Search

Adding anti-PD1 antibodies to 5-FU/platinum chemotherapy improves survival in a subset of advanced gastroesophageal adenocarcinoma (GEA) patients. Beyond PD-L1 expression and mismatch repair status we have limited insight into molecular predictors of response, or the relative contribution of PD-1 blockade. We conducted an investigator sponsored phase II trial (n = 47) sequentially adding pembrolizumab to standard 5-FU/platinum in previously untreated advanced GEA (ClinicalTrials.gov: NCT04249739). With an overall response rate of 67% the activity paralleled phase III chemoimmunotherapy trials. To understand on-treatment tumor and immune adaptations patients underwent serial biopsy of the primary tumor, including baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab. We leveraged transcriptional profiling from 358,067 cells to identify multicellular networks of malignant, stromal, and immune cells after chemotherapy and concurrent chemoimmunotherapy. The relative usage of pro-tumor and anti-tumor interaction hubs differed between fast and slow progressing patients. Chemotherapy induced early on-treatment formation of hubs centered on tumor-reactive T-cell and M1-oriented macrophage interactions with pro-inflammatory cytokines in slow progressors. Faster progression was characterized by increased MUC5A and MSLN containing programs in tumor cells and M2-oriented macrophages with immunosuppressive stromal interactions. After adding pembrolizumab we observed increased CD8 T-cell infiltration by scRNAseq and multiplex immunofluorescence and development of an immunity hub involving co-variation of the tumor-reactive CXCL13 program and epithelial interferon-stimulated gene programs enriched in slow progressors. Together this data provides prospective evidence of differential early on-treatment evolution of the gastric immune microenvironment and nominates candidate cellular interactions for clinical targeting.

NASA’s Juno spacecraft performed close flybys of the Galilean moons Ganymede in June 2021 and Europa in September 2022. During each of these encounters, the Juno spacecraft passed behind the moons as observed from Earth, providing the geometry for a radio occultation experiment to measure the electron densities of the ionospheres of these moons – the first opportunity to do so since the Galileo mission in the 1990s. Electrons encountered along the radio propagation path advance the signal’s phase. These small changes are detectable in the sensitive receivers of the Deep Space Network antennas. Ganymede’s tenuous ionosphere was detected on occultation ingress but no ionosphere was detected on egress. The interaction of the ionosphere with Ganymede’s intrinsic magnetosphere is believed to be the reason for the variability of the ionosphere, since ingress occurred on an open-field line region where electron impact ionization could be higher. At Europa, the occultation probed the Southern mid-latitudes on ingress and near the equatorial region on egress, with results consistent when compared with the six radio occultations of Europa from Galileo. Future occultation science with Juno will occur in 2023 and 2024 with radio occultations of Jupiter’s atmosphere and ionosphere.

We use the magnetic and gravity field data jointly to place constraints on the internal structure of Ganymede. The magnetic induction constraint comes mostly from the Galileo data, as the Juno flyby occurred when Ganymede was near the center of the magnetodisk, thus leading to low sensitivity to magnetic induction. The gravity field model of Ganymede jointly derived from the Galileo and Juno data to place constraints on Ganymede’s internal structure. Unlike in the previous works, the hydrostaticity was not imposed on the degree-2 gravity coefficients. Thus, despite including additional data from Juno, the uncertainties on the degree-2 coefficients increased. In addition, we explicitly treat the effect of non-hydrostaticity on the derived moment of inertia and find significantly wider confidence intervals on the moment of inertia. This leads to a larger allowed parameter space for the internal structure model.The new gravity solution confirms the past detection of non-hydrostatic anomalies. In our analysis, localized non-hydrostatic features with amplitudes higher than those found on Titan by the Cassini mission are identified. Titan is a useful comparison case as it shares with Ganymede nearly the same mean radius, mean density, and therefore, surface gravity. Thus, the non-hydrostatic deviations of the same amplitude either in shape or in gravity would correspond to approximately the same level of non-hydrostatic stress. On Titan, the gravity field for degree l > 2 reaches at most 5 mGal (Durante et al., 2019), which is a factor of 5 smaller than the largest anomalies found on Ganymede. One key difference between the two bodies is the lack of atmosphere-based erosion processes on Ganymede. Such erosional processes could have led to faster removal of non-hydrostatic signals at Titan reducing the amplitude of its gravity anomalies. In addition, Titan’s outer shell could be thinner and, therefore, less rigid than that of Ganymede, thus not being able to support as much non-hydrostaticity.Further insights on Ganymede’s interior will be coming from the JUICE mission in the next decade. Currently, the lack of an accurate shape model prevents separating degree-2 hydrostatic and non-hydrostatic contributions. Combined gravity, topography and rotation data acquired by JUICE will be crucial in determining the non-hydrostatic contribution to the degree-2 field to constrain Ganymede’s internal structure.

