Adjuvant IL-15 does not enhance the efficacy of tumor cell lysate-pulsed dendritic cell vaccines for active immunotherapy of T cell lymphoma

There has been a recent interest in using IL-15 to enhance antitumor activity in several models because of its ability to stimulate CD8 + T cell expansion, inhibit apoptosis and promote memory T cell survival and maintenance. Previously, we reported that C6VL tumor lysate-pulsed dendritic cell vaccines significantly enhanced the survival of tumor-bearing mice by stimulating a potent tumor-specific CD8 + T cell response. In this study, we determined whether IL-15 used as immunologic adjuvant would augment vaccine-primed CD8 + T cell immunity against C6VL and further improve the survival of tumor-bearing mice. We report that IL-15 given after C6VL lysate-pulsed dendritic cell vaccines stimulated local and systemic expansion of NK, NKT and CD8 + CD44 hi T cells. IL-15 did not, however, augment innate or cellular responses against the tumor. T cells from mice infused with IL-15 following vaccination did not secrete increased levels of tumor-specific TNF-α or IFN-γ or have enhanced C6VL-specific CTL activity compared to T cells from recipients of the vaccine alone. Lastly, IL-15 did not enhance the survival of tumor-bearing vaccinated mice. Thus, while activated- and memory-phenotype CD8 + T cells were dramatically expanded by IL-15 infusion, vaccine-primed CD8 + T cell specific for C6VL were not significantly expanded. This is the first account of using IL-15 as an adjuvant in a therapeutic model of active immunotherapy where there was not a preexisting pool of tumor-specific CD8 + T cells. Our results contrast the recent studies where IL-15 was successfully used to augment tumor-reactivity of adoptively transferred transgenic CD8 + T cells. This suggests that the adjuvant potential of IL-15 may be greatest in settings where it can augment the number and activity of preexisting tumor-specific CD8 + T cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46865/1/262_2005_Article_6.pd

T Cell Antigen Receptor Vaccines for Active Therapy of T Cell Malignancies

T cell lymphoproliferative disorders continue to be serious management problems, and so alternative therapeutic modalities are continuously being explored. One such strategy involves immunotherapy using the T cell receptor (TCR) as a target. Specifically we are attempting to develop a T cell receptor idiotype (TCR-Id) vaccine because the TCR-Id can serve as a tumor-specific antigen. In this article we will briefly review the rationale for TCR-Id vaccines, the preclinical models as developed in our laboratory, and a discussion of our current plans for a vaccine trial in mycosis fungoides.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72794/1/j.1749-6632.2001.tb03714.x.pd

Primary cutaneous Epstein-Barr virus-positive diffuse large B-cell lymphoma (DLBCL) in a patient taking fingolimod

A 55-year-old man with relapsing-remitting multiple sclerosis on fingolimod presented to the dermatology clinic with skin lesions on the left temple and cheek. Histopathology showed a diffuse infiltrate of enlarged, atypical lymphocytes throughout the dermis with an overlying grenz zone and a subpopulation of scattered smaller lymphocytes and plasma cells. Epstein-Barr virus-encoded RNA in situ hybridization stain was positive. Based on the morphologic and immunophenotypic findings, a diagnosis of EBV-positive diffuse large B-cell lymphoma was made. This case aims to raise awareness for the dermatologist that patients on fingolimod may be at increased risk of lymphoproliferative disorders

A Hybrid Higgs

We construct composite Higgs models admitting a weakly coupled Seiberg dual description. We focus on the possibility that only the up-type Higgs is an elementary field, while the down-type Higgs arises as a composite hadron. The model, based on a confining SQCD theory, breaks supersymmetry and electroweak symmetry dynamically and calculably. This simultaneously solves the \mu/B_\mu problem and explains the smallness of the bottom and tau masses compared to the top mass. The proposal is then applied to a class of models where the same confining dynamics is used to generate the Standard Model flavor hierarchy by quark and lepton compositeness. This provides a unified framework for flavor, supersymmetry breaking and electroweak physics. The weakly coupled dual is used to explicitly compute the MSSM parameters in terms of a few microscopic couplings, giving interesting relations between the electroweak and soft parameters. The RG evolution down to the TeV scale is obtained and salient phenomenological predictions of this class of "single-sector" models are discussed.Comment: 56 pages, 7 figures, v2: discussion on FCNCs and references added, v3: JHEP versio

