Hallmarks of cancer-the new testament.

Diagnosis and treatment of disease demand a sound understanding of the underlying mechanisms, determining any Achilles' heel that can be targeted in effective therapies. Throughout history, this endeavour to decipher the origin and mechanism of transformation of a normal cell into cancer has led to various theories-from cancer as a curse to an understanding at the level of single-cell heterogeneity, meaning even among a single sub-type of cancer there are myriad molecular challenges to overcome. With increasing insight into cancer genetics and biology, the disease has become ever more complex to understand. The complexity of cancer as a disease was distilled into key traits by Hanahan and Weinberg in their seminal 'Hallmarks of Cancer' reviews. This lucid conceptualization of complex cancer biology is widely accepted and has helped advance cancer therapeutics by targeting the various hallmarks but, with the advancement in technologies, there is greater granularity in how we view cancer as a disease, and the additional understanding over the past decade requires us to revisit the hallmarks of cancer. Based on extensive study of the cancer research literature, we propose four novel hallmarks of cancer, namely, the ability of cells to regress from a specific specialized functional state, epigenetic changes that can affect gene expression, the role of microorganisms and neuronal signalling, to be included in the hallmark conceptualization along with evidence of various means to exploit them therapeutically

The Personal Genome Project-UK, an open access resource of human multi-omics data

Integrative analysis of multi-omics data is a powerful approach for gaining functional insights into biological and medical processes. Conducting these multifaceted analyses on human samples is often complicated by the fact that the raw sequencing output is rarely available under open access. The Personal Genome Project UK (PGP-UK) is one of few resources that recruits its participants under open consent and makes the resulting multi-omics data freely and openly available. As part of this resource, we describe the PGP-UK multi-omics reference panel consisting of ten genomic, methylomic and transcriptomic data. Specifically, we outline the data processing, quality control and validation procedures which were implemented to ensure data integrity and exclude sample mix-ups. In addition, we provide a REST API to facilitate the download of the entire PGP-UK dataset. The data are also available from two cloud-based environments, providing platforms for free integrated analysis. In conclusion, the genotype-validated PGP-UK multi-omics human reference panel described here provides a valuable new open access resource for integrated analyses in support of personal and medical genomics

Characterizing planetary systems with SPIRou: M-dwarf planet-search survey and the multiplanet systems GJ 876 and GJ 1148

SPIRou is a near-infrared spectropolarimeter and a high-precision velocimeter. The SPIRou Legacy Survey collected data from February 2019 to June 2022, half of the time devoted to a blind search for exoplanets around nearby cool stars. The aim of this paper is to present this program and an overview of its properties, and to revisit the radial velocity (RV) data of two multiplanet systems, including new visits with SPIRou. From SPIRou data, we can extract precise RVs using efficient telluric correction and line-by-line measurement techniques, and we can reconstruct stellar magnetic fields from the collection of polarized spectra using the Zeeman-Doppler imaging method. The stellar sample of our blind search in the solar neighborhood, the observing strategy, the RV noise estimates, chromatic behavior, and current limitations of SPIRou RV measurements on bright M dwarfs are described. In addition, SPIRou data over a 2.5-year time span allow us to revisit the known multiplanet systems GJ~876 and GJ~1148. For GJ~876, the new dynamical analysis including the four planets is consistent with previous models and confirms that this system is deep in the Laplace resonance and likely chaotic. The large-scale magnetic map of GJ~876 over two consecutive observing seasons is obtained and shows a dominant dipolar field with a polar strength of 30~G, which defines the magnetic environment in which the inner planet with a period of 1.94~d is embedded. For GJ~1148, we refine the known two-planet model.Comment: accepted in A&

Monitoring the large-scale magnetic field of AD~Leo with SPIRou, ESPaDOnS and Narval. Toward a magnetic polarity reversal?

One manifestation of dynamo action on the Sun is the 22-yr magnetic cycle, exhibiting a polarity reversal and a periodic conversion between poloidal and toroidal fields. For M dwarfs, several authors claim evidence of activity cycles from photometry and analyses of spectroscopic indices, but no clear polarity reversal has been identified from spectropolarimetric observations. Our aim is to monitor the evolution of the large-scale field of AD Leo, which has shown hints of a secular evolution from past dedicated spectropolarimetric campaigns. We analysed near-infrared spectropolarimetric observations of the active M dwarf AD Leo taken with SPIRou between 2019 and 2020 and archival optical data collected with ESPaDOnS and Narval between 2006 and 2019. We searched for long-term variability in the longitudinal field, the width of unpolarised Stokes profiles, the unsigned magnetic flux derived from Zeeman broadening, and the geometry of the large-scale magnetic field using both Zeeman-Doppler Imaging and Principal Component Analysis. We found evidence of a long-term evolution of the magnetic field, featuring a decrease in axisymmetry (from 99% to 60%). This is accompanied by a weakening of the longitudinal field (-300 to -50 G) and a correlated increase in the unsigned magnetic flux (2.8 to 3.6 kG). Likewise, the width of the mean profile computed with selected near-infrared lines manifests a long-term evolution corresponding to field strength changes over the full time series, but does not exhibit modulation with the stellar rotation of AD Leo in individual epochs. The large-scale magnetic field of AD Leo manifested first hints of a polarity reversal in late 2020 in the form of a substantially increased dipole obliquity, while the topology remained predominantly poloidal and dipolar. This suggests that low-mass M dwarfs with a dipole-dominated magnetic field can undergo magnetic cycles.Comment: 26 pages, 18 figures, 8 table