Supplementary Table 1 from Smad3 Deficiency Promotes Tumorigenesis in the Distal Colon of ApcMin/+ Mice

Colorectal cancer, one of the most common human malignancies in the Western world, is often subdivided based on tumor location in either the distal or proximal colon. Several mouse models have been developed to study human colorectal cancer, but few display this clear distinction between the two colonic locations. By crossing ApcMin/+ and Smad3 mutant mice, we showed that combined activation of the Wnt pathway and attenuation of the transforming growth factor-β (TGF-β) pathway causes high multiplicity and rapid onset of invasive tumorigenesis almost exclusively in the distal colon, closely mimicking the familial adenomatous polyposis (FAP) disease and consisting with distinct colorectal cancer etiologies based on tumor location. Transcriptional profiling revealed higher expression of several TGF-β activators in the normal distal mucosa than in proximal mucosa, suggesting a stronger reliance on TGF-β-mediated growth control in the distal than in the proximal colon. ApcMin/+Smad3−/− mice provide an alternative model to ApcMin/+ mice to study FAP and distal sporadic colorectal cancer. This model will be useful in dissecting mechanistic and etiologic differences between proximal and distal colonic cancer, whereas the confinement of tumorigenesis to the distal colon offers unique advantages in monitoring tumor progression by in vivo imaging. (Cancer Res 2006; 66(17): 8430-8)

The thickness of the outer ice shell plays an important role in several geodynamical processes at ocean worlds. Here we show that observations of tidally-driven diurnal surface displacements can constrain the mean effective elastic thickness, ˜del, of the ice shell. Such estimates are sensitive to any significant structural features that break spherical symmetry such as faults and lateral variation in ice shell thickness and structure. We develop a finite-element model of Enceladus to calculate diurnal tidal displacements for a range of ˜del values in the presence of such structural heterogeneities. We find that the presence of variations in ice shell thickness can significantly amplify deformation in thinned regions. If major faults are also activated by tidal forcing—such as Tiger Stripes on Enceladus—their characteristic surface displacement patterns could easily be measured using modern geodetic methods. Within the family of Enceladus models explored, estimates of ˜del that assume spherical symmetry a priori can deviate from the true value by as much as ~ 20% when structural heterogeneities are present. Such uncertainty is smaller than that found with approaches that rely on static gravity and topography (~ 250%) or analyzing diurnal libration amplitudes (~ 25%) to infer ˜del at Enceladus. As such, despite the impact of structural heterogeneities, we find that analysis of diurnal tidal deformation is a relatively robust approach to inferring ˜del.

Tidal interaction is presumed to play a crucial role in the long term evolutionof the orbits of the Galilean satellites. Io's active volcanism and associatedheat flow are probably driven by tidal dissipation within the satellite. It isof high interest to determine whether Io is spiraling toward or away fromJupiter. If the former is true, Io is losing more energy through internaldissipation than it is gaining from the torque on the tidal bulge that it raiseson Jupiter. Lainey et al. (2009 Nature 459, 957) published an investigationof tidal effects in the Jovian system based on an analysis of astrometricobservations through 2007 and mutual events through 2003. Their modellingincluded the tide raised on Jupiter by each Galilean satellite and the tideraised on Io by Jupiter. Subsequently, we extended their analysis addingadditional astrometry through through 2013, mutual events through 2009, Galileansatellite eclipse timings, and data acquired by the Voyager, Cassini, Galileo,and New Horizons spacecraft (Jacobson and Folkner, 2014 AAS/Division forPlanetary Sciences Meeting Abstracts 46 418.03). With the inclusion ofthe spacecraft data, we found that the tidal effects became barely dectectableif at all. On 2021 June 07 the Juno spacecraft flew by Ganymede at an altitude 1046 km.Unlike our previous work, when we added the Juno tracking data to our data set(also extended to astrometry through 2018 and mutual events in 2015), we wereable to obtain a strong determination of the dissipation, k2/Q (k2 is the lovenumber, Q is the tidal quality factor), of both Jupiter and Io. Our analysisincorporated the Jupiter love number recently reported by Wahl et al. (2020 Astrophys. J. 891, 42) from Juno tracking data. Our Jupiter Q falls withinthe bounds postulated by Peale (1999 Ann. Review Astron. Astrophys. 37,533). The heat flux computed with our k2/Q for the tide raised on Io is withinthe estimated range based on the observed heat radiated by Io (McEwen et al.2004, Jupiter, Cambridge Univ. Press, 281). As a consequence of the tidalforces, our orbit for Io is spiraling inward confirming the significant internalenergy loss. Our orbit for Europa is also spiraling inward as it attempts tomaintain its orbital resonance with Io despite the tidal force acting on it fromJupiter. Ganymede, on the other hand, is on an outward spiral, moving out of itsresonance with Europa. The tidal force appears to be too small to detectablyalter Callisto's orbit.

Since the first gravity measurements of Juno at Jupiter, the odd gravity harmonics J3 to J9 have been used to determine the depth of the zonal wind observed at the cloud level. Later on, combining solutions from internal models, the gravity harmonics J6, J8 and J10 were added to the analysis, which reinforced the conclusion that the observed zonal flows extend to a depth of around 3,000 km. The harmonics higher than J10 were not used in the analysis since their individual uncertainty was too large. In this study, we revisit the wind-gravity analysis, using new gravity data from Juno and a new analysis method, showing results for higher harmonic gravity measurements. This gives more detail about the structure of the deep zonal flows and allows better explaining the structure of the gravity spectrum. This confirms that indeed the observed flows are the ones which imprint the gravity spectrum. Moreover, this analysis allows to better determine which part of the wind field most contributes to the gravity signal, implying on the depth of individual jet streams. We also show how the new gravity measurement analysis allows to refine the surface gravity field, particularly in the latitudinal range of the closest approach of the spacecraft.

ESA’s JUICE and NASA’s Europa Clipper (EC) are the next two missions to the Jupiter system, focusing on three of the Galilean moons: Europa, Ganymede, and Callisto.JUICE will spend four years in the Jovian system and after tens of flybys of Europa, Ganymede, and Callisto will enter into orbit around Ganymede where it will nominally remain for nine months, until its end of mission. EC will also spend about four years in orbit around Jupiter, performing more than 50 flybys of Europa, the main mission target, but it will also fly by Ganymede and Callisto several times. Combining the data of the two missions will enable a better global estimation of the moons’ gravity fields and ephemerides.During the Jupiter tours of both missions and JUICE’s Ganymede orbital phase, radiometric tracking data will be acquired at Earth ground stations, enabling precise spacecraft orbit determination, and joint estimation of the main dynamical parameters of the Jupiter system. The two missions rely on different radio links: JUICE is endowed with a triple two-way radio link configuration in two frequency bands (X/X, X/Ka and Ka/Ka) which will allow for a full calibration of dispersive noise sources. EC is capable of X/X and X/Ka links, with X/X being the nominal configuration during Europa flybys. Range, range-rate, as well as VLBI (lateral positioning) tracking data, from both missions, will allow to retrieve the static gravity field and tidal parameters of the moons, together with their orbital position. This will also provide crucial information about Jupiter’s gravity tidal parameters, in particular the imaginary part of its Love numbers at the frequency of the Galilean moons. A better characterization of tidal interactions between Jupiter and the Galilean moons can unveil crucial information about the stability and the evolution of the Laplace resonance, governing the dynamics of the three innermost Galilean moons.In this study, we analyze the attainable uncertainties for the parameters characterizing the ephemerides reconstruction of the Galilean moons using range, range-rate, and VLBI simulated observables. VLBI data mainly provide the spacecraft angular position with respect to reference radio sources (quasars) tied to an inertial frame (“plane of sky”), while range and range and range-rate (being computed along the line of sight) especially constrain the spacecraft state within their orbital plane. Including VLBI data is thus expected to be particularly effective in improving the uncertainty of the moon ephemerides in the out-of-plane direction. We will quantify the synergy between the different radiometric observable types, assess their respective contribution to the moons' ephemerides, the imaginary part of Jupiter’s Love number and analyze the sensitivity of the estimation solution to various parameters (observation planning, expected data quality, etc.)

Background The aim of this exploratory preclinical study was to evaluate the efficacy of 18F-FMAU PET in quantitatively measuring response to a chemotherapeutic agent in experimental prostate cancer models. Methods and Materials: Docetaxel (DTX) ‒ a standard therapy agent in castrate-resistant metastatic prostate cancer was used as the chemotherapy drug. Athymic male nu/nu mice were inoculated with PC-3 cells in the right flank. After the tumor diameter reached 5 mm, DTX (24 mg/kg) was injected intravenously twice/week, whereas the control group was intravenously administered with saline. During the therapeutic period, the tumor size and body weight were monitored, and longitudinal PET scans were acquired with 18F-FMAU to evaluate tumor cell proliferation. 18F-FMAU PET scans were performed at 2 h post-injection of 18F-FMAU on days 0, 11, 18, and 22. Biodistribution studies were carried out after the PET scan on day 22. Results Consecutive administrations of DTX were effective in inhibiting PC-3 tumor growth compared to the control group. For PET imaging, PC-3 tumor uptake of 18F-FMAU in the treatment group was increased significantly from 3.09 ± 0.60%ID/g (day 0) to 5.32 ± 0.37%ID/g (day 22), whereas the 18F-FMAU tumor update in the control group remained relatively similar on day 0 (2.37 ± 0.51%ID/g) vs. day 22 (1.83 ± 0.22%ID/g). The tumor-to-muscle uptake ratio of 18F-FMAU was increased from 2.63 ± 0.20 (day 0) to 5.91 ± 1.1 (day 22) in the treatment group. On day 22, no statistical significance was observed on the tumor-to-muscle uptake ratio of 18F-FMAU in the treatment group vs. the control group. The tumor-to-liver uptake ratio of 18F-FMAU was also similar on day 22 in the treatment group (4.29 ± 0.09) vs. the control group (3.83 ± 0.59). Conclusion 18F-FMAU uptake in implanted PC-3 tumors increases with DTX treatment despite the decline in tumor size. Further investigation is needed to decipher the underlying biological mechanism of this flare effect and its relation to the predictability of therapy response.

