The Apparent Anomalous, Weak, Long-Range Acceleration of Pioneer 10 and 11

Recently we reported that radio Doppler data generated by NASA's Deep Space Network (DSN) from the Pioneer 10 and 11 spacecraft indicate an apparent anomalous, constant, spacecraft acceleration with a magnitude $\sim 8.5\times 10^{-8}$ cm s$^{-2}$, directed towards the Sun (gr-qc/9808081). Analysis of similar Doppler and ranging data from the Galileo and Ulysses spacecraft yielded ambiguous results for the anomalous acceleration, but it was useful in that it ruled out the possibility of a systematic error in the DSN Doppler system that could easily have been mistaken as a spacecraft acceleration. Here we present some new results, including a critique suggestions that the anomalous acceleration could be caused by collimated thermal emission. Based partially on a further data for the Pioneer 10 orbit determination, the data now spans January 1987 to July 1998, our best estimate of the average Pioneer 10 acceleration directed towards the Sun is $\sim 7.5 \times 10^{-8}$ cm s$^{-2}$.Comment: Latex, 7 pages and 2 figures. Invited talk at the XXXIV-th Rencontres de Moriond Meeting on Gravitational Waves and Experimental Gravity. Les Arcs, Savoi, France (January 23-30,1999). Corrected typo

Anderson et al. Reply (to the Comment by Murphy on Pioneer 10/11)

We conclude that Murphy's proposal (radiation of the power of the main-bus electrical systems from the rear of the craft) can not explain the anomalous Pioneer acceleration.Comment: LaTex, 3 pages, Phys. Rev. Lett. (to be published

Anderson et al. Reply (to the Comment by Katz on Pioneer 10/11)

We conclude that Katz's proposal (anisotropic heat reflection off of the back of the spacecraft high-gain antennae, the heat coming from the RTGs) does not provide enough power and so can not explain the Pioneer anomaly.Comment: LaTex, 3 pages, Phys. Rev. Lett. (to be published

A Focus on Intermediate-Risk Acute Myeloid Leukemia: Sub-Classification Updates and Therapeutic Challenges

Simple Summary Risk stratification models, including the European LeukemiaNet 2017 and 2022 guidelines, categorize newly diagnosed acute myeloid leukemia (AML) patients into several subgroups of distinct genetic characteristics and disease outcomes. The intermediate-risk group remains the most heterogenous group, as most AML patients fall into it (i.e., a basket category) by virtue of not fulfilling criteria that identify specific entities (e.g., core-binding factor AML, TP53 mutations, complex karyotypes) of well-recognized prognostic significance. In this review, we aim to discuss the latest updates on intermediate-risk definition and highlight the therapeutic advances and challenges that warrant refining the prognostic classification of this category. Acute myeloid leukemia (AML) represents a heterogeneous group of hematopoietic neoplasms deriving from the abnormal proliferation of myeloid progenitors in the bone marrow. Patients with AML may have highly variable outcomes, which are generally dictated by individual clinical and genomic characteristics. As such, the European LeukemiaNet 2017 and 2022 guidelines categorize newly diagnosed AML into favorable-, intermediate-, and adverse-risk groups, based on their molecular and cytogenetic profiles. Nevertheless, the intermediate-risk category remains poorly defined, as many patients fall into this group as a result of their exclusion from the other two. Moreover, further genomic data with potential prognostic and therapeutic influences continue to emerge, though they are yet to be integrated into the diagnostic and prognostic models of AML. This review highlights the latest therapeutic advances and challenges that warrant refining the prognostic classification of intermediate-risk AML

Indication, from Pioneer 10/11, Galileo, and Ulysses Data, of an Apparent Anomalous, Weak, Long-Range Acceleration

Radio metric data from the Pioneer 10/11, Galileo, and Ulysses spacecraft indicate an apparent anomalous, constant, acceleration acting on the spacecraft with a magnitude $\sim 8.5\times 10^{-8}$ cm/s$^2$, directed towards the Sun. Two independent codes and physical strategies have been used to analyze the data. A number of potential causes have been ruled out. We discuss future kinematic tests and possible origins of the signal.Comment: Revtex, 4 pages and 1 figure. Minor changes for publicatio

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

Hydrogen Epoch of Reionization Array (HERA)

The Hydrogen Epoch of Reionization Array (HERA) is a staged experiment to measure 21 cm emission from the primordial intergalactic medium (IGM) throughout cosmic reionization ($z=6-12$), and to explore earlier epochs of our Cosmic Dawn ($z\sim30$). During these epochs, early stars and black holes heated and ionized the IGM, introducing fluctuations in 21 cm emission. HERA is designed to characterize the evolution of the 21 cm power spectrum to constrain the timing and morphology of reionization, the properties of the first galaxies, the evolution of large-scale structure, and the early sources of heating. The full HERA instrument will be a 350-element interferometer in South Africa consisting of 14-m parabolic dishes observing from 50 to 250 MHz. Currently, 19 dishes have been deployed on site and the next 18 are under construction. HERA has been designated as an SKA Precursor instrument. In this paper, we summarize HERA's scientific context and provide forecasts for its key science results. After reviewing the current state of the art in foreground mitigation, we use the delay-spectrum technique to motivate high-level performance requirements for the HERA instrument. Next, we present the HERA instrument design, along with the subsystem specifications that ensure that HERA meets its performance requirements. Finally, we summarize the schedule and status of the project. We conclude by suggesting that, given the realities of foreground contamination, current-generation 21 cm instruments are approaching their sensitivity limits. HERA is designed to bring both the sensitivity and the precision to deliver its primary science on the basis of proven foreground filtering techniques, while developing new subtraction techniques to unlock new capabilities. The result will be a major step toward realizing the widely recognized scientific potential of 21 cm cosmology.Comment: 26 pages, 24 figures, 2 table

Optimal control of impulsive switched systems with minimum subsystem durations

This paper presents a new computational approach for solving optimal control problems governed by impulsive switched systems. Such systems consist of multiple subsystems operating in succession, with possible instantaneous state jumps occurring when the system switches from one subsystem to another. The control variables are the subsystem durations and a set of system parameters influencing the state jumps. In contrast with most other papers on the control of impulsive switched systems, we do not require every potential subsystem to be active during the time horizon (it may be optimal to delete certain subsystems, especially when the optimal number of switches is unknown). However, any active subsystem must be active for a minimum non-negligible duration of time. This restriction leads to a disjoint feasible region for the subsystem durations. The problem of choosing the subsystem durations and the system parameters to minimize a given cost function is a non-standard optimal control problem that cannot be solved using conventional techniques. By combining a time-scaling transformation and an exact penalty method, we develop a computational algorithm for solving this problem. We then demonstrate the effectiveness of this algorithm by considering a numerical example on the optimization of shrimp harvesting operations