We report the first whole-genome sequences for five strains, two carried and three pathogenic, of the emerging pathogen Haemophilus haemolyticus. Preliminary analyses indicate that these genome ...sequences encode markers that distinguish H. haemolyticus from its closest Haemophilus relatives and provide clues to the identity of its virulence factors.
Abstract 3079
Poster Board III-16
Epigenetic silencing of tumor suppressor genes (TSGs) is among the most common acquired abnormalities observed in AML and is prototypically linked to DNA ...methylation. Aberrant DNA methylation is most prevalent in adverse risk AML patients (Melki, Vincent et al. 1999; Toyota, Kopecky et al. 2001). Reactivated expression of TSGs is commonly implicated in the clinical activity of DNA hypomethylating agents since these genes often have roles in cellular differentiation, apoptosis, DNA repair, and checkpoint control (Jones and Taylor 1980; Pinto, Zagonel et al. 1989; Petti, Mandelli et al. 1993; Schimmer, Pedersen et al. 2003; Schmelz, Sattler et al. 2005; Schmelz, Wagner et al. 2005; Tamm, Wagner et al. 2005). We, and others, have demonstrated that DNA hypomethylating agents can sensitize resistant cancer cells to cytotoxic agents in vitro (Avramis, Mecum et al. 1989; Anzai, Frost et al. 1992; Plumb, Strathdee et al. 2000; Fulda, Kufer et al. 2001; Niitsu, Hayashi et al. 2001; Arnold, Goel et al. 2003; Eramo, Pallini et al. 2005; Kanda, Tada et al. 2005; Qiu, Mirkin et al. 2005) yet this approach has been sparsely studied in clinical trials. We hypothesized that pre-treatment with a hypomethylating agent would increase the efficacy of standard induction chemotherapy for AML.
We conducted a phase I dose-escalation study of decitabine administered just prior to a single, standard induction with infusional cytarabine (100 mg/m2 for 7 days) and daunorubicin (60 mg/m2 × 3 doses) as initial treatment for patients with less-than favorable risk AML. Three dose levels of decitabine (20 mg/m2 for 3, 5 or 7 days), delivered either as a bolus (Arm A) or by continuous infusion (Arm B), were used as priming for standard induction chemotherapy.
At current data cut-off, 25 (of 30 patients planned) were fully evaluable: median age was 56 (range 23–60); 21 (84%) patients had adverse risk AML because of karyotype (No. 15, 60%), or other adverse features (FLT3-ITD or antecedent hematologic disorder, No. 11, 44%), and the remaining 4 (16%) patients had intermediate risk AML. Toxicity was similar to that of standard induction chemotherapy alone. Two patients treated at the highest dose level had grade 3 mucositis that resolved prior to count recovery. We observed no excess hematologic toxicity and all patients had peripheral blood count recovery within 30 days or were found to have persistent AML. There was no induction mortality and no patients required ICU transfer. A maximum tolerated dose was not achieved.
Twenty-one patients (84%) responded to therapy: 14 CR (56%), 7 PR (28%). Of the patients with PR to protocol treatment, 5 achieved remission with a second, standard induction bringing the overall CR rate to 76%. The final cohort of patients is currently accruing. All patients went on to receive additional AML therapy and 14 have received an allogeneic HSCT. Pharmacodynamic analyses of DNA hypomethylation prior to and immediately following priming demonstrate genome-wide DNA hypomethylation at all dose levels. Detailed analyses of DNA methylation are ongoing.
Complete remission is requisite for the cure of AML and this study demonstrates that it is safe to combine the epigenetic modifier, decitabine, with full-dose, standard, cytotoxic chemotherapy as an approach to improve remission rates. Our results suggest that epigenetic priming is potentially superior to standard induction therapy alone as initial therapy for patients with less than favorable risk AML and provide the foundation for a subsequent phase II study.
Off Label Use: Phase I study of decitibine use in AML.
Abstract 2063
Poster Board II-40
Adults with primary refractory or relapsed acute myeloid leukemia (AML) have a poor prognosis with complete responses to salvage therapy from 13-15% and a median ...survival of 1.5-6 months1, 2. From 2006-2009, 79 patients with relapsed or refractory acute myeloid leukemia were given salvage chemotherapy with decitabine 20mg/m2 daily for 10 days or decitabine 20mg/m2 × 5 days with gemtuzumab ozogamicin (GO) 3mg/m2 on day 5 at Weill Cornell Medical Center.