Io, the world with the greatest tidal flexing, volcanic and tectonic activity, and mass-loss in our solar system, begs for dedicated exploration. Missions such as Juno and JUICE, along with Earth-based telescopes such as JWST and ALMA, will acquire important Io observations over the next 15 years, as could Europa Clipper. However, a mission designed for Io science is necessary to accomplish key science goals that have been consistently prioritized in the National Academy of Sciences Decadal Surveys and the ESA Voyage 2050 (Thomas, 2021, Experimental Astronomy online), including understanding the early evolution of terrestrial planets, tidally heated exoplanets and ocean worlds, and magnetospheric physics across the galaxy. The NASA Discovery-class Io Volcano Observer (IVO; McEwen et al., 2021, LPSC 1352) completed Phase A in 2021 and was deemed selectable, but was not chosen for programmatic (i.e., non-science/engineering) reasons. The IVO concept study demonstrated how a total of ten carefully designed, close Io flybys could determine the melt distribution in Io’s interior to confirm or refute the presence of a magma ocean, constrain Io’s global average lithospheric structure, identify where and how Io is losing heat, and determine processes and rates for Io’s volatile loss. Such encounters would also measure Io’s rate of orbital migration, key to determining the stability of the LaPlace resonance that heats Europa and Ganymede, as well as Io. The ambitious (for Discovery) science payload included a magnetometer, plasma instrument, narrow-angle camera, thermal mapper, neutral mass spectrometer, plus a telecom system for gravity science and options for a student-collaboration wide-angle camera (WAC), and a technology demonstration UV spectrometer. The next Discovery mission proposal opportunity is expected in 2025 or later, but an opportunity to propose an Io mission in NASA’s New Frontiers (NF) program is anticipated in 2023. How might that differ from a Discovery-class mission? An Io orbiter to provide better geophysical measurements has been suggested in the past, but would be very challenging deep inside Jupiter’s gravity well and high radiation zone. An orbiter might be feasible if new, more capable launch vehicles become available. On the other hand, the IVO Discovery concept would accomplish all of the science objectives of NF, and could be augmented in several key ways using the additional resources available in NF. A radiation design to support more than 10 encounters is a relatively straightforward enhancement. Ka-band would improve the data downlink capability and gravity science. With twice as many Io encounters, it would be possible to more completely map Io’s surface at multiple wavelengths; encounter Io over additional values of orbital true anomaly for improved gravity science, magnetic induction, and measuring Io’s libration; and sample more longitudes and times of day to understand Io’s atmosphere, plumes, magnetospheric interactions, and mass loss. The WAC, which is especially important for mapping Io’s topography, could be a required Baseline experiment. There are many science instruments that would be valuable additions, including altimetry, ultraviolet and near-IR spectroscopy, a dust mass spectrometer, passive radar sounding (using Jupiter radiation), active radar sounding, and additional fields and particle instruments. Greater emphasis may be placed on tracing the mass and energy flows in the Io-Jupiter system, especially because the new US Planetary Science and Astrobiology Decadal Survey places much emphasis on understanding planetary systems relevant to exoplanets. Interferometric synthetic aperture radar (InSAR) would be challenging but could transform our understanding of active processes on Io. An even more daring idea is to deliver a penetrator that could measure Io’s seismicity and conducted heat flow, perhaps also with a laser retroreflector or radio transponder to measure Io’s rotational and tidal deformation. However, getting substantial data back to the main spacecraft for transmittal to Earth is challenging in the very fast flybys that are preferred to keep the total ionizing radiation dose low. In terms of international collaboration, we expect a thermal mapper from DLR and a neutral mass spectrometer from UBE, plus science co-investigators; additional contributions are possible. In summary, a highly capable mission to one of the most exciting objects in the Solar System is overdue. Figure: Io is a spectacular target to observe both in daytime and at night (simulated hot spots).

Pancreatic cancer is a lethal disease in part because tumor cells exist in distinct transcriptional phenotypes (e.g. basal and classical states), each with a selective ability to evade current chemotherapy regimens. Two major mechanisms have been suggested for treatment evasion: 1) intrinsic resistance of certain phenotypes to particular chemotherapy regimens and 2) plasticity of treatment sensitive phenotypes to adopt more resistant phenotypes. However, the relative contribution of these mechanisms to treatment resistance is still poorly understood. Whereas previous work has described the redistribution of tumor cell states under selective treatment pressure, there is no direct evidence that tumor cells exhibit phenotypic plasticity at steady state or with treatment. By leveraging technological advancements in single-cell methods, lineage tracing and functional genomics, we have now shown direct evidence of phenotypic state switching in human pancreatic cancer cell lines. By performing single-cell RNA-seq on 5 barcoded PDAC cell lines over a steady state timecourse and under chemotherapy selective pressure (>600k cells total), we identify unique plasticity phenotypes within these cell lines and infer regulators of these plastic states. We validate the role of several of these regulators using bulk phenotypic CRISPRi screens in these cell lines. We next perform CRISPRi perturbations along with lineage tracing and single-cell multiomics (>300k cells) to dissect the regulatory relationships that underlie these cell states. We identify several novel epithelial and mesenchymal biasing factors, including those with unique roles in the most plastic clones. Collectively, we nominate several regulators that bias PDAC cell states thus posing a paradigm whereby perturbations may be used to homogenize tumor populations towards treatment-sensitive phenotypes. We believe this approach combined with current chemotherapy regimens could benefit pancreatic cancer patients by targeting residual, resistant tumor cells in the localized and metastatic disease settings to improve patient survival. Citation Format: Arnav Mehta, Lynn Bi, Aziz Al'Khafaji, Martin Jankowiak, Milan Parikh, Mehrtash Babadi, Alex Bloemendal, Marc Schwartz, Glen Munson, Joeseph Chan, Cassandra Burdziak, Elisa Donnard, Ryan Park, Chen Lu, Philippe Rigollet, Andrew Aguirre, Vidya Subramanian, Ray Jones, Eric S. Lander, David T. Ting, Dana Pe'er, Nir Hacohen. Quantifying and dissecting pancreatic cancer cell phenotypic plasticity using lineage tracing, single-cell multiomics and CRISPR perturbations reveals novel regulators of plastic states [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B016.

