Detection of ctDNA in plasma of patients with clinically localised prostate cancer is associated with rapid disease progression.

BACKGROUND DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. METHODS We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort (n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. RESULTS Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014). CONCLUSIONS CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease

Optical spectroscopy of X-Mega targets : II. The massive double-lined O-type binary HD93205

A new high-quality set of orbital parameters for the O-type spectroscopic binary HD 93205 has been obtained combining échelle and coudé CCD observations. The radial velocity orbits derived from the He iiλ4686 Å (primary component) and He iλ4471 Å (secondary component) absorption lines yield semi-amplitudes of 133±2 and 314±2 km s−1 for each binary component, resulting in minimum masses of 31 and 13 M⊙(q=0.42). We also confirm for the binary components the spectral classification of O3 V+ O8 V previously assigned. Assuming for the O8 V component a ‘normal’ mass of 22–25 M⊙ we would derive for the primary O3 V a mass of ‘only’52–60 M⊙ and an inclination of about 55° for the orbital plane. We have also determined for the first time a period of apsidal motion for this system, namely 185±16 yr using all available radial velocity data sets of HD 93205 (from 1975 to 1999). Phase-locked variations of the X-ray emission of HD 93205 consisting of a rise of the observed X-ray flux near periastron passage are also discussed.Facultad de Ciencias Astronómicas y Geofísica

Optical spectroscopy of X-Mega targets : II. The massive double-lined O-type binary HD93205

A new high-quality set of orbital parameters for the O-type spectroscopic binary HD 93205 has been obtained combining échelle and coudé CCD observations. The radial velocity orbits derived from the He iiλ4686 Å (primary component) and He iλ4471 Å (secondary component) absorption lines yield semi-amplitudes of 133±2 and 314±2 km s−1 for each binary component, resulting in minimum masses of 31 and 13 M⊙(q=0.42). We also confirm for the binary components the spectral classification of O3 V+ O8 V previously assigned. Assuming for the O8 V component a ‘normal’ mass of 22–25 M⊙ we would derive for the primary O3 V a mass of ‘only’52–60 M⊙ and an inclination of about 55° for the orbital plane. We have also determined for the first time a period of apsidal motion for this system, namely 185±16 yr using all available radial velocity data sets of HD 93205 (from 1975 to 1999). Phase-locked variations of the X-ray emission of HD 93205 consisting of a rise of the observed X-ray flux near periastron passage are also discussed.Facultad de Ciencias Astronómicas y Geofísica

ETA CARINAE'S THERMAL X-RAY TAIL MEASURED with XMM-Newton and NuSTAR

The evolved, massive highly eccentric binary system, η Car, underwent a periastron passage in the summer of 2014. We obtained two coordinated X-ray observations with XMM-Newton and NuSTAR during the elevated X-ray flux state and just before the X-ray minimum flux state around this passage. These NuSTAR observations clearly detected X-ray emission associated with η Car extending up to ∼50 keV for the first time. The NuSTAR spectrum above 10 keV can be fit with the bremsstrahlung tail from a kT ∼ 6 keV plasma. This temperature is ΔkT ∼ 2 keV higher than those measured from the iron K emission line complex, if the shocked gas is in collisional ionization equilibrium. This result may suggest that the companion star's pre-shock wind velocity is underestimated. The NuSTAR observation near the X-ray minimum state showed a gradual decline in the X-ray emission by 40% at energies above 5 keV in a day, the largest rate of change of the X-ray flux yet observed in individual η Car observations. The column density to the hardest emission component, NH ∼ 1024 H cm-2, marked one of the highest values ever observed for η Car, strongly suggesting increased obscuration of the wind-wind colliding X-ray emission by the thick primary stellar wind prior to superior conjunction. Neither observation detected the power-law component in the extremely hard band that INTEGRAL and Suzaku observed prior to 2011. If the non-detection by NuSTAR is caused by absorption, the power-law source must be small and located very near the wind-wind collision apex. Alternatively, it may be that the power-law source is not related to either η Car or the GeV γ-ray source

The orbit and stellar masses of the archetype colliding-wind binary WR 140

We present updated orbital elements for the Wolf-Rayet (WR) binary WR 140 (HD 193793; WC7pd + O5.5fc). The new orbital elements were derived using previously published measurements along with 160 new radial velocity measurements across the 2016 periastron passage of WR 140. Additionally, four new measurements of the orbital astrometry were collected with the CHARA Array. With these measurements, we derive stellar masses of $M_{\rm WR} = 10.31\pm0.45 M_\odot$ and $M_{\rm O} = 29.27\pm1.14 M_{\odot}$. We also include a discussion of the evolutionary history of this system from the Binary Population and Spectral Synthesis (BPASS) model grid to show that this WR star likely formed primarily through mass loss in the stellar winds, with only a moderate amount of mass lost or transferred through binary interactions.Comment: 10 pages, 5 figure

Global landscape review of serotype-specific invasive pneumococcal disease surveillance among countries using PCV10/13: The pneumococcal serotype replacement and distribution estimation (PSERENADE) project

Serotype-specific surveillance for invasive pneumococcal disease (IPD) is essential for assessing the impact of 10- and 13-valent pneumococcal conjugate vaccines (PCV10/13). The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE) project aimed to evaluate the global evidence to estimate the impact of PCV10/13 by age, product, schedule, and syndrome. Here we systematically characterize and summarize the global landscape of routine serotype-specific IPD surveillance in PCV10/13-using countries and describe the subset that are included in PSERENADE. Of 138 countries using PCV10/13 as of 2018, we identified 109 with IPD surveillance systems, 76 of which met PSERENADE data collection eligibility criteria. PSERENADE received data from most (n = 63, 82.9%), yielding 240,639 post-PCV10/13 introduction IPD cases. Pediatric and adult surveillance was represented from all geographic regions but was limited from lower income and high-burden countries. In PSERENADE, 18 sites evaluated PCV10, 42 PCV13, and 17 both; 17 sites used a 3 + 0 schedule, 38 used 2 + 1, 13 used 3 + 1, and 9 used mixed schedules. With such a sizeable and generally representative dataset, PSERENADE will be able to conduct robust analyses to estimate PCV impact and inform policy at national and global levels regarding adult immunization, schedule, and product choice, including for higher valency PCVs on the horizon

Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment

Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral nucleus of the amygdala (BLA) and prelimbic (PL) medial prefrontal cortex have been implicated in reward-seeking and fear-related responses, but how information flows between these reciprocally connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task wherein competing shock- and sucrose-predictive cues were simultaneously presented. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, BLA neurons optogenetically identified as projecting to PL more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally photostimulation of the BLA→PL projection increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. Therefore, the BLA→PL circuit is critical in governing the selection of behavioral responses in the face of competing signals.National Institutes of Health (U.S.) (Award 1R25-MH092912-01)National Institute of Mental Health (U.S.) (Grant R01- MH102441-01)National Institutes of Health (U.S.) (Award DP2- DK-102256-01

Advances in structure elucidation of small molecules using mass spectrometry

The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple-stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules