The Pandora SmallSat: Multiwavelength Characterization of Exoplanets and their Host Stars

Pandora is a SmallSat mission concept, selected as part of NASA’s Astrophysics Pioneers Program, designed to study the atmospheres of exoplanets using transmission spectroscopy. Transmission spectroscopy of transiting exoplanets provides our best opportunity to identify the makeup of planetary atmospheres in the coming decade. Stellar brightness variations due to star spots, however, can seep into these measurements and contaminate the observed spectra. Pandora is designed to disentangle star and planet signals in transmission spectra and reliably characterize the planetary atmospheres. Pandora will collect long-duration photometric observations with a visible-light channel, and simultaneous spectra with a near-IR channel, where water is a strong molecular absorber. The broad wavelength coverage will provide constraints on spot covering fractions of the stars and determine the impact of these active regions on the planetary spectra. Pandora will observe at least 20 exoplanets with sizes ranging from Earth-size to Jupiter-size, with host stars spanning mid-K to late-M spectral types. The project is made possible by leveraging investments in other projects, including an all-aluminum 0.45-meter Cassegrain telescope design, and an IR sensor chip assembly from the James Webb Space Telescope. The mission will last five years from initial formulation to closeout, with one-year of science operations. Launch is planned for the mid-2020s as a secondary payload in Sun-synchronous low-Earth orbit. By design, Pandora has a diverse team, with over half of mission leadership roles filled by early career scientists and engineers, demonstrating the high value of SmallSats for developing the next generation of space mission leaders

Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans

T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines

The L 98-59 System: Three Transiting, Terrestrial-size Planets Orbiting a Nearby M Dwarf

We report the Transiting Exoplanet Survey Satellite (TESS) discovery of three terrestrial-size planets transiting L 98-59 (TOI-175, TIC 307210830)—a bright M dwarf at a distance of 10.6 pc. Using the Gaia-measured distance and broadband photometry, we find that the host star is an M3 dwarf. Combined with the TESS transits from three sectors, the corresponding stellar parameters yield planet radii ranging from 0.8 R ⊕ to 1.6 R ⊕. All three planets have short orbital periods, ranging from 2.25 to 7.45 days with the outer pair just wide of a 2:1 period resonance. Diagnostic tests produced by the TESS Data Validation Report and the vetting package DAVE rule out common false-positive sources. These analyses, along with dedicated follow-up and the multiplicity of the system, lend confidence that the observed signals are caused by planets transiting L 98-59 and are not associated with other sources in the field. The L 98-59 system is interesting for a number of reasons: the host star is bright (V = 11.7 mag, K = 7.1 mag) and the planets are prime targets for further follow-up observations including precision radial-velocity mass measurements and future transit spectroscopy with the James Webb Space Telescope; the near-resonant configuration makes the system a laboratory to study planetary system dynamical evolution; and three planets of relatively similar size in the same system present an opportunity to study terrestrial planets where other variables (age, metallicity, etc.) can be held constant. L 98-59 will be observed in four more TESS sectors, which will provide a wealth of information on the three currently known planets and have the potential to reveal additional planets in the system

Isolation, characterization, and chromosomal mapping of mouse P450 17[alpha]-hydroxylase/C17-20 lyase

Cytochrome P450 17[alpha]-hydroxylase/C17-20 lyase (P45017[alpha]) catalyzes the conversion of C-21 steroids to C-19 steroids in gonads. A full-length mouse cDNA encoding P45017[alpha] was isolated from a mouse Leydig cell library and characterized by restriction mapping and sequencing. The predieted amino acid sequence has 83% homology to rat, 66% homology to human, and 62% homology to bovine P45017[alpha] amino acid sequences. The protein is 507 amino acids in length, which is 1 amino acid shorter than the human protein and 2 amino acids shorter than the bovine protein. The structural gene encoding P45017[alpha] (Cyp17) was localized utilizing an interspecific testcross to mouse chromosome 19, distal to Got-1. Another cytochrome P450, P4502c (Cyp2c), also is located at the distal end of chromosome 19. CYP17, CYP2c, and GOT1 have been mapped to human chromosome 10, with CYP2C and GOT1 mapped to the distal region, q24.3 and q25.3, respectively. The data in the present study indicate conserved syntenic loci on mouse chromosome 19 and human chromosome 10 and predict that the structural gene encoding P45017[alpha] will be found distal to GOT1 on human chromosome 10.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29359/1/0000427.pd