Higgs Portal to Visible Supersymmetry Breaking

We propose a supersymmetric extension of the standard model whose Higgs sector induces a spontaneous supersymmetry breaking by itself. Unlike the minimal extension, the current Higgs mass bound can be evaded even at the tree-level without the help of the soft breaking terms due to the usual hidden sector, as is reminiscent of the next to minimal case. We also have a possibly light pseudo-goldstino in our visible sector in addition to extra Higgs particles, both of which stem from supersymmetry breaking dynamics. In such a setup of visible supersymmetry breaking, we may see a part of supersymmetry breaking dynamics rather directly in future experiments.Comment: 23 pages, 6 figures, references adde

Developing a digital intervention for cancer survivors: an evidence-, theory- and person-based approach

This paper illustrates a rigorous approach to developing digital interventions using an evidence-, theory- and person-based approach. Intervention planning included a rapid scoping review which identified cancer survivors’ needs, including barriers and facilitators to intervention success. Review evidence (N=49 papers) informed the intervention’s Guiding Principles, theory-based behavioural analysis and logic model. The intervention was optimised based on feedback on a prototype intervention through interviews (N=96) with cancer survivors and focus groups with NHS staff and cancer charity workers (N=31). Interviews with cancer survivors highlighted barriers to engagement, such as concerns about physical activity worsening fatigue. Focus groups highlighted concerns about support appointment length and how to support distressed participants. Feedback informed intervention modifications, to maximise acceptability, feasibility and likelihood of behaviour change. Our systematic method for understanding user views enabled us to anticipate and address important barriers to engagement. This methodology may be useful to others developing digital interventions

Targeting the Replication Initiator of the Second Vibrio Chromosome: Towards Generation of Vibrionaceae-Specific Antimicrobial Agents

The Vibrionaceae is comprised of numerous aquatic species and includes several human pathogens, such as Vibrio cholerae, the cause of cholera. All organisms in this family have two chromosomes, and replication of the smaller one depends on rctB, a gene that is restricted to the Vibrionaceae. Given the increasing prevalence of multi-drug resistance in pathogenic vibrios, there is a need for new targets and drugs to combat these pathogens. Here, we carried out a high throughput cell-based screen to find small molecule inhibitors of RctB. We identified a compound that blocked growth of an E. coli strain bearing an rctB-dependent plasmid but did not influence growth of E. coli lacking this plasmid. This compound, designated vibrepin, had potent cidal activity against V. cholerae and inhibited the growth of all vibrio species tested. Vibrepin blocked RctB oriCII unwinding, apparently by promoting formation of large non-functional RctB complexes. Although vibrepin also appears to have targets other than RctB, our findings suggest that RctB is an attractive target for generation of novel antibiotics that only block growth of vibrios. Vibrio-specific agents, unlike antibiotics currently used in clinical practice, will not engender resistance in the normal human flora or in non-vibrio environmental microorganisms

Down Regulation of a Gene for Cadherin, but Not Alkaline Phosphatase, Associated with Cry1Ab Resistance in the Sugarcane Borer Diatraea saccharalis