Magnetic fields & rotation periods of M dwarfs from SPIRou spectra

We present near-infrared spectropolarimetric observations of a sample of 43 weakly- to moderately-active M dwarfs, carried with SPIRou at the Canada-France-Hawaii Telescope in the framework of the SPIRou Legacy Survey from early 2019 to mid 2022. We use the 6700 circularly polarised spectra collected for this sample to investigate the longitudinal magnetic field and its temporal variations for all sample stars, from which we diagnose, through quasi-periodic Gaussian process regression, the periodic modulation and longer-term fluctuations of the longitudinal field. We detect the large-scale field for 40 of our 43 sample stars, and infer a reliable or tentative rotation period for 38 of them, using a Bayesian framework to diagnose the confidence level at which each rotation period is detected. We find rotation periods ranging from 14 to over 60d for the early-M dwarfs, and from 70 to 200d for most mid- and late-M dwarfs (potentially up to 430d for one of them). We also find that the strength of the detected large-scale fields does not decrease with increasing period or Rossby number for the slowly rotating dwarfs of our sample as it does for higher-mass, more active stars, suggesting that these magnetic fields may be generated through a different dynamo regime than those of more rapidly rotating stars. We also show that the large-scale fields of most sample stars evolve on long timescales, with some of them globally switching sign as stars progress on their putative magnetic cycles.Comment: MNRAS, in press (25 pages, 15 figures, 3 tables

Accuracy of syndrome definitions based on diagnoses in physician claims

<p>Abstract</p> <p>Background</p> <p>Community clinics offer potential for timelier outbreak detection and monitoring than emergency departments. However, the accuracy of syndrome definitions used in surveillance has never been evaluated in community settings. This study's objective was to assess the accuracy of syndrome definitions based on diagnostic codes in physician claims for identifying 5 syndromes (fever, gastrointestinal, neurological, rash, and respiratory including influenza-like illness) in community clinics.</p> <p>Methods</p> <p>We selected a random sample of 3,600 community-based primary care physicians who practiced in the fee-for-service system in the province of Quebec, Canada in 2005-2007. We randomly selected 10 visits per physician from their claims, stratifying on syndrome type and presence, diagnosis, and month. Double-blinded chart reviews were conducted by telephone with consenting physicians to obtain information on patient diagnoses for each sampled visit. The sensitivity, specificity, and positive predictive value (PPV) of physician claims were estimated by comparison to chart review.</p> <p>Results</p> <p>1,098 (30.5%) physicians completed the chart review. A chart entry on the date of the corresponding claim was found for 10,529 (95.9%) visits. The sensitivity of syndrome definitions based on diagnostic codes in physician claims was low, ranging from 0.11 (fever) to 0.44 (respiratory), the specificity was high, and the PPV was moderate to high, ranging from 0.59 (fever) to 0.85 (respiratory). We found that rarely used diagnostic codes had a higher probability of being false-positives, and that more commonly used diagnostic codes had a higher PPV.</p> <p>Conclusions</p> <p>Future research should identify physician, patient, and encounter characteristics associated with the accuracy of diagnostic codes in physician claims. This would enable public health to improve syndromic surveillance, either by focusing on physician claims whose diagnostic code is more likely to be accurate, or by using all physician claims and weighing each according to the likelihood that its diagnostic code is accurate.</p

Optical and near-infrared stellar activity characterization of the early M dwarf Gl~205 with SOPHIE and SPIRou

The stellar activity of M dwarfs is the main limitation for discovering and characterizing exoplanets orbiting them since it induces quasi-periodic RV variations. We aim to characterize the magnetic field and stellar activity of the early, moderately active, M dwarf Gl205 in the optical and nIR domains. We obtained high-precision quasi-simultaneous spectra in the optical and nIR with the SOPHIE spectrograph and SPIRou spectropolarimeter between 2019 and 2022. We computed the RVs from both instruments and the SPIRou Stokes V profiles. We used ZDI to map the large-scale magnetic field over the time span of the observations. We studied the temporal behavior of optical and nIR RVs and activity indicators with the Lomb-Scargle periodogram and a quasi-periodic GP regression. In the nIR, we studied the equivalent width of Al I, Ti I, K I, Fe I, and He I. We modeled the activity-induced RV jitter using a multi-dimensional GP regression with activity indicators as ancillary time series. The optical and nIR RVs have similar scatter but nIR shows a more complex temporal evolution. We observe an evolution of the magnetic field topology from a poloidal dipolar field in 2019 to a dominantly toroidal field in 2022. We measured a stellar rotation period of Prot=34.4$\pm$0.5 d in the longitudinal magnetic field. Using ZDI we measure the amount of latitudinal differential rotation (DR) shearing the stellar surface yielding rotation periods of Peq=32.0$\pm$1.8 d at the stellar equator and Ppol=45.5$\pm$0.3 d at the poles. We observed inconsistencies in the activity indicators' periodicities that could be explained by these DR values. The multi-dimensional GP modeling yields an RMS of the RV residuals down to the noise level of 3 m/s for both instruments, using as ancillary time series H$\alpha$ and the BIS in the optical, and the FWHM in the nIR.Comment: 41 pages, 24 figures. Accepted for publication in A&A. Improved quality of figures and reduced size of Appendi

