High Resolution Magnetic Micro-calorimeters: Thermodynamics, Cooling Requirements, and Noise

Magnetic micro-calorimeters (MMCs) are cryogenic particle detectors well suited for high-precision X-ray spectroscopy. They measure the temperature rise caused by an X-ray impact via the change in magnetization of a paramagnetic temperature sensor. Until now, MMCs have been designed to operate at around 20mK, requiring sophisticated cooling, which limits their application. In this work, we show that magnetic micro-calorimetry is possible at significantly higher temperatures, by developing two novel MMCs with reduced cooling requirements. The first illustrates a new application for MMCs in the field of particle induced X-ray emission spectroscopy. At an operating temperature of 85mK, this detector has a FWHM energy resolution of 19eV at 5.9keV, outperforming current alternatives. Our second MMC is a proof-of-principle detector, which demonstrates that operating temperatures of up to 300mK are feasible. With a third, stand-alone device, we analyze noise sources affecting superconducting microstructures, such as MMCs. By comparing results from three different operation modes, we are able to disentangle noise components, in particular magnetic flux noise. High-precision measurements of noise originating from the sensor show a previously unobserved Johnson noise component and unexpected variations in the magnetic flux noise, which we relate to the dynamics of the magnetic moments in the sensor. Overall, our results broaden the application range of MMCs, and illustrate how noise analysis can improve the performance of superconducting devices

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signaling in The Prefrontal Cortex Modulates Cued Fear Learning, But Not Spatial Working Memory, in Female Rats

A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. Moreover, a neurobiological substrate that may account for the observed link between PAC1R and PTSD in women, but not men, has yet to be identified. Sex differences in PACAP signaling during emotional learning could provide novel targets for the treatment of PTSD. Here we investigated the contribution of PAC1R signaling within the prefrontal cortex to the acquisition of cued fear in female and male rats. We used a variant of fear conditioning called trace fear conditioning, which requires sustained attention to fear cues and depends on working-memory like neuronal activity within the prefrontal cortex. We found that cued fear learning, but not spatial working memory, was impaired by administration of a PAC1R antagonist directly into the prelimbic area of the prefrontal cortex. This effect was specific to females. We also found that levels of mRNA for the PAC1R receptor in the prelimbic cortex were greater in females compared with males, and were highest during and immediately following the proestrus stage of the estrous cycle. Together, these results demonstrate a sex-specific role of PAC1R signaling in learning about threat-related cues

Ground Improvement for Increasing Lateral Pile Group Resistance

Lateral load tests were performed on a full-scale pile cap in untreated clay along with pile groups involving (a) excavation and replacement with sand backfill, (b) a soilcrete wall along the side of the pile group, and (c) a jet grouted zone below the pile cap. The average compressive strength of the soft, plastic clay increased from an average of 50 kPa to an average of about 1000 kPa with soil mixing (10% cement) and to 3000 kPa with jet grouting (20% cement). Excavation and replacement only increased resistance by about 20%; however, the soil mixed wall increased resistance by 60%, and jet grouting increased resistance by 160%. For the soil mixed wall, essentially all of the increased resistance can be explained due to passive pressure and side/base shear against the soil mixed wall. However, for the jet grout treatment, additional resistance can also be attributed to increased structural resistance of the composite soilcrete volume under the cap. Soil mixing and jet grouting provide a means to significantly increase the lateral resistance of existing pile group foundations with relatively little investment of time, effort, and expense relative to the addition of more piles

Measuring Magnetic 1/f Noise in Superconducting Microstructures and the Fluctuation-Dissipation Theorem

The performance of superconducting devices like qubits, SQUIDs, and particle detectors is often limited by finite coherence times and 1/f noise. Various types of slow fluctuators in the Josephson junctions and the passive parts of these superconducting circuits can be the cause, and devices usually suffer from a combination of different noise sources, which are hard to disentangle and therefore hard to eliminate. One contribution is magnetic 1/f noise caused by fluctuating magnetic moments of magnetic impurities or dangling bonds in superconducting inductances, surface oxides, insulating oxide layers, and adsorbates. In an effort to further analyze such sources of noise, we have developed an experimental set-up to measure both the complex impedance of superconducting microstructures, and the overall noise picked up by these structures. This allows for important sanity checks by connecting both quantities via the fluctuation-dissipation theorem. Since these two measurements are sensitive to different types of noise, we are able to identify and quantify individual noise sources. The superconducting inductances under investigation form a Wheatstone-like bridge, read out by two independent cross-correlated dc-SQUID read-out chains. The resulting noise resolution lies beneath the quantum limit of the front-end SQUIDs and lets us measure noise caused by just a few ppm of impurities in close-by materials. We present measurements of the insulating SiO2 layers of our devices, and magnetically doped noble metal layers in the vicinity of the pickup coils at T = 30 mK - 800 mK and f = 1 Hz - 100 kHz.Comment: 13 pages, 5 figure