Immune checkpoint blockade (ICB) has revolutionized the treatment of many cancers but has been ineffective for the treatment of microsatellite stable (MSS) PDAC. The lack of efficacy of immunotherapies in PDAC is due to: 1) a desmoplastic tumor microenvironment (TME); 2) the presence of suppressive cells, including myeloid derived suppressor cells and regulatory T cells; and 3) the lack of antigen-presenting dendritic cells (DCs) that are important in priming an effective immune response to generate functionally effective tumor antigen-specific T cells. We recently completed a pilot study of dual ICB (Ipilumamab and Nivolumab) with radiation therapy (SBRT 8Gy for 3 fractions) in a cohort of 25 metastatic PDAC patients that had progressed on conventional chemotherapy; this combination conferred an impressive 18% ORR and 29% disease control rate measured on non-irradiated lesions (historical 0% ORR with ICB in PDAC). This led to a phase 2 study in 30 metastatic PDAC patients using this dual modality treatment paradigm. To understand the role of radiation and ICB in altering the PDAC tumor microenvironment we performed single-cell RNA-sequencing and TCR-sequencing (>180k cells), and single-nucleus RNA-sequencing (>300k cells) on 36 tumor biopsies (23 pre-treatment, 13 paired on-treatment between day 10 and 21) from patients undergoing treatment in our phase 2 study. Tumor tissue was taken from distinct tissue sites, including primary tumors in the pancreas, and liver and abdominal wall metastases. We identified distinct tumor cell state distributions within different tissues, and a redistribution of cells from basal/mesenchymal states to classical states after radiation. We identified several state-specific interferon stimulated gene programs thus cataloging distinct responses of epithelial cells with different transcriptional states. Importantly, we found a redistribution of T cells states towards proliferating and exhausted T cells with unique clonality after radiation. Additionally, the myeloid compartment after radiation was enriched for C1QC+ and MHCII+ macrophage subsets, as well as infiltrating CD16/CD16 monocytes and CD14 monocytes, each showing induction of unique sets of interferon stimulated genes (ISGs). We next sought to better understand immunotherapy resistance mechanisms within these PDAC patients despite finding strong ISG induction in several subsets. We analyzed covarying gene programs and identified multicellular communities of cells before and after radiation that underlie interaction networks associated with radiation. Together our data provides the most comprehensive single-cell atlas of paired biopsies to study tumor and immune cell states in the context of radiation and ICB response. Citation Format: Arnav Mehta, Aparna Parikh, Milan Parikh, Ryan Park, Moshe Sade-Feldman, Lynn Bi, Nicole Carzo, Tarin M. Grillo, Islam Baiev, Olanike Asupoto, Irena Gushterova, Tom LaSalle, Anna Gonye, Emily Blaum, Sebastien Vigneau, Ronan Chaligne, Ana Lako, Thomas Lila, David Nelson, Caroline Porter, Orr Ashenberg, Karthik Jagadesh, William L. Hwang, Christopher Smillie, David P. Ryan, David T. Ting, Theodore Hong, Dana Pe'er, Nir Hacohen. Dissecting the reorganization of pancreatic tumor microenvironments after radiation and immunotherapy reveals insights into immunotherapy resistance [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C012.

