The enigmatic young brown dwarf binary FU Tau: accretion and activity

FU Tau belongs to a rare class of young, wide brown dwarf binaries. We have resolved the system in a Chandra X-ray observation and detected only the primary, FU Tau A. Hard X-ray emission, presumably from a corona, is present but, unexpectedly, we detect also a strong and unusually soft component from FU Tau A. Its X-ray properties, so far unique among brown dwarfs, are very similar to those of the T Tauri star TW Hya. The analogy with TW Hya suggests that the dominating soft X-ray component can be explained by emission from accretion shocks. However, the typical free-fall velocities of a brown dwarf are too low for an interpretation of the observed X-ray temperature as post-shock region. On the other hand, velocities in excess of the free-fall speed are derived from archival optical spectroscopy, and independent pieces of evidence for strong accretion in FU Tau A are found in optical photometry. The high X-ray luminosity of FU Tau A coincides with a high bolometric luminosity confirming an unexplained trend among young brown dwarfs. In fact, FU Tau A is overluminous with respect to evolutionary models while FU Tau B is on the 1 Myr isochrone suggesting non-contemporaneous formation of the two components in the binary. The extreme youth of FU Tau A could be responsible for its peculiar X-ray properties, in terms of atypical magnetic activity or accretion. Alternatively, rotation and magnetic field effects may reduce the efficiency of convection which in turn affects the effective temperature and radius of FU Tau A shifting its position in the HR diagram. Although there is no direct prove of this latter scenario so far we present arguments for its plausibility.Comment: Accepted for publication in MNRAS; 9 pages, 5 figure

Future of 5-fluorouracil in cancer therapeutics, current pharmacokinetics issues and a way forward

Background: In addition to exhibiting antitumor potential, antitumor drugs exhibit toxicity due to a poor pharmacokinetic profile. An enormous amount of research has been carried out and is still ongoing to obtain more targeted, potent, and safe drugs to treat cancer, and pharmacokinetic evaluations of anticancer drugs are needed. Objectives: The present review examined different delivery systems and methodologies designed in recent years to investigate the pharmacokinetics of the anticancer drug, 5-fluorouracil (5-FU). These methodologies highlight how the issues of bioavailability, absorption, half-life, targeted neoplastic cell potential, and high therapeutic index of 5-FU are resolved. Results: A number of naturally occurring macromolecules such as modified starch, porphyran, peptides, and folic acids have been found to be successful in vitro to improve the permeability and retention effect of 5-FU against solid tumors. A promising approach for targeted 5-FU delivery to oncoproteins has resulted in a number of potentially sound anticancer nanocomposites. Chitosan nanoparticles loaded with 5-FU have been shown to exhibit cytotoxicity equivalent to 5-FU injections against gastric carcinoma. At the level of inter- and intra-molecular interactions, the co-crystal approach has been found to be successful against colorectal cancer proteins. Because of the 5-FU ligand-like nature and its metal-binding potential, researchers have shifted attention toward the synergistic co-administration of gold complexes with this drug. Conclusions: This study highlighted the techniques used to improve the pharmacokinetics of 5-FU and that “nanocarriers” are a promising approach in this field. The conclusion is supported by solid evidence

Curcumin Chemosensitizes 5-Fluorouracil Resistant MMR-Deficient Human Colon Cancer Cells in High Density Cultures

Objective Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50–60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells. Methods High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays. Results Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting. Conclusion Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population

Chandra Reveals Variable Multi-Component X-ray Emission from FU Orionis

FU Orionis is the prototype of a class of eruptive young stars (``FUors'') characterized by strong optical outbursts. We recently completed an exploratory survey of FUors using XMM-Newton to determine their X-ray properties, about which little was previously known. The prototype FU Ori and V1735 Cyg were detected. The X-ray spectrum of FU Ori was found to be unusual, consisting of a cool moderately-absorbed component plus a hotter component viewed through an absorption column density that is an order of magnitude higher. We present here a sensitive (99 ks) follow-up X-ray observation of FU Ori obtained at higher angular resolution with Chandra ACIS-S. The unusual multi-component spectrum is confirmed. The hot component is centered on FU Ori and dominates the emission above 2 keV. It is variable (a signature of magnetic activity) and is probably coronal emission originating close to FU Ori's surface viewed through cool gas in FU Ori's strong wind or accretion stream. In contrast, the X-ray centroid of the soft emission below 2 keV is offset 0.20 arcsec to the southeast of FU Ori, toward the near-IR companion (FU Ori S). This offset amounts to slightly less than half the separation between the two stars. The most likely explanation for the offset is that the companion contributes significantly to the softer X-ray emission below 2 keV (and weakly above 2 keV). The superimposed X-ray contributions from FU Ori and the companion resolve the paradox posed by XMM-Newton of an apparently single X-ray source viewed through two different absorption columns.Comment: 21 pages, 3 tables, 6 figure

