Loose Ends for the Exomoon Candidate Host Kepler-1625b

The claim of an exomoon candidate in the Kepler-1625b system has generated substantial discussion regarding possible alternative explanations for the purported signal. In this work we examine in detail these possibilities. First, the effect of more flexible trend models is explored and we show that sufficiently flexible models are capable of attenuating the signal, although this is an expected byproduct of invoking such models. We also explore trend models using X and Y centroid positions and show that there is no data-driven impetus to adopt such models over temporal ones. We quantify the probability that the 500 ppm moon-like dip could be caused by a Neptune-sized transiting planet to be < 0.75%. We show that neither autocorrelation, Gaussian processes nor a Lomb-Scargle periodogram are able to recover a stellar rotation period, demonstrating that K1625 is a quiet star with periodic behavior < 200 ppm. Through injection and recovery tests, we find that the star does not exhibit a tendency to introduce false-positive dip-like features above that of pure Gaussian noise. Finally, we address a recent re-analysis by Kreidberg et al (2019) and show that the difference in conclusions is not from differing systematics models but rather the reduction itself. We show that their reduction exhibits i) slightly higher intra-orbit and post-fit residual scatter, ii) $\simeq$ 900 ppm larger flux offset at the visit change, iii) $\simeq$ 2 times larger Y-centroid variations, and iv) $\simeq$ 3.5 times stronger flux-centroid correlation coefficient than the original analysis. These points could be explained by larger systematics in their reduction, potentially impacting their conclusions.Comment: 21 pages, 4 tables, 11 figures. Accepted for publication in The Astronomical Journal, January 202

CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition.

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy

Loose Ends for the Exomoon Candidate Host Kepler-1625b

The claim of an exomoon candidate in the Kepler-1625b system has generated substantial discussion regarding possible alternative explanations for the purported signal. In this work, we examine these possibilities in detail. First, the effect of more flexible trend models is explored, and we show that sufficiently flexible models are capable of attenuating the signal—although this is an expected byproduct of invoking such models. We also explore trend models using x- and y-centroid positions, and show that there is no data-driven impetus to adopt such models over temporal ones. We quantify the probability that the 500 ppm moon-like dip could be caused by a Neptune-sized transiting planet to be <0.75%. We show that neither autocorrelation, Gaussian processes, nor a Lomb–Scargle periodogram are able to recover a stellar rotation period, demonstrating that K1625 is a quiet star with periodic behavior <200 ppm. Through injection and recovery tests, we find that the star does not exhibit a tendency to introduce false-positive dip-like features above that of pure Gaussian noise. Finally, we address a recent reanalysis by Kreidberg et al. and show that the difference in conclusions is not from differing systematics models but rather the reduction itself. We show that their reduction exhibits, in comparison to the original analysis: (i) slightly higher intraorbit and post-fit residual scatter, (ii) ≃900 ppm larger flux offset at the visit change, (iii) ≃2 times larger y-centroid variations, and (iv) ≃3.5 times stronger flux-centroid correlation coefficient. These points could be explained by larger systematics in their reduction, potentially impacting their conclusions

Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy

Cytokine release syndrome (CRS) is a systemic inflammatory response associated with chimeric antigen receptor T-cell (CAR-T) therapies. In severe cases, CRS can be associated with coagulopathy and hypofibrinogenemia. We present our global multicenter experience with CRS-associated coagulopathy after tisagenlecleucel therapy in 137 patients with relapsed or refractory B-cell acute lymphoblastic leukemia from the ELIANA and ENSIGN trials. These trials included clinical guidelines for fibrinogen replacement during CRS-associated coagulopathy. Hypofibrinogenemia requiring replacement was observed only in patients with severe CRS. A higher percentage of patients who required replacement were <10 years old, compared with those who did not require replacement. Twenty-three patients received replacement for hypofibrinogenemia (<1.5 g/L); 9 of them developed marked hypofibrinogenemia (<1 g/L). Very low fibrinogen levels (<1 g/L) were documented in patients before maximal CRS (n = 1), during maximal CRS (n = 7), and at CRS improvement (n = 1). Although hypofibrinogenemia was the most clinically significant coagulopathy, some patients also developed prolonged prothrombin time and activated partial thromboplastin time and increased international normalized ratio, further increasing the risk of bleeding. Hypofibrinogenemia was effectively managed using fibrinogen concentrate or cryoprecipitate replacement; severe (grade 4) bleeding events were rare (n = 2). CRS-associated coagulopathy with hypofibrinogenemia is manageable according to empiric guidelines of fibrinogen replacement for CAR-T trials. Fibrinogen concentrate should be used when cryoprecipitate is not reliably available. Monitoring fibrinogen levels in patients with moderate or severe CRS is essential for avoiding potentially fatal bleeding events

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondria) apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, FED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1. These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response