LEE011 and ruxolitinib: a synergistic drug combination for natural killer/T-cell lymphoma (NKTCL).

Natural killer/T-cell lymphoma (NKTCL) is an aggressive non-Hodgkin lymphoma that has been facing limited success with conventional treatments, urging for the discovery of alternative strategies. Recent studies including ours have revealed that EZH2 and JAK-STAT signalling pathways are key contributors to NKTCL pathogenesis. In particular, we found that EZH2 is overexpressed and directly transcriptionally activates the CCND1 gene to confer growth advantage. CCND1 codes for cyclin D1, which complexes with CDK4/6 to promote G1 to S phase transition. Therefore in this study we investigated whether inhibiting both JAK1/2 and CDK4/6, using LEE011 and ruxolitinib respectively is effective in NKTL. We first demonstrate that separate LEE011 and ruxolitinib treatment is sufficient to cause growth inhibition of NKTCL cells. More importantly, we found that there is synergistic growth inhibitory effects on NKTCL cells with combination treatment of LEE011 and ruxolitinib. The results obtained shows that the targeting of both CDK4/6 and JAK1/2 are promising to develop better treatment alternatives for NKTCL.This study was supported by the National Medical Research Council (NMRC) grants NMRC/Clinician Scientist-Individual Research/1343/2012 (WJC), NMRC/Basic Research Grant-New Investigator/2021/2014 (JY) and the Singapore Ministry of Education Academic Research Fund Tier 2 grant MOE2015-T2-2-119 (DN). WJC was also supported by the NMRC Clinician Scientist Investigator Award

Lipid profiles and outcomes of patients with prior cancer and subsequent myocardial infarction or stroke

Patients with cancer are at increased risk of myocardial infarction (MI) and stroke. Guidelines do not address lipid profile targets for these patients. Within the lipid profiles, we hypothesized that patients with cancer develop MI or stroke at lower low density lipoprotein cholesterol (LDL-C) concentrations than patients without cancer and suffer worse outcomes. We linked nationwide longitudinal MI, stroke and cancer registries from years 2007-2017. We identified 42,148 eligible patients with MI (2421 prior cancer; 39,727 no cancer) and 43,888 eligible patients with stroke (3152 prior cancer; 40,738 no cancer). Median LDL-C concentration was lower in the prior cancer group than the no cancer group at incident MI [2.43 versus 3.10 mmol/L, adjusted ratio 0.87 (95% CI 0.85-0.89)] and stroke [2.81 versus 3.22 mmol/L, adjusted ratio 0.93, 95% CI 0.91-0.95)]. Similarly, median triglyceride and total cholesterol concentrations were lower in the prior cancer group, with no difference in high density lipoprotein cholesterol. Prior cancer was associated with higher post-MI mortality [adjusted hazard ratio (HR) 1.48, 95% CI 1.37-1.59] and post-stroke mortality (adjusted HR 1.95, 95% CI 1.52-2.52). Despite lower LDL-C concentrations, patients with prior cancer had worse post-MI and stroke mortality than patients without cancer

Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC50=22 n) and Janus kinase 2 (JAK2, IC50=23 n). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy

Generalized Weyl solutions in d=5 Einstein-Gauss-Bonnet theory: the static black ring

We argue that the Weyl coordinates and the rod-structure employed to construct static axisymmetric solutions in higher dimensional Einstein gravity can be generalized to the Einstein-Gauss-Bonnet theory. As a concrete application of the general formalism, we present numerical evidence for the existence of static black ring solutions in Einstein-Gauss-Bonnet theory in five spacetime dimensions. They approach asymptotically the Minkowski background and are supported against collapse by a conical singularity in the form of a disk. An interesting feature of these solutions is that the Gauss-Bonnet term reduces the conical excess of the static black rings. Analogous to the Einstein-Gauss-Bonnet black strings, for a given mass the static black rings exist up to a maximal value of the Gauss-Bonnet coupling constant $\alpha'$. Moreover, in the limit of large ring radius, the suitably rescaled black ring maximal value of $\alpha'$ and the black string maximal value of $\alpha'$ agree.Comment: 43 pages, 14 figure

