Atypical B cells (CD21-CD27-IgD-) correlate with lack of response to checkpoint inhibitor therapy in NSCLC

Introduction: Checkpoint inhibitor (CI) therapy has revolutionized treatment for non-small cell lung cancer (NSCLC). However, a proportion of patients do not respond to CI therapy for unknown reasons. Although the current paradigm in anti-tumor immunity evolves around T cells, the presence of tertiary lymphoid structures and memory B cells has been positively correlated with response to CI therapy in NSCLC. In addition, double negative (DN) (CD27- IgD-) B cells have been shown to be abundant in NSCLC compared to healthy lung tissue and inversely correlate with the intratumoral presence of memory B cells. Nonetheless, no study has correlated DN B cells to survival in NSCLC. Methods: In this study, we evaluated the presence and phenotype of B cells in peripheral blood with flow cytometry of patients with NSCLC and mesothelioma before receiving CI therapy and correlated these with clinical outcome. Results: Non-responding patients showed decreased frequencies of B cells, yet increased frequencies of antigen-experienced CD21- DN (Atypical) B cells compared to responding patients and HC, which was confirmed in patients with mesothelioma treated with CI therapy. Conclusions: These data show that the frequency of CD21- DN B cells correlates with lack of response to CI therapy in thoracic malignancies. The mechanism by which CD21- DN B cells hamper CI therapy remains unknown. Our findings support the hypothesis that CD21- DN B cells resemble phenotypically identical exhausted B cells that are seen in chronic infection or function as antigen presenting cells that induce regulatory T cells.</p

Nivolumab and ipilimumab in the real-world setting in patients with mesothelioma

Objectives: Nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) is a new first-line treatment combination for patients with pleural mesothelioma. Nivolumab-ipilimumab improved the survival, however, 30.3% of the patients suffered from grade 3–4 treatment related adverse events (TRAE's) and TRAE's led to discontinuation in 23.0% of all patients. Here, we present the first real-world data of nivolumab plus ipilimumab in patients with malignant mesothelioma treated in two mesothelioma expert centers. Methods: Clinical data of patients with mesothelioma treated with nivolumab and ipilimumab were prospectively collected. Clinical parameters were obtained every visit, CT scans were evaluated every 12 weeks and adverse events were assessed continuously during the treatment. Data on grade 2–5 TRAE's and activity (overall response rate (ORR), duration of response (DOR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS) were reported. Results: Between January 2021 and August 2022, 184 patients were treated with nivolumab plus ipilimumab. The median follow-up was 12.1 months (95 %CI 11.1 – 13.1). Grade 3–4 TRAEs were seen in 27.7 % of the patients and 25.0 % discontinued immunotherapy treatment early because of TRAE's. ORR was 21.7 % (95 % CI 15.7–27.7), median DOR was 5.7 months (IQR 3.2–8.7) and DCR at 12 weeks 56.0 % (95 % CI 48.8–63.2). The mPFS was 5.5 months (95 %CI 4.1–6.9), mOS was 14.1 months (95 % CI 11.1–18.2). Conclusions: Nivolumab plus ipilimumab had an equal efficacy in a real-world comparable population but also a high risk of TRAE's, leading to discontinuation of treatment in 25% of the patients.</p

Scaling relations of z ∼ 0.25–1.5 galaxies in various environments from the morpho-kinematics analysis of the MAGIC sample

