Search

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT recipients is gastrointestinal (GI) GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. We analyzed serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and compared it with ST2 and REG3α in a large group of patients treated at multiple centers. A total of 526 patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who had received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed. Serum concentrations of elafin, ST2, and REG3α were measured by ELISA in all patients. The patients were divided at random into equal training and validation sets, and a competing-risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3α or the combination of all 3 biomarkers as predictors. Receiver operating characteristic (ROC) curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival (OS), and 4-week treatment response were compared between the risk groups. Unexpectedly, patients in the low-risk elafin group demonstrated a higher incidence of 6-month NRM, although the difference was not statistically significant (17% versus 11%; P = .19). OS at 6 months (68% versus 68%; P > .99) and 4-week response (78% versus 78%; P = .98) were similar in the low-risk and high-risk elafin groups. The area under the ROC curve (AUC) was 0.55 for elafin and 0.75 for the combination of ST2 and REG3α. The addition of elafin to the other 2 biomarkers did not improve the AUC. Our data indicate that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD did not predict 6-month NRM, OS, or treatment response in a multicenter population of patients treated systemically for acute GVHD. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM, and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD.

This study examines whether adolescent motivations for social media use, social comparison tendencies and gender are related to online aggression victimization and/or perpetration. Results from a national cross-sectional survey of adolescents (N = 340) reveal that social media use, romantic motivations, social belongingness motivations and greater social comparison tendencies are associated with online aggression victimization (R2 = 0.38). Information motivations and entertainment motivations are negatively associated with online aggression perpetration, but romantic motivations, social comparison, and social media use were positive predictors (R2 = 0.34). Further examination of interactions and indirect effects suggests that romantic motivations for social media use are an important predictor of involvement in online aggression among adolescents.

We present the design of a laboratory-astrophysics experiment to study magnetospheric accretion relevant to young, pre-main-sequence stars. Spectra of young stars show evidence of hotspots created when streams of accreting material impact the surface of the star and create shocks. The structures that form during this process are poorly understood, as the surfaces of young stars cannot be spatially resolved. Our experiment would create a scaled “accretion shock” at a major (several kJ) laser facility. The experiment drives a plasma jet (the “accretion stream”) into a solid block (the “stellar surface”), in the presence of a parallel magnetic field analogous to the star’s local field. We show that this experiment is well-scaled when the incoming jet has ρ ∼ 10 − 6 − 10 − 5 g cm − 3 and u ∼ 100 − 200 km s − 1 in an imposed field of B ∼ 10 T. Such an experiment would represent an average accretion stream onto a pre-main sequence star with B ∼ 700 G.

Recent experiments at the Jupiter Laser Facility investigated magnetization effects on collimated plasma jets. Laser-irradiated plastic-cone-targets produced collimated, millimeter-scale plasma flows as indicated by optical interferometry. Proton radiography of these jets showed no indication of strong, self-generated magnetic fields, suggesting a dominantly hydrodynamic collimating mechanism. Targets were placed in a custom-designed solenoid capable of generating field strengths up to 5 T. Proton radiographs of the well-characterized B-field, without a plasma jet, suggested an external source of trapped electrons that affects proton trajectories. The background magnetic field was aligned with the jet propagation direction, as is the case in many astrophysical systems. Optical interferometry showed that magnetization of the plasma results in disruption of the collimated flow and instead produces a hollow cavity. This result is a topic of ongoing investigation.

Interest in digital microfluidics (DMF), where discrete droplets are manipulated in a miniaturized device, has grown rapidly due to the versatility that arises from non-linear control of fluids. Adding superparamagnetic particles to the fluid allows the droplet to be manipulated by magnetic fields, such as that from a simple permanent magnet, removing some of the complexity of previous DMF devices and adding enhanced robustness. The magnetic field strength need not be high to control commercially available magnetic silica microparticles, however a hydrophobic surface is required to provide reduced friction. In this study, three types of hydrophobic surfaces were explored for their use in the magnetic actuation of water droplets containing magnetic particles. A conventional fluoropolymer film was found to have excessive frictional resistance to effectively actuate droplets. A natural superhydrophobic surface, the Colocasia leaf, was found to have too much surface microstructure to allow the magnetic particles to move freely over the surface. The commercially available Ultra-Ever Dry®, on the other hand, was suitable for effective magnetic actuation of aqueous and mixed droplets as it provided a robust, virtually frictionless surface. Based on fluorinated silica nanoparticles, this surface allowed a 20 μL water droplet to be manually pulled by a magnet at speeds in excess of 550 mm s−1.

