Search

Systemic treatment options for patients with locally advanced or metastatic basal cell carcinoma (BCC) are limited, particularly when tumors are refractory to anti-programmed cell death protein-1 (PD-1). A better understanding of immune checkpoint expression within the BCC tumor microenvironment may inform combinatorial treatment strategies to optimize response rates. CD3, PD-1, programmed death ligand-1 (PD-L1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3)+ cell densities within the tumor microenvironment of 34 archival, histologically aggressive BCCs were assessed. Tumor infiltrating lymphocyte (TIL) expression of PD-1, PD-L1, and LAG-3, and to a lesser degree TIM-3, correlated with increasing CD3+ T-cell densities (Pearson’s r=0.89, 0.72, 0.87, and 0.63, respectively). 100% of BCCs (34/34) demonstrated LAG-3 and PD-1 expression in >1% TIL; and the correlation between PD-1 and LAG-3 densities was high (Pearson’s r=0.89). LAG-3 was expressed at ~50% of the level of PD-1. Additionally, we present a patient with locally-advanced BCC who experienced stable disease during and after 45 weeks of first-line anti-PD-1 (nivolumab), followed by a partial response after the addition of anti-LAG-3 (relatlimab). Longitudinal biopsies throughout the treatment course showed a graduated increase in LAG-3 expression after anti-PD-1 therapy, lending support for coordinated immunosuppression and suggesting LAG-3 as a co-target for combination therapy to augment the clinical impact of anti-PD-(L)1.

Probing fundamental quantum systems and their phase change is interesting. Here the authors demonstrate the existence of mobile quantum solid phase composed of dimerized 3He atoms and topology-induced vacancies using 3He adsorbed on carbon nanotube.

Abstract The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration–response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.

We use 23 yr of astrometric and radial velocity data on the orbit of the star S0-2 to constrain a hypothetical intermediate-mass black hole orbiting the massive black hole Sgr A* at the Galactic center. The data place upper limits on variations of the orientation of the stellar orbit at levels between 0.°02 and 0.°07 per year. We use a combination of analytic estimates and full numerical integrations of the orbit of S0-2 in the presence of a black hole binary. For a companion intermediate-mass black hole outside the orbit of S0-2 (1020 au), we find that a companion black hole with mass m _c between 10 ^3 and 10 ^5 M _⊙ is excluded, with a boundary behaving as ${a}_{c}\sim {m}_{c}^{1/3}$ . For a companion with a _c < 1020 au, a black hole with mass between 10 ^3 and 10 ^5 M _⊙ is excluded, with ${a}_{c}\sim {m}_{c}^{-1/2}$ . These bounds arise from quadrupolar perturbations of the orbit of S0-2. Significantly stronger bounds on an inner companion arise from the fact that the location of S0-2 is measured relative to the bright emission of Sgr A* and that separation is perturbed by the “wobble” of Sgr A* about the center of mass between it and the companion. The result is a set of bounds as small as 400 M _⊙ at 200 au; the numerical simulations suggest a bound from these effects varying as ${a}_{c}\sim {m}_{c}^{-1}$ . We compare and contrast our results with those from a recent analysis by the GRAVITY collaboration.

The Cherenkov Telescope Array (CTA) is a next-generation ground-based observatory for gamma-ray astronomy at very high energies. The Large-Sized Telescope prototype (LST-1) is located at the CTA-North site, on the Canary Island of La Palma. LSTs are designed to provide optimal performance in the lowest part of the energy range covered by CTA, down to ≃20 GeV. LST-1 started performing astronomical observations in 2019 November, during its commissioning phase, and it has been taking data ever since. We present the first LST-1 observations of the Crab Nebula, the standard candle of very-high-energy gamma-ray astronomy, and use them, together with simulations, to assess the performance of the telescope. LST-1 has reached the expected performance during its commissioning period—only a minor adjustment of the preexisting simulations was needed to match the telescope’s behavior. The energy threshold at trigger level is around 20 GeV, rising to ≃30 GeV after data analysis. Performance parameters depend strongly on energy, and on the strength of the gamma-ray selection cuts in the analysis: angular resolution ranges from 0.°12–0.°40, and energy resolution from 15%–50%. Flux sensitivity is around 1.1% of the Crab Nebula flux above 250 GeV for a 50 hr observation (12% for 30 minutes). The spectral energy distribution (in the 0.03–30 TeV range) and the light curve obtained for the Crab Nebula agree with previous measurements, considering statistical and systematic uncertainties. A clear periodic signal is also detected from the pulsar at the center of the Nebula.

The gravitational three-body problem is a fundamental problem in physics and has significant applications to astronomy. Three-body configurations are often considered stable as long the system is hierarchical; that is, the two orbital distances are well-separated. However, instability, which is often associated with significant energy exchange between orbits, takes time to develop. Assuming two massive objects in a circular orbit and a test particle in an eccentric orbit, we develop an analytical formula estimating the time it takes for the test particle’s orbital energy to change by an order of itself. We show its consistency with results from N -body simulations. For eccentric orbits in particular, the instability is primarily driven not by close encounters of the test particle with one of the other bodies, but by the fundamental susceptibility of eccentric orbits to exchange energy at their periapsis. Motivated by recent suggestions that the galactic center may host an intermediate-mass black hole (IMBH) as a companion to the massive black hole Sgr A*, we use our timescale to explore the parameter space that could harbor an IMBH for the lifetime of the S-cluster of stars surrounding Sgr A*. Furthermore, we show that the orbit of an S-star can be stable for long timescales in the presence of other orbital crossing stars, thus suggesting that the S-cluster may be stable for the lifetimes of its member stars.