Context. The evolution of galaxies is influenced by many physical processes, which may vary depending on their environment. Aims. We combine Hubble Space Telescope (HST) and Multi-Unit Spectroscopic Explorer (MUSE) data of galaxies at 0.25-1.5 to probe the impact of environment on the size-mass relation, the main sequence (MS) relation, and the Tully-Fisher relation (TFR). Methods. We perform a morpho-kinematics modelling of 593 [O-II] emitters in various environments in the COSMOS area from the MUSE-gAlaxy Groups In Cosmos survey. The HST F814W images are modelled with a bulge-disk decomposition to estimate their bulge-disk ratio, effective radius, and disk inclination. We use the [O-II]λλ3727, 3729 doublet to extract the galaxies ionised gas kinematics maps from the MUSE cubes, and we model those maps for a sample of 146 [O-II] emitters, including bulge and disk components constrained from morphology and a dark matter halo. Results. We find an offset of 0.03 dex (1 significant) on the size-mass relation zero point between the field and the large structure sub-samples, with a richness threshold of N=10 to separate between small and large structures, and of 0.06 dex (2) with N=20. Similarly, we find a 0.1 dex (2A) difference on the MS relation with N=10 and 0.15 dex (3) with N=20. These results suggest that galaxies in massive structures are smaller by 14% and have star formation rates reduced by a factor of 1.31.5 with respect to field galaxies at z 0.7. Finally, we do not find any impact of the environment on the TFR, except when using N=20 with an offset of 0.04 dex (1). We discard the effect of quenching for the largest structures, which would lead to an offset in the opposite direction. We find that, at z0.7, if quenching impacts the mass budget of galaxies in structures, these galaxies would have been affected quite recently and for roughly 0.7-+1.5 Gyr. This result holds when including the gas mass but vanishes once we include the asymmetric drift correction

Characterizing non-Markovian Quantum Processes by Fast Bayesian Tomography

To push gate performance to levels beyond the thresholds for quantum error correction, it is important to characterize the error sources occurring on quantum gates. However, the characterization of non-Markovian error poses a challenge to current quantum process tomography techniques. Fast Bayesian Tomography (FBT) is a self-consistent gate set tomography protocol that can be bootstrapped from earlier characterization knowledge and be updated in real-time with arbitrary gate sequences. Here we demonstrate how FBT allows for the characterization of key non-Markovian error processes. We introduce two experimental protocols for FBT to diagnose the non-Markovian behavior of two-qubit systems on silicon quantum dots. To increase the efficiency and scalability of the experiment-analysis loop, we develop an online FBT software stack. To reduce experiment cost and analysis time, we also introduce a native readout method and warm boot strategy. Our results demonstrate that FBT is a useful tool for probing non-Markovian errors that can be detrimental to the ultimate realization of fault-tolerant operation on quantum computing

Cyber Security: China and Russia\u27s Erosion of 21st Century United States\u27 Hegemony

With Russia and China emerging as challengers to U.S. hegemony, the use of cyber warfare could tilt the current balance of power in either of their favors. Using various methods, hackers can acquire sensitive information and destroy online infrastructures. In the development of cyber warfare, China has become a seasoned veteran with computer virus operations dating back to 199714. Russia has emerged as a cyber aggressor, as seen in Russia’s cyber attacks on several countries in the last decade. This paper argues that, with the growth of foreign cyber technology, the probability of cyberspace being used as a military front by state or non-state actors against the United States increases

Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. Objectives: AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. Results: We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. Conclusion: Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention

Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials

Objective To compare the effectiveness of elective single embryo transfer versus double embryo transfer on the outcomes of live birth, multiple live birth, miscarriage, preterm birth, term singleton birth, and low birth weight after fresh embryo transfer, and on the outcomes of cumulative live birth and multiple live birth after fresh and frozen embryo transfers

Local Cooperativity in an Amyloidogenic State of Human Lysozyme Observed at Atomic Resolution

