies, with breastfeeding issues being one of the most common. In this study, we investigated factors and variables that could interfere with breastfeeding initiation and duration in this population. We conducted a prospective observational study, in which we administered questionnaires on breastfeeding variables and habits to mothers of late preterm infants who were delivered in the well-baby nursery of our hospital and followed up for three months after delivery. We enrolled 149 mothers and 189 neonates, including 40 pairs of twins. Our findings showed that late preterm infants had a low rate of breastfeeding initiation and early breastfeeding discontinuation at 15, 40 and 90 days of life. The mothers with higher educational levels and previous positive breastfeeding experience had a longer breastfeeding duration. The negative factors for breastfeeding were the following: Advanced maternal age, Italian ethnicity, the feeling of reduced milk supply and having twins. This study underlines the importance of considering these variables in the promotion and protection of breastfeeding in this vulnerable population, thus offering mothers tailored support

All timelike supersymmetric solutions of N=2, D=4 gauged supergravity coupled to abelian vector multiplets

The timelike supersymmetric solutions of N=2, D=4 gauged supergravity coupled to an arbitrary number of abelian vector multiplets are classified using spinorial geometry techniques. We show that the generalized holonomy group for vacua preserving N supersymmetries is GL((8-N)/2,C) $\ltimes$ N/2 C^((8-N)/2) $\subseteq$ GL(8,R), where N=0,2,4,6,8. The spacetime turns out to be a fibration over a three-dimensional base manifold with U(1) holonomy and nontrivial torsion. Our results can be used to construct new supersymmetric AdS black holes with nontrivial scalar fields turned on.Comment: 35 pages, uses JHEP3.cl