Hot Halos and Galactic Glasses

We initiate a systematic study of the state space of non-extremal, stationary black hole bound states in four-dimensional N = 2 supergravity. Specifically, we show that an exponential multitude of classically stable "halo" bound states can be formed between large finite temperature D4-D0 black hole cores and much smaller, arbitrarily charged black holes at the same temperature. We map out in full the regions of existence for thermodynamically stable and metastable bound states in terms of the core's charges and temperature, as well as the region of stability of the core itself. Several features of these systems, such as a macroscopic configurational entropy and exponential relaxation timescales, are similar to those of the extended family of glasses. We draw parallels between the two with a view toward understanding complex systems in fundamental physics.Comment: 29 pages, 5 figures, v2: typos corrected, references adde

Distribution of cerebral blood flow in the caudate nucleus, lentiform nucleus and thalamus in patients with carotid artery stenosis

To investigate the influence of internal carotid artery (ICA) stenosis on the distribution of blood flow to the caudate nucleus, lentiform nucleus, and thalamus. We studied 18 healthy control subjects, 20 patients with a unilateral asymptomatic ICA stenosis, and 15 patients with a recently symptomatic unilateral ICA stenosis. The contribution of the ICAs and the basilar artery to the perfusion of the deep brain structures was assessed by perfusion territory selective arterial spin labeling (ASL) MRI. Differences were tested with a two-tailed Fishers' exact test. The caudate nucleus was predominantly supplied with blood by the ipsilateral ICA in all groups. In 4 of the 15 (27%) the symptomatic patients, the caudate nucleus partially received blood from the contralateral ICA, compared to none of the 18 healthy control subjects (p = 0.03). The lentiform nucleus and the thalamus were predominantly supplied with blood by the ipsilateral ICA and basilar artery respectively in all groups. In patients with a symptomatic ICA stenosis, the caudate nucleus may be supplied with blood by the contralateral ICA more often than in healthy controls.Neuro Imaging Researc

The I4U Mega Fusion and Collaboration for NIST Speaker Recognition Evaluation 2016

The 2016 speaker recognition evaluation (SRE'16) is the latest edition in the series of benchmarking events conducted by the National Institute of Standards and Technology (NIST). I4U is a joint entry to SRE'16 as the result from the collaboration and active exchange of information among researchers from sixteen Institutes and Universities across 4 continents. The joint submission and several of its 32 sub-systems were among top-performing systems. A lot of efforts have been devoted to two major challenges, namely, unlabeled training data and dataset shift from Switchboard-Mixer to the new Call My Net dataset. This paper summarizes the lessons learned, presents our shared view from the sixteen research groups on recent advances, major paradigm shift, and common tool chain used in speaker recognition as we have witnessed in SRE'16. More importantly, we look into the intriguing question of fusing a large ensemble of sub-systems and the potential benefit of large-scale collaboration.Peer reviewe

Behavior in behavioral strategy : capturing, measuring, analyzing

Measuring behavior requires research methods that can capture observed outcomes and expose underlying processes and mechanisms. In this chapter, we present a toolbox of instruments and techniques we designed experimental tasks to simulate decision environments and capture behavior. We deployed protocol analysis and text analysis to examine the underlying cognitive processes. In combination, these can simultaneously grasp antecedents, outcomes, processes, and mechanisms. We applied them to collect rich behavioral data on two key topics in strategic management: the exploration–exploitation trade-off and strategic risk-taking. This mix of methods is particularly useful in describing actual behavior as it is, not as it should be, replacing assumptions with data and offering a finer-grained perspective of strategic decision-making

Has land use pushed terrestrial biodiversity beyond the planetary boundary? A global assessment

Land use and related pressures have reduced local terrestrial biodiversity, but it is unclear how the magnitude of change relates to the recently proposed planetary boundary (“safe limit”). We estimate that land use and related pressures have already reduced local biodiversity intactness—the average proportion of natural biodiversity remaining in local ecosystems—beyond its recently proposed planetary boundary across 58.1% of the world’s land surface, where 71.4% of the human population live. Biodiversity intactness within most biomes (especially grassland biomes), most biodiversity hotspots, and even some wilderness areas is inferred to be beyond the boundary. Such widespread transgression of safe limits suggests that biodiversity loss, if unchecked, will undermine efforts toward long-term sustainable development