During the Galileo mission, eight radio occultations of Ganymede were made with only one strong detection of an ionosphere. On June 7, 2021, the Juno spacecraft executed a close flyby of Ganymede, the third Galilean moon of Jupiter. During this close flyby, a detection attempt of Ganymede’s elusive ionosphere was made with an Earth radio occultation. The radio science instrumentation consisted of X-band and Ka-band downlink signals referenced to an X-band uplink signal from the Deep Space Network. Electrons encountered along the radio propagation path induce a dispersive phase delay on the radio link. Taking advantage of the dispersive nature, a linear combination of X-band and Ka-band signals provided a direct measurement of the electron content along the propagation path. The ingress occultation occurred at small ram angle and egress occultation occurred at a small solar zenith angle on the sun-lit side, providing a diverse geometry for detection.BackgroundGanymede’s ionosphere is tenuous. The atmosphere of Ganymede is predominately oxygen. It is thought the ionosphere is generated via photoionization of the neutral atmospheric oxygen from the Sun (McGrath et al 2004). The Galileo spacecraft executed a total of eight radio occultations of Ganymede throughout its mission, resulting in five non-detections, two weak detections, and one strong detection of an ionosphere. The strong ionosphere detection occurred during the Ganymede G8 ingress occultation (Kliore 1998) resulting in a peak electron density of 5,000 el/cm3 at an altitude of 16 km above the surface. Initially, the lack of detection was surprising, but it was hypothesized that positive detections occurred where the trailing hemisphere of the satellite was in sunlight; therefore, the atmosphere can be ionized by solar radiation to produce an observable ionosphere (Kliore et al 2001). Radio occultation measurements will help understand better the connection between Ganymede’s elusive ionosphere, its intrinsic magnetic field and Jupiter’s magnetosphere.ObservationJuno Gravity Science Instrument (Asmar et al 2017) is a radio science instrument which utilizes dual-frequency X-band (8.4 GHz) and Ka-band (32 GHz) radio links between the Juno spacecraft and the Earth-based observing stations of NASA’s Deep Space Network (DSN). On June 7, 2021 Juno’s extended mission trajectory will take the spacecraft on a close encounter with Ganymede at an altitude of 1000 km. An Earth occultation occurred during this flyby as shown in Figure 1. Measurement of Ganymede’s ionosphere is made via a radio occultation geometry, where the Juno spacecraft will set behind Ganymede as observed from Earth. In this way, the radio ray path propagates directly through the ionosphere of Ganymede twice, once on ingress and once on egress. During the radio occultation, Juno transmitted dual-frequency X-band and Ka-band to the DSS-43 and DSS-35 antennas at the Canberra DSN complex. Both downlink signals were referenced to a single X-band uplink signal sent from the DSS-35 antenna.Figure 1. Occultation geometry of Juno's encounter of Ganymede on June 7, 2021, inbound to the Perijove-34 Jupiter flyby. As viewed from Earth, the spacecraft passed directly behind Ganymede for approximately 15 minutes.MethodsThe ionosphere perturbation is detectable in small changes in the received frequency. A refractivity profile is derived from the perturbations. The refractivity profile can then be inverted to determine electron density. In the link configuration used during the Ganymede flyby, two inversion techniques are available to compute the electron density from the signal frequency, with three independent analysis results:a) X-band downlink referenced to X-band uplink (2-Way)b) Ka-band downlink referenced to X-band uplink (2-Way)c) Dual-Frequency X-band and Ka-band downlink (1-Way linear combination)Methods (a) and (b) estimates the bending angle through geometric optics and the medium refractivity through an Abel transform (e.g. Withers and Moore 2020). In method (c), the integrated Total Electron Content (TEC) will be computed by combing the dual frequency measurements, given the dispersive nature of the plasma noise. In turn, this can be converted into electron density (el/cm3) via Abel Transform. The transponder configuration allows for the isolation of the plasma signature on the downlink only, analogously to a one-way measurement (e.g. Dalba and Withers 2019).AcknowledgementsThe work of DB, MP, RP, and SL was carried out at the Jet Propulsion Lab, California Institute of Technology, under a contract with the National Aeronautics and Space Administration. Government sponsorship acknowledged. EG, LGC, PT and MZ are grateful to the Italian Space Agency (ASI) for financial support through Agreement No. 2017-40-H.0, and its extension 2017-40-H.1-2020, for ESA’s BepiColombo and NASA’s Juno radio science experiments. PS and AH were supported by NASA Contract NNM06AA75C from the Marshall Space Flight Center under subcontract 699054X from Southwest Research Institute.© 2021 California Institute of Technology. Government sponsorship acknowledged.ReferencesMcGrath, Melissa A., et al. "Satellite atmospheres." Jupiter: The Planet, Satellites and Magnetosphere(2004): 457-483. Kliore, A. J. (1998). Satellite atmospheres and magnetospheres. Highlights of Astronomy, 11(2), 1065-1069. Kliore, A. J., Anabtawi, A., & Nagy, A. F. (2001, December). The ionospheres of Europa, Ganymede, and Callisto. In AGU Fall Meeting Abstracts(Vol. 2001, pp. P12B-0506). Asmar, S. W., Bolton, S. J., Buccino, D. R., Cornish, T. P., Folkner, W. M., Formaro, R., ... & Simone, L. (2017). The Juno gravity science instrument. Space Science Reviews, 213(1), 205-218. Withers, P., & Moore, L. (2020). How to process radio occultation data: 2. From time series of two-way, single-frequency frequency residuals to vertical profiles of ionospheric properties. Radio Science, 55(8), 1-25. Dalba, P. A., & Withers, P. (2019). Cassini radio occultation observations of Titan's ionosphere: The complete set of electron density profiles. Journal of Geophysical Research: Space Physics, 124(1), 643-660.

As individuals interested in clinical and medical research, we have observed an increasing need for methodological research skills by grassroots, not-for-profit, and for-profit organizations. However, research methodology skills and resources are often available only in post-secondary institutions (i.e., graduate programs and communities of practice). Undergraduate learners often face the challenge of accessing post-graduate research training. This guest editorial de-scribes the Research Empowerment & Development (RED) Fellowship, a six-week collaborative program that aims to build capacity in individuals to conduct, develop, and implement high-quality research. This editorial will discuss the rationale for this program, the program plan, program design process, target audience, program timeline, future goals, and contact information.

Background: Immunosuppression remains the main treatment for progressing skin involvement, interstitial lung disease and inflammatory joint or muscle disease in systemic sclerosis. This study investigated the pattern and trends in immunosuppressive agents used in early systemic sclerosis (diagnosed before and after 2007) to determine whether the changes in the preferred type, timing and combination of immunosuppression took place over the past decade. Methods: In total, 397 Canadian Scleroderma Research Group database patients (183 diffuse cutaneous systemic sclerosis and 214 limited cutaneous systemic sclerosis) who had baseline and follow-up visits within 3 years (mean: 1.8 ± 0.8) after disease onset were included: 82% females, age at diagnosis 53 ± 13 years. Bivariate, chi-square, analysis of variance and adjusted regression analyses were used. Results: In total, 115 diffuse cutaneous systemic sclerosis patients (63%) and 62 limited cutaneous systemic sclerosis (29%) received immunosuppressive drugs, most commonly methotrexate, followed by mycophenolate mofetil and cyclophosphamide. In diffuse cutaneous systemic sclerosis, immunosuppressants were prescribed after 2007 more often (74% vs 50%, p = 0.001), especially methotrexate ( p = 0.02) and mycophenolate mofetil ( p = 0.04), and earlier (peak at 2 years after onset). Immunosuppressive therapy was associated with male gender, interstitial lung disease, anti-Scl70 positivity, ACA negativity and inflammatory joint disease in limited cutaneous systemic sclerosis and with ACA negativity and a higher modified Rodnan skin score in diffuse cutaneous systemic sclerosis. Multivariate regression analysis showed that the use of immunosuppressants after 2007 was predicted only by ACA negativity in limited cutaneous systemic sclerosis and by younger age in diffuse cutaneous systemic sclerosis. Conclusion: Over the past decade, there has been a trend to prescribe immunosuppressants more often and earlier in diffuse cutaneous systemic sclerosis patients, regardless of modified Rodnan skin score. Methotrexate is being more frequently used, and mycophenolate mofetil has gained favour over cyclophosphamide. Autoantibody status was the most consistent predictor of immunosuppressive therapy.