Phase I Clinical Trial of DNA Methyltransferase Inhibitor Decitabine and PARP Inhibitor Talazoparib Combination Therapy in Relapsed/Refractory Acute Myeloid Leukemia

PURPOSE: Acute myeloid leukemia (AML) patients unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTis). Novel combinations may increase efficacy. In addition to demethylating CpG island gene promoter regions, DNMTis enhance poly (ADP-ribose) polymerase (PARP1) recruitment and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair and sensitizing cells to PARP inhibitor (PARPi). We previously demonstrated DNMTi and PARPi combination efficacy in AML in vitro and in vivo. Here we report a phase I clinical trial combining the DNMTi decitabine and the PARPi talazoparib in refractory/relapsed AML. EXPERIMENTAL DESIGN: Decitabine and talazoparib doses were escalated using a 3 + 3 design. Pharmacodynamic studies were performed on Cycle 1 Days 1 (pre-treatment), 5 and 8 blood blasts. RESULTS: Doses were escalated in seven cohorts [25 patients, including 22 previously treated with DNMTi(s)] to a recommended phase II dose combination of decitabine 20 mg/m(2) intravenously daily for 5 or 10 days and talazoparib 1 mg orally daily for 28 days, in 28-day cycles. Grade 3–5 events included fever in 19 and lung infections in 15, attributed to AML. Responses included complete remission with incomplete count recovery in two patients (8%) hematologic improvement in three. Pharmacodynamic studies showed the expected DNA demethylation, increased PARP trapping in chromatin, increased γH2AX foci and decreased HR activity in responders. γH2AX foci increased significantly with increasing talazoparib doses combined with 20 mg/m(2) decitabine. CONCLUSIONS: Decitabine/talazoparib combination was well tolerated. Expected pharmacodynamic effects occurred, especially in responders

Safety, Outcomes, and T-Cell Characteristics in Patients with Relapsed or Refractory MDS or CMML Treated with Atezolizumab in Combination with Guadecitabine

Purpose: We hypothesized that resistance to hypomethylating agents(HMA)amongpatients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) would be overcome by combining a programmed death-ligand 1 antibody with an HMA. Patients and Methods: We conducted a Phase I/II, multicenter clinical trial for patients with MDS not achieving an International Working Group response after at least 4 cycles of an HMA ("refractory") or progressing after a response ("relapsed") with 3+ or higher risk MDS by the revised International Prognostic Scoring System (IPSS-R) and CMML-1 or -2. Phase I consisted of a 3+3 dose-escalation design beginningwith guadecitabine at 30 mg/m2 and escalating to 60 mg/m2 Days 1 to 5 with fixed-dose atezolizumab: 840 mg intravenously Days 8 and 22 of a 28-day cycle. Primary endpoints were safety and tolerability; secondary endpoints were overall response rate (ORR) and survival. Results: Thirty-three patients, median age 73 (range 54-85), were treated. Thirty patients had MDS and 3 had CMML, with 30% relapsed and 70% refractory. No dose-limiting toxicities were observed in Phase I. There were 3 (9%) deaths in ≤ 30 days. Five patients (16%) came off study for drug-related toxicity. Immune-related adverse events (IRAE) occurred in 12 (36%) patients (4 grade 3, 3 grade 2, and 5 grade1). ORR was 33%[95% confidence interval (CI), 19%-52%] with 2 complete remission (CR), 3 hematologic improvement, 5 marrow CR, and 1 partial remission. Median overall survival was 15.1 (95% CI, 8.5-25.3) months. Conclusions: Guadecitabine with atezolizumab has modest efficacy with manageable IRAEs and typical cytopenia-related safety concerns for patients with relapsed or refractory MDS and CMML.</p