There are no validated biomarkers that measure a patient's response to therapy for acute graft-versus-host disease (GVHD), the leading cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP estimates GVHD-mediated damage to crypts throughout the lower GI tract at single time points (Hartwell et al., JCI Insight, 2017; Major- Monfried et al., Blood, 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker and would compare favorably to clinical response, the gold standard which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT, 2009; MacMillan et al., Blood, 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We computed MAPs and clinical responses for each patient. MAPs of patients who experienced 6 month NRM increased significantly compared to MAPs of patients who survived (p=0.0004). In patients whose initial MAPs were low (Ann Arbor 1, MAP 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). We found that patients whose MAPs rose above the previously determined high-risk threshold MAP of 0.290 had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold had a large increase in mortality (Fig 2). When measured at day 28, MAPs predicted NRM more accurately than clinical responses, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p We conclude that the MAP is, to our knowledge, the first laboratory test validated as a response biomarker for acute GVHD treatment and more accurately predicts survival than clinical response after 28 days of treatment. The MAP may serve as a novel endpoint in future trials of GVHD treatment.

Relapse is most common cause of death after HCT. However, given the heterogeneity of diseases and disease states among patients (pts), risk for relapse is often difficult to manage in clinical trials when survival is the endpoint. The Disease Risk Index (DRI) predicts overall survival (OS) based on pre-HCT disease characteristics such as type of disease, remission status, and cytogenetic abnormalities and can be used to group heterogeneous diseases into 4 risk strata: very high risk [VHR, 1% of pts], high risk [HR, 23%], intermediate risk [IR, 64%], and low risk [LR, 12%] (Armand, Blood, 2014). OS for each of these strata is distinctly different. The DRI has been validated for adults, but not for children. Furthermore, the DRI cannot be calculated for some pediatric diseases like juvenile myelomonocytic leukemia (JMML). To determine its validity for children we calculated the DRI for 280 pediatric pts transplanted between 2008 and 2018 at Mount Sinai Acute GVHD International Consortium centers. The median age was 8.9 years (range, 0.4 - 17). The most common indications for HCT were ALL (51%), AML (31%), MDS (10%), and JMML (4%). Donors were adult unrelated donors (48%), unrelated cord blood (20%), haploidentical donors (17%), and matched siblings (15%). We first determined 2y survival by DRI for the 270 pts without JMML. Survival for JMML was closest to the VHR strata and we grouped JMML with VHR for all further analyses. The size of each of the risk strata were different for children compared to adults, VHR (n=32, 11%), HR (n=108, 39%), IR (n=128, 46%), and LR (n=12, 4%). Given the small number of LR pts, we excluded them from further analyses. We then determined that DRI effectively stratified pts into distinct strata for relapse (FIG 1A) and disease-free survival (FIG 1B). Because transplant practices are different for children compared to adults (e.g., more myeloablative conditioning), we examined whether DRI remained predictive of outcomes after adjustment for age, donor type, stem cell source, and conditioning intensity. We used IR as the reference group for these multivariate analyses. Children with HR DRI were significantly more likely to relapse (HR 2.1, 95% CI 1.2-3.7) and have worse DFS (HR 1.6, 95% CI 1.0-2.5). The risks for relapse and worse DFS were even greater for children with VHR DRI (relapse, HR 3.4, 95% CI 1.6-7.3, DFS 3.59, 95% CI 2.0-6.5). There were no significant differences in 2y non-relapse mortality by DRI. VHR pts had significantly worse 2y OS (HR 3.2, 95% CI 1.6-6.4) but HR pts were not significantly different for 2y OS than IR pts (HR 1.3, 95% CI 0.7-2.2). OS for HR and IR pts may diverge with longer follow-up. In summary, the LR strata is small and more pts are needed to determine their outcomes. However, for >95% of children the DRI creates 3 distinct risk strata. The DRI can be used in pediatric clinical trials to stratify for risk of relapse.

The sequence homology between Acanthamoeba myosin I heavy chain kinase (MIHCK) and other p21-activated kinases (PAKs) is relatively low, including only the catalytic domain and a short PAK N-terminal motif (PAN), and even these regions are not highly homologous. In this paper, we report the expression in insect cells of full-length, fully regulated Acanthamoeba MIHCK and further characterize the regulation of this PAK by Rac, calmodulin, and autoinhibition. We map the autoinhibitory region of MIHCK to its PAN region and show that the PAN region inhibits autophosphorylation and kinase activity of unphosphorylated full-length MIHCK and its expressed catalytic domain but has very little effect on either when they are phosphorylated. These properties are similar to those reported for mammalian PAK1. Unlike PAK1, MIHCK is activated by Rac only in the presence of phospholipid. However, peptides containing the PAN region of MIHCK bind Rac in the absence of lipid, and Rac binding reverses the inhibition of the MIHCK catalytic domain by PAN peptides. Our data suggest that a region N-terminal to PAN is required for optimal binding of Rac. Also unlike mammalian PAK, phospholipid stimulation of Acanthamoeba MIHCK and Dictyostelium MIHCK) (which is also a PAK) is inhibited by Ca(2+)-calmodulin. In contrast to Dictyostelium MIHCK, however, Ca(2+)-calmodulin also inhibits Rac-induced activity of Acanthamoeba MIHCK. The basic region N-terminal to PAN is essential for calmodulin binding.