This chapter explains the Power Purchase Agreement and its advantages over other forms of financing. At this time there are several ways to proceed with a solar electricity project: cash purchase, project finance, capital or operational lease, or power purchase agreement (PPA). The primary benefit for using a PPA is to get a solar system on your roof with zero upfront costs, while also having a known price for energy for 20 years-which reduces risk from energy supply price spikes. PPA providers realize that solar electricity systems will last decades. In order to reduce the starting kWh price as much as possible, the PPA agreement will have a set kWh price inflation per year. Many solar system integrators can handle everything in house and also some PPA providers will only work with a few solar installers for their projects because they are confident the installation will be quality.

Lung cancer is the leading cause of cancer mortality worldwide and KRAS is the most commonly mutated gene in lung adenocarcinoma (LUAD). The 78-kDa glucose-regulated protein GRP78/BiP is a key endoplasmic reticulum (ER) chaperone protein and a major pro-survival effector of the unfolded protein response (UPR). Analysis of the Cancer Genome Altas (TCGA) database and immunostain of patient tissues revealed that compared to normal lung, GRP78 expression is generally elevated in human lung cancers, including tumors bearing the KRAS(G12D) mutation. To test the requirement of GRP78 in human lung oncogenesis, we generated mouse models containing floxed Grp78 and Kras Lox-Stop-Lox G12D (Kras(LSL-G12D)) alleles. Simultaneous activation of the Kras(G12D) allele and knockout of the Grp78 alleles were achieved in the whole lung or selectively in lung alveolar epithelial type 2 cells known to be precursors for adenomas which progress to LUAD. Here we report that GRP78 haploinsufficiency is sufficient to suppress Kras(G12D)-mediated lung tumor progression and prolong survival. Furthermore, GRP78 knockdown in human lung cancer cell line A427 (Kras(G12D/+)) leads to activation of UPR and apoptotic markers and loss of cell viability. Our studies provide evidence that targeting GRP78 represents a novel therapeutic approach to suppress mutant KRAS-mediated lung tumorigenesis.

Immune checkpoints have been the subject of a wave of new studies. Among these checkpoints are tytotoxic T-lymphocyte-associated antigen 4, checkpoints programmed death-1 and programmed death-ligand 1; their blockades have been approved by the Food and Drug Administration for therapy of melanoma and other types of cancers. Immunogenomics, which combines the latest nucleic acid sequencing strategy with immunotherapy, provides precise information about genomic alterations (e.g. mutations) and enables a paradigm shift of immune checkpoint therapy from tumor types to molecular signatures. Studying these critical checkpoints in relation to genomic mutations and neoantigens has produced groundbreaking results. This article examines these studies and delves into the relationships between immune checkpoint blockade and tumors harboring certain genomic mutations. Moreover, this article reviews recent studies on resistance to immune checkpoint therapy.

Aim We assessed the association between the presence and absence of androgen on the normal biodistribution of the positron emission tomography (PET) cellular proliferation imaging biomarker, [18F]-2'-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU), in mice. Materials and methods Non-castrated (n=4) and castrated (n=4) athymic non-tumor-bearing male mice served as models for presence and absence, respectively, of androgen. MicroPET-CT scans were performed 1 h following tail vein administration of 200 uCi of 18F-FMAU. Imaging was performed at baseline and then at 7-day intervals longitudinally for 35 days only in castrated mice following subcutaneous introduction of a 12.5 mg, 21-day release, dihydrotestosterone pellet. Mean standardized uptake values (SUVmean) were obtained for liver, heart, and muscle. Several two-group comparisons of average of SUVmean were performed. Results Pre-pellet baseline average SUVmean (±s.d.) values in castrated mice were significantly lower than baseline non-castrated values, increased on day 15 and reached peak values on day 28, at which time they were significantly higher than corresponding baseline levels in both non-castrated and pre-pellet castrated mice. The peak values decreased significantly following dihydrotestosterone withdrawal. Conclusion There is a significant modulatory effect of androgen on normal 18F-FMAU uptake levels in mice liver, heart and muscle tissues.