The partial unfolding of human lysozyme underlies its conversion from the soluble state into amyloid fibrils observed in a fatal hereditary form of systemic amyloidosis. To understand the molecular origins of the disease, it is critical to characterize the structural and physicochemical properties of the amyloidogenic states of the protein. Here we provide a high-resolution view of the unfolding process at low pH for three different lysozyme variants, the wild-type protein and the mutants I56T and I59T, which show variable stabilities and propensities to aggregate in vitro. Using a range of biophysical techniques that includes differential scanning calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate that thermal unfolding under amyloidogenic solution conditions involves a cooperative loss of native tertiary structure, followed by progressive unfolding of a compact, molten globule-like denatured state ensemble as the temperature is increased. The width of the temperature window over which the denatured ensemble progressively unfolds correlates with the relative amyloidogenicity and stability of these variants, and the region of lysozyme that unfolds first maps to that which forms the core of the amyloid fibrils formed under similar conditions. Together, these results present a coherent picture at atomic resolution of the initial events underlying amyloid formation by a globular protein

First Season QUIET Observations: Measurements of CMB Polarization Power Spectra at 43 GHz in the Multipole Range 25 <= ell <= 475

The Q/U Imaging ExperimenT (QUIET) employs coherent receivers at 43GHz and 95GHz, operating on the Chajnantor plateau in the Atacama Desert in Chile, to measure the anisotropy in the polarization of the CMB. QUIET primarily targets the B modes from primordial gravitational waves. The combination of these frequencies gives sensitivity to foreground contributions from diffuse Galactic synchrotron radiation. Between 2008 October and 2010 December, >10,000hours of data were collected, first with the 19-element 43GHz array (3458hours) and then with the 90-element 95GHz array. Each array observes the same four fields, selected for low foregrounds, together covering ~1000deg^2. This paper reports initial results from the 43GHz receiver which has an array sensitivity to CMB fluctuations of 69uK sqrt(s). The data were extensively studied with a large suite of null tests before the power spectra, determined with two independent pipelines, were examined. Analysis choices, including data selection, were modified until the null tests passed. Cross correlating maps with different telescope pointings is used to eliminate a bias. This paper reports the EE, BB and EB power spectra in the multipole range ell=25-475. With the exception of the lowest multipole bin for one of the fields, where a polarized foreground, consistent with Galactic synchrotron radiation, is detected with 3sigma significance, the E-mode spectrum is consistent with the LCDM model, confirming the only previous detection of the first acoustic peak. The B-mode spectrum is consistent with zero, leading to a measurement of the tensor-to-scalar ratio of r=0.35+1.06-0.87. The combination of a new time-stream double-demodulation technique, Mizuguchi-Dragone optics, natural sky rotation, and frequent boresight rotation leads to the lowest level of systematic contamination in the B-mode power so far reported, below the level of r=0.1Comment: 19 pages, 14 figures, higher quality figures are available at http://quiet.uchicago.edu/results/index.html; Fixed a typo and corrected statistical error values used as a reference in Figure 14, showing our systematic uncertainties (unchanged) vs. multipole; Revision to ApJ accepted version, this paper should be cited as "QUIET Collaboration et al. (2011)

The QUIET Instrument

The Q/U Imaging ExperimenT (QUIET) is designed to measure polarization in the Cosmic Microwave Background, targeting the imprint of inflationary gravitational waves at large angular scales (~ 1 degree). Between 2008 October and 2010 December, two independent receiver arrays were deployed sequentially on a 1.4 m side-fed Dragonian telescope. The polarimeters which form the focal planes use a highly compact design based on High Electron Mobility Transistors (HEMTs) that provides simultaneous measurements of the Stokes parameters Q, U, and I in a single module. The 17-element Q-band polarimeter array, with a central frequency of 43.1 GHz, has the best sensitivity (69 uK sqrt(s)) and the lowest instrumental systematic errors ever achieved in this band, contributing to the tensor-to-scalar ratio at r < 0.1. The 84-element W-band polarimeter array has a sensitivity of 87 uK sqrt(s) at a central frequency of 94.5 GHz. It has the lowest systematic errors to date, contributing at r < 0.01. The two arrays together cover multipoles in the range l= 25-975. These are the largest HEMT-based arrays deployed to date. This article describes the design, calibration, performance of, and sources of systematic error for the instrument