Michael Garcia

Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors.

Graft-versus-host disease (GVHD) is a significant complication of allogeneic stem cell transplantation (alloSCT). The proteasome inhibitor bortezomib has immunomodulatory properties of potential benefit for GVHD control. We undertook a phase 1 trial of bortezomib, tacrolimus, and methotrexate for GVHD prophylaxis after reduced-intensity conditioning alloSCT using human leukocyte antigen-mismatched unrelated donors. Twenty-three patients were enrolled. Bortezomib dose levels of 1, 1.3, and 1.5 mg/m2 were evaluated with 5, 3, and 5 patients, respectively. Ten additional patients were accrued at the 1.3 mg/m2 bortezomib dose level. Bortezomib-related toxicity was minimal. With a 12-month median follow-up, grade II-IV acute GVHD occurred in 3 patients, a 180-day cumulative incidence of 13%. Chronic GVHD occurred in 9 patients, a 1-year cumulative incidence of 41%. At 1-year, the nonrelapse mortality was zero, cumulative incidence of relapse/progression was 29%, and overall, progression-free, and event-free survival were 75%, 64%, and 59%, respectively. Bortezomib is a promising novel immunomodulatory agent in allogeneic transplantation. This study was registered at http://www.clinicaltrials.gov as #NCT00369226.

Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis

The immune and coagulation systems are both implicated in the pathogenesis of rheumatoid arthritis (RA). Plasma carboxypeptidase B (CPB), which is activated by the thrombin/thrombomodulin complex, plays a procoagulant role during fibrin clot formation. However, an antiinflammatory role for CPB is suggested by the recent observation that CPB can cleave proinflammatory mediators, such as C5a, bradykinin, and osteopontin. Here, we show that CPB plays a central role in downregulating C5a-mediated inflammatory responses in autoimmune arthritis. CPB deficiency exacerbated inflammatory arthritis in a mouse model of RA, and cleavage of C5a by CPB suppressed the ability of C5a to recruit immune cells in vivo. In human patients with RA, genotyping of nonsynonymous SNPs in the CPB-encoding gene revealed that the allele encoding a CPB variant with longer half-life was associated with a lower risk of developing radiographically severe RA. Functionally, this CPB variant was more effective at abrogating the proinflammatory properties of C5a. Additionally, expression of both CPB and C5a in synovial fluid was higher in patients with RA than in those with osteoarthritis. These findings suggest that CPB plays a critical role in dampening local, C5a-mediated inflammation and represents a molecular link between inflammation and coagulation in autoimmune arthritis.

The rapid decay of the optical emission from GRB 980326 and its possible implications

We report the discovery of the optical counterpart to GRB 980326. Its rapid optical decay can be characterized by a power law with exponent - 2.10+/-0.13 and a constant underlying source at R_{{c}}=25.5+/-0.5 . Its optical colors 2.1 days after the burst imply a spectral slope of - 0.66+/-0.70 . The gamma -ray spectrum as observed with BATSE shows that it is among the 4% softest bursts ever recorded. We argue that the rapid optical decay may be a reason for the nondetection of some low-energy afterglows of GRBs

A New Way to Detect Massive Black Holes in Galaxies: The Stellar Remnants of Tidal Disruption

We point out that the tidal disruption of a giant may leave a luminous (10 35 –10 39 ergs s 1 ), hot (10–100 eV) stellar core. The “supersoft” source detected by Chandra at the center of M31 may be such a core; whether or not it is, the observations have shown that such a core is detectable, even in the center of a galaxy. We therefore explore the range of expected observational signatures and how they may be used to (1) test the hypothesis that the M31 source is a remnant of tidal stripping and (2) discover evidence of black holes and disruption events in other galaxies.

Loss of Function of TET2 Cooperates with Constitutively Active KIT in Murine and Human Models of Mastocytosis

Systemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM.