Near-IR and optical radial velocities of the active M-dwarf star Gl 388 (AD Leo) with SPIRou at CFHT and SOPHIE at OHP

Context: The search for extrasolar planets around the nearest M-dwarfs is a crucial step towards identifying the nearest Earth-like planets. One of the main challenges in this search is that M-dwarfs can be magnetically active and stellar activity can produce radial velocity (RV) signals that could mimic those of a planet. Aims: We aim to investigate whether the 2.2 day period observed in optical RVs of the nearby active M-dwarf star Gl 388 (AD Leo) is due to stellar activity or to a planet which co-rotates with the star as suggested in the past. Methods: We obtained quasi-simultaneous optical RVs of Gl 388 from 2019 to 2021 with SOPHIE (R$\sim$75k) at the OHP in France, and near-IR RV and Stokes V measurements with SPIRou at the CFHT (R$\sim$70k). Results: The SOPHIE RV time-series displays a periodic signal with 2.23$\pm$0.01 days period and 23.6$\pm$0.5 m/s amplitude, which is consistent with previous HARPS observations obtained in 2005-2006. The SPIRou RV time-series is flat at 5 m/s rms and displays no periodic signals. RV signals of amplitude higher than 5.3 m/s at a period of 2.23 days can be excluded with a confidence level higher than 99%. Using the modulation of the longitudinal magnetic field (Bl) measured with SPIRou, we derive a stellar rotation period of 2.2305$\pm$0.0016 days. Conclusions: SPIRou RV measurements provide solid evidence that the periodic variability of the optical RVs of Gl 388 is due to stellar activity rather than to a co-rotating planet. The magnetic activity nature of the optical RV signal is further confirmed by the modulation of Bl with the same period. The SPIRou campaign on Gl 388 demonstrates the power of near-IR RV to confirm or infirm planet candidates discovered in the optical around active stars. SPIRou observations reiterate how effective spectropolarimetry is at determining the stellar rotation period.Comment: 25 pages, 23 figures, Accepted by Astronomy and Astrophysic

An ultra-short-period transiting super-Earth orbiting the M3 dwarf TOI-1685

Funding: We acknowledge financial support from the Agencia Estatal de Investigación of the Ministerio de Ciencia, Innovación y Universidades and the ERDF through projects PID2019-109522GB-C5[1:4]/AEI/10.13039/501100011033, PGC2018-098153-B-C33, and the Centre of Excellence “Severo Ochoa” and “María deMaeztu” awards to the Instituto de Astrofísica de Canarias (SEV-2015-0548), Instituto de Astrofísica de Andalucía (SEV-2017-0709), and Centro de Astro-biología (MDM-2017-0737), the Generalitat de Catalunya/CERCA programme,“la Caixa” Foundation (100010434), European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 847648 (LCF/BQ/PI20/11760023), a University Research Support Grant from the National Astronomical Observatory of Japan, JSPS KAKENHI (JP15H02063, JP18H01265, JP18H05439, JP18H05442, and JP22000005), JSTPRESTO (JPMJPR1775), UK Science and Technology Facilities Council (ST/R000824/1), and NASA (NNX17AG24G).Dynamical histories of planetary systems, as well as the atmospheric evolution of highly irradiated planets, can be studied by characterizing the ultra-short-period planet population, which the TESS mission is particularly well suited to discover. Here, we report on the follow-up of a transit signal detected in the TESS sector 19 photometric time series of the M3.0 V star TOI-1685 (2MASS J04342248+4302148). We confirm the planetary nature of the transit signal, which has a period of Pb = 0.6691403−0.0000021+0.0000023 d, using precise radial velocity measurements taken with the CARMENES spectrograph. From the joint photometry and radial velocity analysis, we estimate the following parameters for TOI-1685 b: a mass of Mb = 3.78−0.63+0.63 M⊕, a radius of Rb = 1.70−0.07+0.07 R⊕, which together result in a bulk density of ρb = 4.21−0.82+0.95 g cm−3, and an equilibrium temperature of Teq = 1069−16+16 K. TOI-1685 b is the least dense ultra-short-period planet around an M dwarf known to date. TOI-1685 b is also one of the hottest transiting super-Earth planets with accurate dynamical mass measurements, which makes it a particularly attractive target for thermal emission spectroscopy. Additionally, we report with moderate evidence an additional non-transiting planet candidate in the system, TOI-1685 [c], which has an orbital period of Pc = 9.02−0.12+0.10 d.Publisher PDFPeer reviewe