Constraining mass ratio and extinction in the FU Orionis binary system with infrared integral field spectroscopy

We report low resolution near infrared spectroscopic observations of the eruptive star FU Orionis using the Integral Field Spectrograph Project 1640 installed at the Palomar Hale telescope. This work focuses on elucidating the nature of the faint source, located 0.5" south of FU Ori, and identified in 2003 as FU Ori S. We first use our observations in conjunction with published data to demonstrate that the two stars are indeed physically associated and form a true binary pair. We then proceed to extract J and H band spectro-photometry using the damped LOCI algorithm, a reduction method tailored for high contrast science with IFS. This is the first communication reporting the high accuracy of this technique, pioneered by the Project 1640 team, on a faint astronomical source. We use our low resolution near infrared spectrum in conjunction with 10.2 micron interferometric data to constrain the infrared excess of FU Ori S. We then focus on estimating the bulk physical properties of FU Ori S. Our models lead to estimates of an object heavily reddened, A_V =8-12, with an effective temperature of ~ 4000-6500 K . Finally we put these results in the context of the FU Ori N-S system and argue that our analysis provides evidence that FU Ori S might be the more massive component of this binary syste

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

BACKGROUND. Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. METHODS. The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. RESULTS. Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4(+) T cell infiltration, which peaked on days 10–11 after treatment, without pain, crusting, or ulceration. CONCLUSION. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4(+) T cell–mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs. TRIAL REGISTRATION. ClinicalTrials.gov NCT02019355. FUNDING. Not applicable (investigator-initiated clinical trial)

On the distance of the Magellanic Clouds using Cepheid NIR and optical-NIR Period Wesenheit Relations

We present the largest near-infrared (NIR) data sets, $JHKs$, ever collected for classical Cepheids in the Magellanic Clouds (MCs). We selected fundamental (FU) and first overtone (FO) pulsators, and found 4150 (2571 FU, 1579 FO) Cepheids for Small Magellanic Cloud (SMC) and 3042 (1840 FU, 1202 FO) for Large Magellanic Cloud (LMC). Current sample is 2--3 times larger than any sample used in previous investigations with NIR photometry. We also discuss optical $VI$ photometry from OGLE-III. NIR and optical--NIR Period-Wesenheit (PW) relations are linear over the entire period range ($0.0<\log P_{\rm FU} \le1.65$) and their slopes are, within the intrinsic dispersions, common between the MCs. These are consistent with recent results from pulsation models and observations suggesting that the PW relations are minimally affected by the metal content. The new FU and FO PW relations were calibrated using a sample of Galactic Cepheids with distances based on trigonometric parallaxes and Cepheid pulsation models. By using FU Cepheids we found a true distance moduli of $18.45\pm0.02{\rm(random)}\pm0.10{\rm(systematic)}$ mag (LMC) and $18.93\pm0.02{\rm(random)}\pm0.10{\rm(systematic)}$ mag (SMC). These estimates are the weighted mean over ten PW relations and the systematic errors account for uncertainties in the zero-point and in the reddening law. We found similar distances using FO Cepheids ($18.60\pm0.03{\rm(random)}\pm0.10{\rm(systematic)}$ mag [LMC] and $19.12\pm0.03{\rm(random)}\pm0.10{\rm(systematic)}$ mag [SMC]). These new MC distances lead to the relative distance, $\Delta\mu=0.48\pm0.03$ mag (FU, $\log P=1$) and $\Delta\mu=0.52\pm0.03$ mag (FO, $\log P=0.5$),which agrees quite well with previous estimates based on robust distance indicators.Comment: 17 pages, 7 figure