The sugarcane borer, Diatraea saccharalis, is a major target pest of transgenic corn expressing Bacillus thuringiensis (Bt) proteins (i.e., Cry1Ab) in South America and the mid-southern region of the United States. Evolution of insecticide resistance in such target pests is a major threat to the durability of transgenic Bt crops. Understanding the pests' resistance mechanisms will facilitate development of effective strategies for delaying or countering resistance. Alterations in expression of cadherin- and alkaline phosphatase (ALP) have been associated with Bt resistance in several species of pest insects. In this study, neither the activity nor gene regulation of ALP was associated with Cry1Ab resistance in D. saccharalis. Total ALP enzymatic activity was similar between Cry1Ab-susceptible (Cry1Ab-SS) and -resistant (Cry1Ab-RR) strains of D. saccharalis. In addition, expression levels of three ALP genes were also similar between Cry1Ab-SS and -RR, and cDNA sequences did not differ between susceptible and resistant larvae. In contrast, altered expression of a midgut cadherin (DsCAD1) was associated with the Cry1Ab resistance. Whereas cDNA sequences of DsCAD1 were identical between the two strains, the transcript abundance of DsCAD1 was significantly lower in Cry1Ab-RR. To verify the involvement of DsCAD1 in susceptibility to Cry1Ab, RNA interference (RNAi) was employed to knock-down DsCAD1 expression in the susceptible larvae. Down-regulation of DsCAD1 expression by RNAi was functionally correlated with a decrease in Cry1Ab susceptibility. These results suggest that down-regulation of DsCAD1 is associated with resistance to Cry1Ab in D. saccharalis

Identification of neural networks that contribute to motion sickness through principal components analysis of fos labeling induced by galvanic vestibular stimulation

Motion sickness is a complex condition that includes both overt signs (e.g., vomiting) and more covert symptoms (e.g., anxiety and foreboding). The neural pathways that mediate these signs and symptoms are yet to identified. This study mapped the distribution of c-fos protein (Fos)-like immunoreactivity elicited during a galvanic vestibular stimulation paradigm that is known to induce motion sickness in felines. A principal components analysis was used to identify networks of neurons activated during this stimulus paradigm from functional correlations between Fos labeling in different nuclei. This analysis identified five principal components (neural networks) that accounted for greater than 95% of the variance in Fos labeling. Two of the components were correlated with the severity of motion sickness symptoms, and likely participated in generating the overt signs of the condition. One of these networks included neurons in locus coeruleus, medial, inferior and lateral vestibular nuclei, lateral nucleus tractus solitarius, medial parabrachial nucleus and periaqueductal gray. The second included neurons in the superior vestibular nucleus, precerebellar nuclei, periaqueductal gray, and parabrachial nuclei, with weaker associations of raphe nuclei. Three additional components (networks) were also identified that were not correlated with the severity of motion sickness symptoms. These networks likely mediated the covert aspects of motion sickness, such as affective components. The identification of five statistically independent component networks associated with the development of motion sickness provides an opportunity to consider, in network activation dimensions, the complex progression of signs and symptoms that are precipitated in provocative environments. Similar methodology can be used to parse the neural networks that mediate other complex responses to environmental stimuli. © 2014 Balaban et al

Higgs Working Group Report of the Snowmass 2013 Community Planning Study

This report summarizes the work of the Energy Frontier Higgs Boson working group of the 2013 Community Summer Study (Snowmass). We identify the key elements of a precision Higgs physics program and document the physics potential of future experimental facilities as elucidated during the Snowmass study. We study Higgs couplings to gauge boson and fermion pairs, double Higgs production for the Higgs self-coupling, its quantum numbers and $CP$-mixing in Higgs couplings, the Higgs mass and total width, and prospects for direct searches for additional Higgs bosons in extensions of the Standard Model. Our report includes projections of measurement capabilities from detailed studies of the Compact Linear Collider (CLIC), a Gamma-Gamma Collider, the International Linear Collider (ILC), the Large Hadron Collider High-Luminosity Upgrade (HL-LHC), Very Large Hadron Colliders up to 100 TeV (VLHC), a Muon Collider, and a Triple-Large Electron Positron Collider (TLEP)