Abstract: Along with the rapid development of space technology, extraterrestrial exploration has gradually tended to further-distanced and longer-termed planet exploration. As the first step of an attempt for humans to build a perpetual planet base, building a lunar base by in situ resource utilization (ISRU) will drastically reduce the reliance of supplies from Earth. Lunar resources including mineral resources, water/ice resources, volatiles, and solar energy will contribute to the establishment of a lunar base for long-term life support and scientific exploration missions, although we must consider the challenges from high vacuum, low gravity, extreme temperature conditions, etc. This article provides a comprehensive review of the past developing processes of ISRU and the latest progress of several ISRU technologies, including in situ water access, in situ oxygen production, in situ construction and manufacture, in situ energy utilization, and in situ life support and plant cultivation on the Moon. Despite being able to provide some material and energy supplies for lunar base construction and scientific exploration, the ISRU technologies need continuous validation and upgrade to satisfy the higher requirements from further lunar exploration missions. Ultimately, a 3-step development plan for lunar ISRU technologies in the next decade is proposed, which consists of providing technological solutions, conducting technical verification on payloads, and carrying out in situ experiments, with the ultimate aim of establishing a permanent lunar station and carrying out long-term lunar surface scientific activities. The overview of ISRU techniques and our suggestions will provide potential guidance for China’s future lunar exploration missions.

Abstract: 4532 Background: A majority of mUC pts progress on standard platinum-based chemo regimens. Atezo (anti–PD-L1) was approved in the US for mUC in the post-platinum setting. Here we report the preliminary safety results from an expanded access program conducted to grant access to atezo, prior to commercial availability, to a broader range of mUC pts than are typically eligible for Phase I-III studies. Methods: From Nov 2015-Aug 2016, this study (NCT02589717) enrolled mUC pts who progressed during or following platinum. Atezo was given 1200 mg IV q3w, and pts could be treated post RECIST v1.1 PD until lack of clinical benefit (per investigator). Safety and clinical activity were key endpoints. PD-L1 expression on immune cells (IC) was assessed with the VENTANA SP142 IHC assay on the first 73 pts prior to protocol amendment omitting this requirement. This study was ended early following FDA approval of atezo. Results: 218 pts were enrolled at 36 sites in the US, with 214 treated pts comprising the safety/efficacy population (Table). Median treatment duration was 9 wks (range 3-26), corresponding to a median of 3 doses of atezo (range 1-8). Overall, 89% of pts had an AE. Treatment-related AEs (TRAEs) occurred in 46% (any Gr) and 7% (Gr3-4) of pts; 2 treatment-related Gr 5 AEs were seen (ileus; acute respiratory failure). TRAEs ≥ 5% were fatigue, decreased appetite and anemia. TRAEs leading to dose interruption or discontinuation occurred in 11% and 6% of pts, respectively. Investigator-assessed RECIST v1.1 ORR was 15% (95% CI: 9, 23), and disease control rate (ORR + SD) was 49% (95% CI: 40, 59). Additional clinical data will be reported. Conclusions: In this expanded access study, atezo was administered to 〉 200 mUC pts. Overall, atezo was safe and tolerable, supporting its use in a wider platinum-based population. Clinical trial information: NCT02589717. [Table: see text]

Abstract: COVID-19 disproportionately results in hospitalization and death in older patients and those with underlying comorbidities. Sotrovimab is a pan-sarbecovirus monoclonal antibody that binds a highly conserved epitope of the SARS-CoV-2 receptor binding domain and has an Fc modification that increases half-life. Sotrovimab retains activity against UK, S. Africa, Brazil, India, New York and California variants in vitro. Objectives To evaluate the efficacy and safety of treatment with sotrovimab in high-risk, non-hospitalized patients with mild/moderate COVID-19, as part of the COMET-ICE clinical trial. Methods Multicenter, double-blind, phase 3 trial in non-hospitalized patients with symptomatic COVID-19 and ≥1 risk factor for disease progression were randomized 1:1 to an IV infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was the proportion of patients with COVID-19 progression, defined as hospitalization & gt; 24 hours or death, due to any cause, ≤29 days of randomization. Results The study met the pre-defined primary efficacy endpoint in a preplanned interim analysis: the risk of COVID-19 progression was significantly reduced by 85% (97.24% CI, 44% to 96%; P = 0.002) in 583 patients. In the final intention-to-treat analysis (N = 1057), the adjusted relative risk reduction was 79% (95% CI, 50% to 91%; p & lt; 