A noninvasive multi-analyte diagnostic assay: Combining protein and DNA markers to stratify bladder cancer patients

Purpose: The authors recently reported the development of a noninvasive diagnostic assay using urinary matrix metalloproteinases (MMPs) as monitors of disease-free status and bladder cancer in high-risk populations. Using an approach called clinical intervention determining diagnostic (CIDD), they identified with high confidence those patients who could be excluded from additional intervention. To maximize performance, MMPs were combined with DNAbased markers and CIDD was applied to a population of patients undergoing monitoring for recurrence. Patients and methods: Urine samples were obtained from 323 patients, 48 of whom had a recurrence and 275 of whom did not have cancer upon cytoscopic evaluation. Twist1 and Nid2 methylation status was determined using methylation-specific polymerase chain reaction, FGFR3 mutational status by quantitative PCR, and MMP levels by enzyme-linked immunosorbent assay. Results: Using a combination of these DNA and protein markers, the authors identified with high confidence (97% negative predicted value) those patients who do not have cancer. Cutoffs were adjusted such that at 92% sensitivity, 51% of disease-free patients might be triaged from receiving further tests. Conclusion: The multi-analyte diagnostic readout assay described here is the first to combine protein and DNA biomarkers into one assay for optimal clinical performance. Using this approach, the detection of FGFR3 mutations and Twist1 and Nid2 methylation in the urine of patients undergoing bladder cancer recurrence screening increase the sensitivity and negative predictive value at an established MMP protein cutoff. This noninvasive urinary diagnostic assay could lead to the more efficient triage of patients undergoing recurrence monitoring

Exoplanet phase curves: observations and theory

Phase curves are the best technique to probe the three dimensional structure of exoplanets' atmospheres. In this chapter we first review current exoplanets phase curve observations and the particular challenges they face. We then describe the different physical mechanisms shaping the atmospheric phase curves of highly irradiated tidally locked exoplanets. Finally, we discuss the potential for future missions to further advance our understanding of these new worlds.Comment: Fig.5 has been updated. Table 1 and corresponding figures have been updated with new values for WASP-103b and WASP-18b. Contains a table sumarizing phase curve observation

Platelet Factor 4 Activity against P. falciparum and Its Translation to Nonpeptidic Mimics as Antimalarials

SummaryPlasmodium falciparum pathogenesis is affected by various cell types in the blood, including platelets, which can kill intraerythrocytic malaria parasites. Platelets could mediate these antimalarial effects through human defense peptides (HDPs), which exert antimicrobial effects by permeabilizing membranes. Therefore, we screened a panel of HDPs and determined that human platelet factor 4 (hPF4) kills malaria parasites inside erythrocytes by selectively lysing the parasite digestive vacuole (DV). PF4 rapidly accumulates only within infected erythrocytes and is required for parasite killing in infected erythrocyte-platelet cocultures. To exploit this antimalarial mechanism, we tested a library of small, nonpeptidic mimics of HDPs (smHDPs) and identified compounds that kill P. falciparum by rapidly lysing the parasite DV while sparing the erythrocyte plasma membrane. Lead smHDPs also reduced parasitemia in a murine malaria model. Thus, identifying host molecules that control parasite growth can further the development of related molecules with therapeutic potential

An end is in sight: a perspective on PCR as an endpoint for Chagas disease treatment trials

Novel therapies for chronic indeterminate Chagas disease (CICD) are needed, but trials are limited by the absence of tests to detect infection and early treatment efficacy. This perspective highlights the shortfalls and strengths of polymerase chain reaction (PCR) as a study endpoint for anti-parasitic drug development. Serologic reversion, the gold standard test of cure, may take decades to occur in adults and therefore is challenging as an endpoint for drug development. Use of PCR as a marker of infection and treatment response has notable limitations due to low parasitemia in CICD, fluctuations in circulating (versus tissue) parasite burden, strain differences, and assay performance. It is, however, rapidly responsive to therapy, and technological advances have improved detection of different strains and may allow for parasite quantification. Until we have more sensitive tests for parasitological clearance, PCR as a measure of treatment failure may be the best available efficacy endpoint to accelerate early development of much-needed novel therapies. Adequately designed clinical studies are needed to correlate PCR clearance with clinical outcomes and to identify novel biomarkers predictive of clinical outcomes in patients with CICD. Public-private partnerships and health authority engagement are paramount to identify feasible trial endpoints and deliver promising new drug candidates for Chagas disease

Two super-Earths at the edge of the habitable zone of the nearby M dwarf TOI-2095

The main scientific goal of TESS is to find planets smaller than Neptune around stars bright enough to allow further characterization studies. Given our current instrumentation and detection biases, M dwarfs are prime targets to search for small planets that are in (or nearby) the habitable zone of their host star. Here we use photometric observations and CARMENES radial velocity measurements to validate a pair of transiting planet candidates found by TESS. The data was fitted simultaneously using a Bayesian MCMC procedure taking into account the stellar variability present in the photometric and spectroscopic time series. We confirm the planetary origin of the two transiting candidates orbiting around TOI-2095 (TIC 235678745). The star is a nearby M dwarf ($d = 41.90 \pm 0.03$ pc, $T_{\rm eff} = 3759 \pm 87$ K, $V = 12.6$ mag) with a stellar mass and radius of $M_\star = 0.44 \pm 0.02 \; M_\odot$ and $R_\star = 0.44 \pm 0.02 \; R_\odot$, respectively. The planetary system is composed of two transiting planets: TOI-2095b with an orbital period of $P_b = 17.66484 \pm (7\times 10^{-5})$ days and TOI-2095c with $P_c = 28.17232 \pm (14\times 10^{-5})$ days. Both planets have similar sizes with $R_b = 1.25 \pm 0.07 \; R_\oplus$ and $R_c = 1.33 \pm 0.08 \; R_\oplus$ for planet b and c, respectively. We put upper limits on the masses of these objects with $M_b < 4.1 \; M_\oplus$ for the inner and $M_c < 7.4 \; M_\oplus$ for the outer planet (95\% confidence level). These two planets present equilibrium temperatures in the range of 300 - 350 K and are close to the inner edge of the habitable zone of their star.Comment: Submitted to Astronomy & Astrophysic