Medical records of 79 patients who received decitabine-based salvage therapy were reviewed from September 2006 through July 2009 at Weill Cornell Medical College. Survival was calculated by the Kaplan Meir method and differences in survival calculated by the log-rank test using STATA software.
Twenty-five patients received decitabine-based therapy as first salvage, 32 patients as second salvage, and 22 patients as third or greater salvage. Fifty-one patients were treated with decitabine/GO and 29 patients received decitabine alone. Median age of patients was 65.5 years with a range of 24 -89 years (first salvage 75 years, second salvage 62 years, and third or greater salvage 64 years). Median survival of all patients was 205 days, range 7-732 days. Overall 34% patients responded: 16% CR (<5% blasts in bone marrow, recovery ANC >1000 and Plts > 100,000) with median survival not yet reached; 5% CRp (< 5% blasts in bone marrow, ANC >1000 and plts < 100,000) with median survival 223 days; 13% PR (blasts 6-11%) with median survival 205 days; and 66% no response with median survival 118 days. Patients receiving first salvage had median survival 181 days with CR 13%, CRp 6%, PR 17%. Patients receiving second salvage had median survival 207 days with CR 9%, CRp 4%, PR 9%. Patients with third or greater salvage had median survival 209 days with CR 23%, CRp 0%, PR 14%. Patients receiving decitabine alone had a median survival of 209 days and those receiving decitabine/GO had a median survival of 177 days but the difference was not significant. Median survival for normal, favorable, intermediate and unfavorable cytogenetics was 282, 224, 157 and 176 days respectively (p=0.06). Conclusions: Decitabine-based treatment for relapsed and refractory AML is a low intensity alternative that has activity rivaling more intensive regimens. This retrospective study suggests that further investigation of decitabine-based salvage is warranted.
1. Sievers, E.L., et al., Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol, 2001. 19(13): p. 3244-54.
2. Giles, F., et al., Outcome of patients with acute myelogenous leukemia after second salvage therapy. Cancer, 2005. 104(3): p. 547-54.
Off Label Use: Phase I trial of decitabine in AML is off-label .
Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected ...haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College.
We analyzed 42 lymphoma and CLL patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin’s lymphoma (n=9, 21%), CLL (n=5, 12%) and non-Hodgkin lymphomas (n=28, 67%), including 13 T-cell lymphoma. Twenty four patients (52%) had 3 or more lines of therapies. Six (14%) and one (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant, 12 patients (29%) were in complete remission (CR), 18 had chemotherapy-sensitive disease and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%) and 24 (57%) patients had low, intermediate and high disease risk index (DRI) prior to transplant. Comorbidity index was evenly distributed among 3 groups with 13 (31%), 14 (33%) and 15(36%) patients scored 0, 1–2 and ≥3. Median age for the cohort was 49 years (23–71). All patients received fludarabine/melphalan/ATG conditioning regimen and post-transplant GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF). The median time to neutrophil engraftment was 11 days (9–60) and to platelet engraftment was 19.5 days (11–88).
Cumulative Incidence of non-relapse mortality (NRM) was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow up of survivors of 42 months, the three-year GVHD/Progression Free Survival (GPFS), progression free survival (PFS) and overall survival (OS) was 53%, 62%, and 65% respectively for these patients. Only 8% of the survivors have chronic GVHD.
In conclusion, haplo-cord transplantation offers a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors. Both neutrophil and platelet count recovery is rapid, non-relapse mortality is limited, excellent disease control can be achieved and the incidence of chronic GVHD is limited. Thus, haplo-cord achieves high rates of engraftment and encouraging results.
ABSTRACT
Private equity funds intermediate investment and affect portfolio firm performance by actively engaging in operational, governance, and financial engineering. We study this type of ...intermediation in a dynamic agency model in which an active intermediary raises funds from outside investors and invests in a firm run by an agent. Optimal contracting addresses moral hazard at the intermediary and firm levels. The intermediary's incentives to affect firm performance are strongest after poor performance, while the agent's incentives are strongest after good performance. We also show how financial engineering, that is, financial contracting with outside investors, interacts with operational and governance engineering.