0.001) through Day 29 in recipients of sotrovimab (n=528) vs. placebo (n=529). Treatment with sotrovimab (ITT) resulted in a numerical reduction in the need for ER visits for illness management, hospitalization for acute illness management (any duration) or death (any cause) compared to placebo. No participants on sotrovimab required ICU admission, compared to 9 participants on placebo, of whom 4 participants required mechanical ventilation. No participants who received sotrovimab died, compared to 4 participants on placebo. The incidence of adverse events was similar between treatment arms and SAEs were numerically more common in the placebo arm. Conclusion Treatment with sotrovimab 500 mg IV resulted in a clinically and statistically significant reduction in progression of COVID-19 to hospitalization or death in patients with mild/moderate disease and was well-tolerated. Study funding GSK & VIR; NCT04545060 Disclosures Jaynier Moya, MD, VIR Biotechnology (Other Financial or Material Support, Jaynier Moya received non-financial support for serving as a clinical trial investigator for Vir Biotechnology) Diego Rodrigues Falci, MD, MSc, PhD, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker's Bureau)GSK (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)MSD (Speaker's Bureau)Pfizer (Speaker's Bureau)United Medical (Speaker's Bureau, Other Financial or Material Support) Joel Solis, MD, VIR Biotechnology (Other Financial or Material Support, Joel Solis received non-financial support for serving as a clinical trial investigator for Vir Biotechnology) Hanzhe Zheng, PhD, VIR Biotechnology (Employee) Nicola Scott, MSc, GlaxoSmithKline (Employee, Shareholder) Andrea L. Cathcart, PhD, Gilead (Shareholder)VIR (Employee, Shareholder) Christy Hebner, PhD, Vir Biotechnology (Employee, Shareholder) Jennifer Sager, PhD, GSK (Other Financial or Material Support)Vir Biotechnology (Employee, Shareholder) Erik Mogalian, PharmD, PhD, Vir Biotechnology (Employee, Shareholder) Daren Austin, PhD, GlaxoSmithKline (Employee, Shareholder) Amanda Peppercorn, MD, GlaxoSmithKline (Employee) Elizabeth L. Alexander, MD, MSc, GlaxoSmithKline (Grant/Research Support, Other Financial or Material Support)VIR Biotechnology (Employee, Shareholder, GSK pharmaceuticals) Wendy W. Yeh, MD, Vir Biotechnology (Employee) Almena Free, MD, Amgen (Scientific Research Study Investigator)Astra Zeneca (Scientific Research Study Investigator)Cardurian (Scientific Research Study Investigator)Coherus (Scientific Research Study Investigator)Freenome (Scientific Research Study Investigator)GlaxoSmithKline/Vir (Scientific Research Study Investigator)Ionis (Scientific Research Study Investigator)Kowa (Scientific Research Study Investigator)New Amsterdam (Scientific Research Study Investigator)Regenacy (Scientific Research Study Investigator)Romark (Scientific Research Study Investigator)Scynexis (Scientific Research Study Investigator) Cynthia Brinson, MD, Abbvie (Scientific Research Study Investigator)BI (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau, Personal fees)GSK (Scientific Research Study Investigator)Novo Nordisk (Scientific Research Study Investigator)ViiV Healthcare (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau) Melissa Aldinger, PharmD, VIR Biotechnology (Employee) Adrienne Shapiro, MD, PhD, Vir Biotechnology (Scientific Research Study Investigator)

Abstract: The epidermis of cotton ovule produces fibers, the most important natural cellulose source for the global textile industry. However, the molecular mechanism of fiber cell growth is still poorly understood. Results Here, we develop an optimized protoplasting method, and integrate single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) to systematically characterize the cells of the outer integument of ovules from wild type and fuzzless/lintless ( fl ) cotton (Gossypium hirsutum ). By jointly analyzing the scRNA-seq data from wildtype and fl, we identify five cell populations including the fiber cell type and construct the development trajectory for fiber lineage cells. Interestingly, by time-course diurnal transcriptomic analysis, we demonstrate that the primary growth of fiber cells is a highly regulated circadian rhythmic process. Moreover, we identify a small peptide GhRALF1 that circadian rhythmically controls fiber growth possibly through oscillating auxin signaling and proton pump activity in the plasma membrane. Combining with scATAC-seq, we further identify two cardinal cis-regulatory elements (CREs, TCP motif, and TCP-like motif) which are bound by the trans factors GhTCP14s to modulate the circadian rhythmic metabolism of mitochondria and protein translation through regulating approximately one third of genes that are highly expressed in fiber cells. Conclusions We uncover a fiber-specific circadian clock-controlled gene expression program in regulating fiber growth. This study unprecedentedly reveals a new route to improve fiber traits by engineering the circadian clock of fiber cells.