TOI-5126: A hot super-Neptune and warm Neptune pair discovered by TESS\textit{TESS} and CHEOPS\textit{CHEOPS}

We present the confirmation of a hot super-Neptune with an exterior Neptune companion orbiting a bright (V = 10.1 mag) F-dwarf identified by the $\textit{Transiting Exoplanet Survey Satellite}$ ($\textit{TESS}$). The two planets, observed in sectors 45, 46 and 48 of the $\textit{TESS}$ extended mission, are $4.74^{+0.16}_{-0.14}$ $R_{\oplus}$ and $3.86^{+0.17}_{-0.16}$ $R_{\oplus}$ with $5.4588385^{+0.0000070}_{-0.0000072}$ d and $17.8999^{+0.0018}_{-0.0013}$ d orbital periods, respectively. We also obtained precise space based photometric follow-up of the system with ESAs $\textit{CHaracterising ExOplanets Satellite}$ ($\textit{CHEOPS}$) to constrain the radius and ephemeris of TOI-5126 b. TOI 5126 b is located in the "hot Neptune Desert" and is an ideal candidate for follow-up transmission spectroscopy due to its high predicted equilibrium temperature ($T_{eq} = 1442^{+46}_{-40}$ K) implying a cloud-free atmosphere. TOI-5126 c is a warm Neptune ($T_{eq}= 971^{+31}_{-27}$ K) also suitable for follow-up. Tentative transit timing variations (TTVs) have also been identified in analysis, suggesting the presence of at least one additional planet, however this signal may be caused by spot-crossing events, necessitating further precise photometric follow-up to confirm these signals.Comment: Accepted in MNRAS, 18 pages, 14 figure

Dynamical analysis of three distant trans-Neptunian objects with similar orbits

This paper reports the discovery and orbital characterization of two extreme trans-Neptunian objects (ETNOs), 2016 QV 89 and 2016 QU 89 , which have orbits that appear similar to that of a previously known object, 2013 UH 15 . All three ETNOs have semi-major axes a≈172 AU and eccentricities e≈0.77 . The angular elements (i,ω,Ω) vary by 6, 15, and 49 deg, respectively between the three objects. The two new objects add to the small number of TNOs currently known to have semi-major axes between 150 and 250 AU, and serve as an interesting dynamical laboratory to study the outer realm of our Solar System. Using a large ensemble of numerical integrations, we find that the orbits are expected to reside in close proximity in the (a,e) phase plane for roughly 100 Myr before diffusing to more separated values. We then explore other scenarios that could influence their orbits. With aphelion distances over 300 AU, the orbits of these ETNOs extend far beyond the classical Kuiper Belt, and an order of magnitude beyond Neptune. As a result, their orbital dynamics can be affected by the proposed new Solar System member, referred to as Planet Nine in this work. With perihelion distances of 35-40 AU, these orbits are also influenced by resonant interactions with Neptune. A full assessment of any possible, new Solar System planets must thus take into account this emerging class of TNOs

TOI 564 b and TOI 905 b: Grazing and Fully Transiting Hot Jupiters Discovered by TESS

We report the discovery and confirmation of two new hot Jupiters discovered by the Transiting Exoplanet Survey Satellite (TESS): TOI 564 b and TOI 905 b. The transits of these two planets were initially observed by TESS with orbital periods of 1.651 and 3.739 days, respectively. We conducted follow-up observations of each system from the ground, including photometry in multiple filters, speckle interferometry, and radial velocity measurements. For TOI 564 b, our global fitting revealed a classical hot Jupiter with a mass of MJ and a radius of RJ. Also a classical hot Jupiter, TOI 905 b has a mass of MJ and radius of RJ. Both planets orbit Sun-like, moderately bright, mid-G dwarf stars with V ∼ 11. While TOI 905 b fully transits its star, we found that TOI 564 b has a very high transit impact parameter of, making it one of only ∼20 known systems to exhibit a grazing transit and one of the brightest host stars among them. Therefore, TOI 564 b is one of the most attractive systems to search for additional nontransiting, smaller planets by exploiting the sensitivity of grazing transits to small changes in inclination and transit duration over a timescale of several years

Discovery and dynamical analysis of an extreme trans-neptunian object with a high orbital inclination

We report the discovery and dynamical analysis of 2015 BP519, an extreme trans-Neptunian object (TNO) detected by the Dark Energy Survey at a heliocentric distance of 55 au, perihelion of ∼36 au, and absolute magnitude Hr= 4.3. The current orbit, determined from a 1110 day observational arc, has a semimajor axis a ≈ 450 au, eccentricity e ≈ 0.92, and inclination i ≈ 547deg;. With these orbital elements, 2015 BP519is the most extreme TNO discovered to date, as quantified by the reduced Kozai action, , which is a conserved quantity at fixed semimajor axis a for axisymmetric perturbations. We discuss the orbital stability and evolution of this object and find that, under the influence of the four known giant planets, 2015 BP519displays rich dynamical behavior, including rapid diffusion in semimajor axis and more constrained variations in eccentricity and inclination. We also consider the long-term orbital stability and evolutionary behavior within the context of the Planet Nine hypothesis and find that 2015 BP519adds to the circumstantial evidence for the existence of this proposed new member of the solar system, as it would represent the first member of the population of high-i, π-shepherded TNOs