The Orbit and Occultations of KH 15D

The unusual flux variations of the pre-main-sequence binary star KH 15D have been attributed to occultations by a circumbinary disk. We test whether or not this theory is compatible with newly available data, including recent radial velocity measurements, CCD photometry over the past decade, and photographic photometry over the past 50 years. We find the model to be successful, after two refinements: a more realistic motion of the occulting feature, and a halo around each star that probably represents scattering by the disk. The occulting feature is exceptionally sharp-edged, raising the possibility that the dust in the disk has settled into a thin layer, and providing a tool for fine-scale mapping of the immediate environment of a T Tauri star. However, the window of opportunity is closing, as the currently visible star may be hidden at all orbital phases by as early as 2008.Comment: To appear in ApJ [16 pages, 13 figures

Health-related quality of life in KEYNOTE-010 : a phase II/III study of pembrolizumab versus docetaxel in patients with previously treated advanced, programmed death ligand 1-expressing NSCLC

Introduction: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score >= 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here. Methods: Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks or docetaxel 75 mg/m(2) every 3 weeks. HRQoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30 (C30), EORTC QLQ-Lung Cancer 13 (LC13), and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain. Results: Patient reported outcomes compliance was high across all three instruments. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or tumor proportion score status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had "deteriorated" status and more had "improved" status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true time to deterioration for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided p = 0.03), but not for the 2-mg/kg dose. Conclusions: These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus During Macrophage Cell Death.

RATIONALE: Pulmonary aspergillosis is a lethal mould infection in the immunocompromised host. Understanding initial control of infection, and how this is altered in the immunocompromised host, is a key goal for understanding the pathogenesis of pulmonary aspergillosis. OBJECTIVES: To characterise the outcome of human macrophage infection with Aspergillus fumigatus, and how this is altered in transplant recipients on calcineurin inhibitor immunosuppressants. METHODS: We defined the outcome of human macrophage infection with Aspergillus fumigatus, and the impact of calcineurin inhibitors, through a combination of single cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies. MEASUREMENTS AND MAIN RESULTS: Macrophage phagocytosis of Aspergillus fumigatus enabled control of 90% of fungal germination. However fungal germination in the late phagosome led to macrophage necrosis. During programmed necroptosis, we observed frequent cell-cell transfer of Aspergillus fumigatus between macrophages which assists subsequent control of germination in recipient macrophages. Lateral transfer occurred through actin-dependent exocytosis of the late endosome in a vasodilator-stimulated phosphoprotein (VASP) envelope. Its relevance to the control of fungal germination was also shown by direct visualisation in our zebrafish aspergillosis model in vivo. The calcineurin inhibitor FK506/tacrolimus reduced cell death and lateral transfer in vitro by 50%. This resulted in uncontrolled fungal germination in macrophages and hyphal escape. CONCLUSIONS: These observations identify programmed necrosis-dependent lateral transfer of Aspergillus fumigatus between macrophages as an important host strategy for controlling fungal germination. This process is critically dependent on calcineurin. Our studies provide fundamental insights into the pathogenesis of pulmonary aspergillosis in the immunocompromised host

Planetary Construction Zones in Occultation: Discovery of an Extrasolar Ring System Transiting a Young Sun-like Star and Future Prospects for Detecting Eclipses by Circumsecondary and Circumplanetary Disks

The large relative sizes of circumstellar and circumplanetary disks imply that they might be seen in eclipse in stellar light curves. We estimate that a survey of ~10^4 young (~10 Myr old) post-accretion pre-MS stars monitored for ~10 years should yield at least a few deep eclipses from circumplanetary disks and disks surrounding low mass companion stars. We present photometric and spectroscopic data for a pre-MS K5 star (1SWASP J140747.93-394542.6), a newly discovered ~0.9 Msun member of the ~16 Myr-old Upper Cen-Lup subgroup of Sco-Cen at a kinematic distance of 128 pc. SuperWASP and ASAS light curves for this star show a remarkably long, deep, and complex eclipse event centered on 29 April 2007. At least 5 multi-day dimming events of >0.5 mag are identified, with a >3.3 mag deep eclipse bracketed by two pairs of ~1 mag eclipses symmetrically occurring +-12 days and +-26 days before and after. Hence, significant dimming of the star was taking place on and off over at least a ~54 day period in 2007, and a strong >1 mag dimming event occurred over a ~12 day span. We place a firm lower limit on the period of 850 days (i.e. the orbital radius of the eclipser must be >1.7 AU and orbital velocity must be <22 km/s). The shape of the light curve is similar to the lop-sided eclipses of the Be star EE Cep. We suspect that this new star is being eclipsed by a low-mass object orbited by a dense inner disk, girded by at least 3 dusty rings of lower optical depth. Between these rings are at least two annuli of near-zero optical depth (i.e. gaps), possibly cleared out by planets or moons, depending on the nature of the secondary. For possible periods in the range 2.33-200 yr, the estimated total ring mass is ~8-0.4 Mmoon (if the rings have optical opacity similar to Saturn's rings), and the edge of the outermost detected ring has orbital radius ~0.4-0.09 AU.Comment: Astronomical Journal, in press, 13 figure