The molecular chaperones of the Hsp70 family have been recognized as targets for anti-cancer therapy. Since several paralogs of Hsp70 proteins exist in cytosol, endoplasmic reticulum and ...mitochondria, we investigated which isoform needs to be down-regulated for reducing viability of cancer cells. For two recently identified small molecule inhibitors, VER-155008 and 2-phenylethynesulfonamide (PES), which are proposed to target different sites in Hsp70s, we analyzed the molecular mode of action in vitro. We found that for significant reduction of viability of cancer cells simultaneous knockdown of heat-inducible Hsp70 (HSPA1) and constitutive Hsc70 (HSPA8) is necessary. The compound VER-155008, which binds to the nucleotide binding site of Hsp70, arrests the nucleotide binding domain (NBD) in a half-open conformation and thereby acts as ATP-competitive inhibitor that prevents allosteric control between NBD and substrate binding domain (SBD). Compound PES interacts with the SBD of Hsp70 in an unspecific, detergent-like fashion, under the conditions tested. None of the two inhibitors investigated was isoform-specific.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Microplastics released into freshwaters from anthropogenic sources settle in the sediments, where they may pose an environmental threat to benthic organisms. However, few studies have considered the ...ecotoxicological hazard of microplastic particles for nematodes, one of the most abundant taxa of the benthic meiofauna. This study investigated the toxic effects of polystyrene (PS) beads (0.1–10.0 μm) and the underlying mechanisms thereof on the reproduction of the nematode Caenorhabditis elegans. The observed effect of the PS beads on the nematodes correlated well with the total surface area of the beads per volume, with a 50% inhibition of reproduction at 55.4 ± 12.9 cm2/mL, independent of the bead size. The adverse effects were not explained by styrene monomers leaching from the beads because chemical activities of styrene in PS suspensions were well below the toxic levels. However, the observed effects could be related to the bead material because the same-sized silica (SiO2) beads had considerably less impact, probably due to their higher specific density. PS and SiO2 beads affected the food availability of C. elegans, with greater effects by the PS beads. Our results demonstrate the importance of including indirect food web effects in studies of the ecological risks posed by microplastics.
RNA viruses exist in genetically diverse populations due to high levels of mutations, many of which reduce viral fitness. Interestingly, intestinal bacteria can promote infection of several mammalian ...enteric RNA viruses, but the mechanisms and consequences are unclear. We screened a panel of 41 bacterial strains as a platform to determine how different bacteria impact infection of poliovirus, a model enteric virus. Most bacterial strains, including those extracted from cecal contents of mice, bound poliovirus, with each bacterium binding multiple virions. Certain bacterial strains increased viral co-infection of mammalian cells even at a low virus-to-host cell ratio. Bacteria-mediated viral co-infection correlated with bacterial adherence to cells. Importantly, bacterial strains that induced viral co-infection facilitated genetic recombination between two different viruses, thereby removing deleterious mutations and restoring viral fitness. Thus, bacteria-virus interactions may increase viral fitness through viral recombination at initial sites of infection, potentially limiting abortive infections.
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•We screened a panel of bacterial strains for their effects on enteric virus infection•Multiple poliovirus virions bind to a variety of bacterial strains•Bacteria facilitate poliovirus co-infection under low MOI conditions•Bacteria enhance viral fitness by promoting genetic recombination
Enteric viruses rely on intestinal bacteria for replication and transmission. By screening a diverse panel of bacterial strains, Erickson et al. demonstrate that bacteria differentially bind poliovirus and that some bacterial strains promote viral co-infection and genetic recombination, thus enhancing viral fitness.
We develop a model in which a start-up firm issues tokens to finance a digital platform, which creates agency conflicts between platform developers and outsiders. We show that token financing is ...preferred to equity financing unless the platform expects strong cash flows, has large financing needs, or faces severe agency conflicts. Tokens are characterized by their utility features, facilitating transactions, and security features, granting cash flow rights. While security features trigger endogenous network effects and spur platform adoption, they also dilute developers’ equity stake and incentives so that the optimal level of security features decreases with agency conflicts and financing needs.
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