Abstract: Introduction. wAIHA is a rare and often serious disease in which red blood cells (RBCs) coated with autoantibodies bind to Fcγ receptor-bearing macrophages, triggering a spleen tyrosine kinase (SYK) dependent signaling pathway that leads to RBC phagocytosis. Fostamatinib is a potent SYK inhibitor administered orally that was approved by the US FDA for the treatment of chronic ITP in adults. A phase 2, multicenter, open-label study (the SOAR study; NCT02612558) evaluated the response to fostamatinib in adult patients with wAIHA. We report the final results of the initial 24-week treatment period and the extension period of the phase 2 study. Methods. The study included adult patients with primary or secondary wAIHA, documented by IgG positive direct antiglobulin test (DAT), who had: failed ≥1 prior treatment for wAIHA, hemoglobin (Hgb) & lt;10 g/dL, haptoglobin & lt;10 mg/dL and lactate dehydrogenase (LDH) & gt;ULN (upper limit of normal). Patients were initiated on fostamatinib at 150mg BID with dose reduction permitted based on tolerability. Patients were seen every 2 weeks for 12 weeks, then every 3 weeks for 12 weeks, and every 6 weeks thereafter. The primary efficacy endpoint was achieving Hgb & gt;10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion. Patients who responded or showed clinical benefit were allowed to enter the extension period as long as they were tolerating the study drug. Results. The study included 25 evaluable patients (15 women) with median age 61 (range 27-88) years, median duration of wAIHA of 2 years ( & lt;1 to 26 years), and median Hgb of 9.0 g/dL (range 6.8-10.6). Most (80%) had primary AIHA; 3 patients had lymphoproliferative disease, 1 had systemic lupus erythematosus, and 1 had other secondary cause. Patients had received a median of 2 unique prior treatments (range 1-9), including corticosteroids (84%), splenectomy (20%) and rituximab (52%), and 52% were on corticosteroids at baseline. As of June 2019, median exposure to fostamatinib was 110.0 days (range, 26-847); median treatment compliance 100%. Eleven of 25 (44%) achieved the primary efficacy endpoint by Week 24 plus 1 late responder at Week 30 (total of 12 responders [48%]). Increases in median Hgb were generally detected at Week 2 (first visit) and sustained over time, with 24% achieving the primary endpoint by Week 2 (Figure). Median Hgb of responders increased by & gt;2.0 g/dL from baseline by Week 4 vs. no change for nonresponders. 13 eligible patients entered the extension period of the study, including 9 of 11 responders, 1 late responder, and 3 patients with a beneficial trend. Seven patients are still on treatment, and 6 discontinued the study, including 3 who withdrew, 1 was lost to follow up, and 2 had a loss of response (1 of whom also had increased alanine aminotransferase). Overall, adverse events (AE) were manageable and consistent with the fostamatinib safety database of & gt;3500 patients across all disease programs. No new safety signals were detected. The most common AEs during the initial treatment period were diarrhea in 9, fatigue in 8, hypertension in 7, and dizziness in 6. AEs were mostly mild to moderate. Seven patients had serious AEs, including anemia, acute myocardial infarction, fall, Hgb decreased, inappropriate secretion of antidiuretic hormone, infection, pneumonia, rhabdomyolysis, sepsis, skin necrosis, and systemic inflammatory response syndrome. Two patients had AEs leading to death: one had infection with skin necrosis and calciphylaxis; the other had pneumonia. Neither were considered related to treatment, and both patients were immunosuppressed due to steroids. Six subjects (24%) received rescue therapy, including RBC transfusion, prednisone and/or immunoglobulins. Conclusions. In this phase 2, multicenter, open-label study, fostamatinib markedly improved Hgb levels in 48% of 25 evaluable patients with wAIHA. Adverse events were manageable and consistent with those previously reported with fostamatinib in other conditions. Figure Disclosures Rogers: Janssen: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Acerta Pharma: Consultancy. Boxer:Arizona Oncology: Employment; Incyte: Speakers Bureau; Best Doctors: Consultancy; Abbvie: Honoraria, Speakers Bureau; Gerson Lerman: Consultancy; Rigel: Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Choi:Oncternal: Research Funding; Gilead: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Arnold:Novartis: Honoraria, Research Funding; Rigel: Consultancy, Research Funding; Principia: Consultancy; Bristol-Myers Squibb: Research Funding. Broome:Cellphire: Research Funding; Alexion: Honoraria, Research Funding; Incyte: Research Funding; Sanofi Genzyme: Honoraria, Research Funding; Rigel: Research Funding. Field:Ironwood: Consultancy, Research Funding; Rigel: Research Funding; Prolong: Research Funding; Incyte: Research Funding. Murakhovskaya:Momenta: Membership on an entity's Board of Directors or advisory committees. Chow:Rigel: Employment, Equity Ownership. Numerof:Rigel: Employment, Equity Ownership. Zheng:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Kuter:Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Kezar: Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; UCB: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Kezar: Research Funding; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Fostamatinib is a tyrosine kinase (SYK) inhibitor for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. The use of fostamatinib in other diseases is off-label.