457 KEYNOTE-495/KeyImPaCT: interim analysis of a randomized, biomarker-directed, phase 2 trial of pembrolizumab-based combination therapy for non–small cell lung cancer (NSCLC)

BackgroundT-cell–inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) are clinically validated biomarkers that independently predict pembrolizumab response. This study investigated prospective TcellinfGEP and TMB assessment in evaluating first-line pembrolizumab-based combination therapies; the different treatment combinations evaluated may provide insight into the unique biology of each biomarker subgroup.MethodsKEYNOTE-495/KeyImPaCT is a group-sequential, adaptively randomized, multisite, open-label, phase 2 study investigating first-line pembrolizumab plus the VEGF/FGFR inhibitor lenvatinib, CTLA-4 inhibitor quavonlimab (MK-1308), or LAG-3 inhibitor favezelimab (MK-4280) in patients with advanced NSCLC. DNA and RNA were extracted from tumor tissue to determine TcellinfGEP and TMB; patients were assigned to one of four biomarker-defined subgroups (TcellinfGEPlowTMBlow, TcellinfGEPlowTMBhigh, TcellinfGEPhighTMBlow, TcellinfGEPhighTMBhigh) and randomly assigned 1:1:1 to receive pembrolizumab (200mg IV Q3W)+lenvatinib (20mg oral QD), pembrolizumab+quavonlimab (75mg IV Q6W), or pembrolizumab+favezelimab (200mg [n=30] or 800mg [n=34] Q3W; the initial prespecified dose was 200mg but changed to 800mg based on emerging data). The primary end point was investigator-assessed ORR per RECIST v1.1. Multiple interim analyses will be performed until the prespecified clinical signal is observed. The first interim analysis for each combination therapy occurred after ≥10 patients had ≥12 weeks of follow-up.ResultsAt the data cutoff (January 11, 2021), 208 patients were treated (pembrolizumab+lenvatinib, n=72; pembrolizumab+quavonlimab, n=72; pembrolizumab+favezelimab 200mg, n=30; pembrolizumab+favezelimab 800mg, n=34). The overall assay success rate for testing and determining TcellinfGEP and TMB was 94%. In patients treated with pembrolizumab+lenvatinib, pembrolizumab+quavonlimab, or pembrolizumab+favezelimab, ORRs were generally highest in the TcellinfGEPhighTMBhigh subgroup (table 1); response rates were similar across combinations within this subgroup. ORR was low across combinations within the TcellinfGEPlowTMBlow subgroup. Treatment-related adverse events (TRAEs) occurred in 88%, 65%, 57%, and 59% of patients in the pembrolizumab+lenvatinib, pembrolizumab+quavonlimab, pembrolizumab+favezelimab 200mg and pembrolizumab+favezelimab 800mg arms, respectively. Consistent with the known TRAEs of these agents, most TRAEs were grade 1 or 2 in severity except in the pembrolizumab+lenvatinib arm (grade 3–5, 63%). Three deaths from TRAEs occurred (pembrolizumab+lenvatinib [n=2], brain hemorrhage and myocardial infarction; pembrolizumab+favezelimab 800 mg [n=1], pneumonitis).Abstract 457 Table 1Confirmed ORR by Therapy and Biomarker StatusConclusionsThese data demonstrate the feasibility and clinical usefulness of prospective TcellinfGEP and TMB assessment to study the clinical activity of three first-line pembrolizumab-based combination therapies in patients with advanced NSCLC. Although sample sizes were small, the TcellinfGEPhighTMBhigh subgroup demonstrated the best response among the biomarker subgroups for all three combination therapies; further validation is needed to determine additional signals and may be addressed as more mature data become available.AcknowledgementsJeanne Fahey, PhD, of Merck & Co., Inc., Kenilworth, New Jersey, USA, provided critical review of the abstract. Elisha Dettman PhD, Mark Ayers MS, and Andrey Loboda PhD of Merck & Co., Inc., Kenilworth, New Jersey, USA, provided critical review of study translational data. Medical writing and/or editorial assistance was provided by Shane Walton, PhD, and Lei Bai, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicalTrials.gov, NCT03516981Ethics ApprovalThe study protocol and all amendments were approved by the relevant institutional review board or ethics committee at each study site. All patients provided written informed consent to participate in the clinical trial

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC)

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy – characterized by some benefit but only rare durable responses – was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field