A novel recombinant disintegrin, vicrostatin (VCN), displays high binding affinity to a broad range of human integrins in substantial competitive biological advantage over other integrin-based antagonists. In this study, we synthesized a new (64)Cu-labeled VCN probe and evaluated its imaging properties for prostate cancer in PC-3 tumor bearing mice. Macrocyclic chelating agent 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosine (DiAmSar) was conjugated with PEG unit, and followed by a coupling with VCN. The precursor was then radiolabeled with positron emitter (64)Cu (t(1/2) = 12.7h) in ammonium acetate buffer to provide (64)Cu-Sar-PEG-VCN, which was subsequently subject to in vitro studies, small animal PET, and biodistribution studies. The PC-3 tumor targeting efficacy of (64)Cu-Sar-PEG-VCN was compared to a cyclic RGD peptide based PET probe ((64)Cu-Sar-RGD). (64)Cu labeling was achieved in 75% decay-corrected yield with radiochemical purity of >98%. The specific activity of (64)Cu-Sar-PEG-VCN was estimated to be 37 MBq/nmol. MicroPET imaging results showed that (64)Cu-Sar-PEG-VCN has preferential tumor uptake and good tumor retention in PC-3 tumor xenografts. As compared to (64)Cu-Sar-RGD, (64)Cu-Sar-PEG-VCN produces higher tumor-to-muscle (T/M) imaging contrast ratios at 2 h (4.66 ± 0.34 vs. 2.88 ± 0.46) and 24 h (4.98 ± 0.80 vs. 3.22 ± 0.30) post-injection (pi), and similar tumor-to-liver ratios at 2 h (0.43 ± 0.09 vs. 0.37 ± 0.04) and 24 h (0.57 ± 0.13 vs. 0.52 ± 0.07) pi. The biodistribution results were consistent with the quantitative analysis of microPET imaging, demonstrating good T/M ratio (2.73 ± 0.36) of (64)Cu-Sar-PEG-VCN at 48 h pi in PC-3 tumor xenografts. For both microPET and biodistribution studies at 48 h pi, the PC-3 tumor uptake of (64)Cu-Sar-PEG-VCN is lower than that of (64)Cu-Sar-RGD. (64)Cu-Sar-PEG-VCN has the potential for in vivo imaging of prostate cancer with PET, which may provide a unique non-invasive method to quantitatively localize and characterize prostate cancer.

Heparin anticoagulation therapy is an indispensable feature of clinical care yet has a narrow therapeutic window and is the second most common intensive care unit (ICU) medication error. The active partial thromboplastin time (aPTT) monitors heparin but suffers from long turnaround times, a variable reference range, limited utility with low molecular weight heparin, and poor correlation to dose. Here, we describe a photoacoustic imaging technique to monitor heparin concentration using methylene blue as a simple and Federal Drug Administration-approved contrast agent. We found a strong correlation between heparin concentration and photoacoustic signal measured in phosphate buffered saline (PBS) and blood. Clinically relevant heparin concentrations were detected in blood in 32 s with a detection limit of 0.28 U/mL. We validated this imaging approach by correlation to the aPTT (Pearson's r = 0.86; p0.05) as well as with protamine sulfate treatment. This technique also has good utility with low molecular weight heparin (enoxaparin) including a blood detection limit of 72 μg/mL. We then used these findings to create a nanoparticle-based hybrid material that can immobilize methylene blue for potential applications as a wearable/implantable heparin sensor to maintain drug levels in the therapeutic window. To the best of our knowledge, this is the first use of photoacoustics to image anticoagulation therapy with significant potential implications to the cardiovascular and surgical community.

We examined servant leadership as a precursor to a knowledge-sharing climate and demonstrated the mediating role of knowledge-sharing climate in the relationship between servant leadership and team performance. Data from 67 teams, comprising 1,884 direct sales representatives of a large cosmetics company in South Korea, were analyzed at the team level. Actual team sales data were obtained from the company 3 months after surveying, and regression analyses and bootstrapping were used to test the hypotheses. The results showed 2 key findings: servant leadership positively affected the knowledge-sharing climate of the team; and knowledge-sharing climate mediated the relationship between servant leadership and team sales performance. Theoretical and practical implications of the findings are discussed.

Introduction:64Cu-BaBaSar-RGD2 is a positron emission radiotracer taken up by integrin αvβ3, which is overexpressed in many malignancies. The aim of this study was to evaluate the biodistribution of 64Cu-BaBaSar-RGD2 in a non-human primate with positron emission tomography (PET) and to estimate the absorbed doses in major organs for human.Materials and Methods: Whole-body PET imaging was done on a Siemens Biograph scanner with a male macaque monkey. After an i.v. injection of 13.1–19.7 MBq/kg of 64Cu-BaBaSar-RGD2, whole body scan was collected for a total duration of 180 min. Attenuation and scatter corrections were applied to reconstructions of the whole-body emission scan. After image reconstruction, three-dimensional volumes of interest (VOI) were hand-drawn on the PET transaxial or coronal slices of the frame where the organ was most conspicuous. Time-activity curves (TACs) for each VOI were obtained, and residence times of each organ were calculated by integration of the time-activity curves. Human absorbed doses were estimated using the standard human model in OLINDA/EXM software.Results: Injection of 64Cu-BaBaSar-RGD2 was well-tolerated in the macaque monkey, with no serious tracer-related adverse events observed. 64Cu-BaBaSar-RGD2 was cleared rapidly from the blood pool, with a 12.1-min biological half-life. Increased 64Cu-BaBaSar-RGD2 uptake was observed in the kidneys, and bladder, with mean percentage injected dose (ID%) values at 1 h after injection ~35.50 ± 6.47 and 36.89 ± 5.48, respectively. The calculated effective dose was 15.30 ± 2.21 μSv/MBq, and the kidneys had the highest absorbed dose at 108.43 ± 16.41 μGy/MBq using the non-voiding model. For an injected activity of 925 MBq 64Cu for human, the effective dose would be 14.2 ± 2.1 mSv.Discussion: Due to the limited availability of the primates, we evaluated 64Cu-BaBaSar-RGD2 in the same monkey using three imaging sessions. Measured absorbed doses and effective doses of 64Cu-BaBaSar-RGD2 are comparable to other reported RGD-derived radiopharmaceuticals labeled with 64Cu and 18F. Therefore, 64Cu-BaBaSar-RGD2 can be safely injected into humans for studying integrin αvβ3 expression non-invasively.