12 YEARS OF X-RAY VARIABILITY IN M31 GLOBULAR CLUSTERS, INCLUDING 8 BLACK HOLE CANDIDATES, AS SEEN BY CHANDRA

We examined 134 Chandra observations of the population of X-ray sources associated with globular clusters (GCs) in the central region of M31. These are expected to be X-ray binary systems (XBs), consisting of a neutron star or black hole accreting material from a close companion. We created long-term light curves for these sources, correcting for background, interstellar absorption, and instrumental effects. We tested for variability by examining the goodness of fit for the best-fit constant intensity. We also created structure functions (SFs) for every object in our sample, the first time this technique has been applied to XBs. We found significant variability in 28 out of 34 GCs and GC candidates; the other 6 sources had 0.3‐10 keV luminosities fainter than ∼2 × 10 36 erg s −1 , limiting our ability to detect similar variability. The SFs of XBs with 0.3‐10 keV luminosities ∼2‐50 × 10 36 erg s −1 generally showed considerably more variability than the published ensemble SF of active galactic nuclei (AGNs). Our brightest XBs were mostly consistent with the AGN SF; however, their 2‐10 keV fluxes could be matched by <1 AGN per square degree. These encouraging results suggest that examining the long-term light curves of other X-ray sources in the field may provide an important distinction between X-ray binaries and background galaxies, as the X-ray emission spectra from these two classes of X-ray sources are similar. Additionally, we identify 3 new black hole candidates (BHCs) using additional XMM-Newton data, bringing the total number of M31 GC BHCs to 9, with 8 covered in this survey.

CD45 Expression in Mitral Valve Endothelial Cells After Myocardial Infarction.

RATIONALE Ischemic mitral regurgitation, a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to ischemic mitral regurgitation. OBJECTIVE Endothelial, interstitial, and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post MI, was analyzed in vitro. METHODS AND RESULTS Ovine MVs, harvested 6 months after inferior MI, showed CD45, a protein tyrosine phosphatase, colocalized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45+ endothelial cells (VE-cadherin+/CD45+/α-smooth muscle actin [SMA]+ and VE-cadherin+/CD45+/αSMA- cells) and possible fibrocytes (VE-cadherin-/CD45+/αSMA+) in inferior MI compared with sham-operated and normal sheep. CD45+ cells correlated with MV fibrosis and mitral regurgitation severity. VE-cadherin+/CD45+/αSMA+ cells suggested that CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with transforming growth factor-β1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and transforming growth factor-β1 to 3, not observed in transforming growth factor-β1-treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers and inhibited EndMT-associated migration of MV endothelial cells. CONCLUSIONS MV endothelial cells express CD45, both in vivo post MI and in vitro in response to transforming growth factor-β1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45+ endothelial cells to MV adaptation and fibrosis post MI warrants investigation.

Exploiting molecular biology for diagnosis and targeted management of pediatric low-grade gliomas

The majority of brain tumors arising in children are low-grade gliomas. Although historically categorized together as pediatric low-grade gliomas (PLGGs), there is significant histologic and genetic diversity within this group. In general, prognosis for PLGGs is excellent, and limitation of sequelae from tumor and treatment is paramount. Advances in high-throughput genetic sequencing and gene expression profiling are fundamentally changing the way PLGGs are classified and managed. Here, we review the histologic subtypes and highlight how recent advances in elucidating the molecular pathogenesis of these tumors have refined diagnosis and prognostication. Additionally, we discuss how characterizing specific genetic alterations has paved the way for the rational use of targeted therapies that are currently in various phase clinical trials.

Histopathologic review of pineal parenchymal tumors identifies novel morphologic subtypes and prognostic factors for outcome

Background. Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions. Methods. Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed. Freedom from progression (FFP) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using log-rank tests. Results. Median follow-up was 4.1 years. All patients initially underwent surgery; 78% of patients with PPT of intermediate differentiation (PPTID) and all patients with pineoblastoma received adjuvant therapy. Pathologic re-review refined classification in 27% of cases, with the majority of these being adult patients with pineal tumors originally classified as pineoblastomas that more accurately resembled PPTID based on the 2007 WHO classification. Classification. Our histologic review also identified that PPTIDs can be classified into small-cell and large-cell morphologic subtypes, which have distinct clinical outcomes. Tumor grade, extent of resection, and neuraxis spread were prognostic for FFP. PPTID subtype, extent of resection, and neuraxis spread were prognostic for OS. Genetic analysis of a pineoblastoma case identified somatic mutations of DICER1, ARID1A, and KDM5C genes. Conclusions. PPTIDs can be classified into 1 of 2 novel morphologic subtypes that are associated with distinct clinical outcomes. Tumor grade, neuraxis spread, and extent of resection also influence outcome for patients with PPT.

The NASA X-ray Mission concepts study

The 2010 Astrophysics Decadal Survey recommended a significant technology development program towards realizing the scientific goals of the International X-ray Observatory (IXO). NASA has undertaken an X-ray mission concepts study to determine alternative approaches to accomplishing IXO’s high ranking scientific objectives over the next decade given the budget realities, which make a flagship mission challenging to implement. The goal of the study is to determine the degree to which missions in various cost ranges from