We study the broadband emission of Mrk 501 using multiwavelength observations from 2017 to 2020 performed with a multitude of instruments, involving, among others, MAGIC, Fermi's Large Area Telescope (LAT), NuSTAR, Swift, GASP-WEBT, and the Owens Valley Radio Observatory. Mrk 501 showed an extremely low broadband activity, which may help to unravel its baseline emission. Nonetheless, significant flux variations are detected at all wave bands, with the highest occurring at X-rays and very-high-energy (VHE) γ -rays. A significant correlation (>3 σ ) between X-rays and VHE γ -rays is measured, supporting leptonic scenarios to explain the variable parts of the emission, also during low activity. This is further supported when we extend our data from 2008 to 2020, and identify, for the first time, significant correlations between the Swift X-Ray Telescope and Fermi-LAT. We additionally find correlations between high-energy γ -rays and radio, with the radio lagging by more than 100 days, placing the γ -ray emission zone upstream of the radio-bright regions in the jet. Furthermore, Mrk 501 showed a historically low activity in X-rays and VHE γ -rays from mid-2017 to mid-2019 with a stable VHE flux (>0.2 TeV) of 5% the emission of the Crab Nebula. The broadband spectral energy distribution (SED) of this 2 yr long low state, the potential baseline emission of Mrk 501, can be characterized with one-zone leptonic models, and with (lepto)-hadronic models fulfilling neutrino flux constraints from IceCube. We explore the time evolution of the SED toward the low state, revealing that the stable baseline emission may be ascribed to a standing shock, and the variable emission to an additional expanding or traveling shock.

Background: Home self-monitoring of blood pressure is widely used in primary care to assist in the diagnosis of hypertension, as well as to improve clinical outcomes and support adherence to medication. The National Institute for Health and Care Excellence (NICE) care pathways for hypertension recommend specific guidelines, although they lack detail on supporting patients to self-monitor. Aim: To elicit primary care practitioners’ experiences of managing patients’ home blood pressure self-monitoring, across surgeries located in different socioeconomic areas. Design & setting: A qualitative focus group study was conducted with a total of 21 primary care professionals. Method: Participants were GPs and practice nurses (PNs), purposively recruited from surgeries in areas of low and high deprivation, according to the English indices of multiple deprivation. Six vignettes were developed featuring data from interviews with people who self-monitor and these were used in five focus groups. Results were thematically analysed. Results: Themes derived in the thematic analysis largely reflected topics covered by the vignettes. These included: advice on purchase of a device; supporting home monitoring; mitigating patient anxiety experienced as a result of home monitoring; valuing patients’ data; and effect of socioeconomic factors. Conclusion: The work provides an account of methods used by primary care practitioners in the management of home blood pressure self-monitoring, where guidance may be lacking and primary care practitioners act on their own judgement. Findings complement recent policy documentation, which recognises the need to adopt new ways of working to empower patients (for example, additional support from healthcare assistants), but lacks detail on how this should be done.

Nonlinear phenomena in superconducting resonator circuits are of great significance in the field of quantum technology. We observe thermal self-oscillations in a monolayer graphene flake coupled to molybdenum–rhenium superconducting resonator. The graphene flake forms a SINIS junction coupled to the resonator with strong temperature dependent resistance. In certain conditions of pump power and frequency, this nonlinearity leads to thermal self-oscillations appearing as sidebands in cavity transmission measurements with strong temperature dependence and gate tunability. The experimental observations fit well with theoretical model based on thermal instability. The modelling of the oscillation sidebands provides a method to evaluate electron phonon coupling in disordered graphene sample at low energies.

Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1. Rebalance of H3K27me3 levels at specific genes through EZH2 inhibitors may be a therapeutic strategy in MM cases harboring UTX mutations.

We discuss the interaction of a quantum impurity with a one-dimensional degenerate Bose gas forming a Bose polaron. In three spatial dimension, the quasiparticle is typically well described by the extended Fröhlich model, in full analogy with the solid-state counterpart. This description, which assumes an undepleted condensate, fails, however, in 1D, where the backaction of the impurity on the condensate leads to a self-bound mean-field polaron for arbitrarily weak impurity-boson interactions. We present a model that takes into account this backaction and describes the impurity-condensate interaction as coupling to phononlike excitations of a deformed condensate. A comparison of polaron energies and masses to diffusion quantum Monte Carlo simulations shows very good agreement already on the level of analytical mean-field solutions and is further improved when taking into account quantum fluctuations.

Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRasG12V or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, although both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRasG12V transformation or Sprouty deletion are largely distinct. Oncogenic HRasG12V elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRasG12V-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling.