Eotaxin and FGF enhance signaling through an Extracellular signal-related kinase (ERK)-dependent pathway in the pathogenesis of Eosinophilic Esophagitis

<p>Abstract</p> <p>Background</p> <p>Eosinophilic esophagitis (EoE) is characterized by the inflammation of the esophagus and the infiltration of eosinophils into the esophagus, leading to symptoms such as dysphagia and stricture formation. Systemic immune indicators like eotaxin and fibroblast growth factor were evaluated for possible synergistic pathological effects. Moreover, blood cells, local tissue, and plasma from EoE and control subjects were studied to determine if the localized disease was associated with a systemic effect that correlated with presence of EoE disease.</p> <p>Method</p> <p>Real-time polymerase chain reaction from peripheral blood mononuclear cells (PBMC), immunohistochemistry from local esophageal biopsies, fluid assays on plasma, and fluorescence-activated cell sorting on peripheral blood cells from subjects were used to study the systemic immune indicators in newly diagnosed EoE (n = 35), treated EoE (n = 9), Gastroesophageal reflux disease (GERD) (n = 8), ulcerative colitis (n = 5), Crohn's disease (n = 5), and healthy controls (n = 8).</p> <p>Result</p> <p>Of the transcripts tested for possible immune indicators, we found extracellular signal-regulated kinase (ERK), Bcl-2, bFGF (basic fibroblast growth factor), and eotaxin levels were highly upregulated in PBMC and associated with disease presence of EoE. Increased FGF detected by immunohistochemistry in esophageal tissues and in PBMC was correlated with low levels of pro-apoptotic factors (Fas, Caspase 8) in PBMC from EoE subjects. Plasma-derived bFGF was shown to be the most elevated and most specific in EoE subjects in comparison to healthy controls and disease control subjects.</p> <p>Conclusion</p> <p>We describe for the first time a possible mechanism by which increased FGF is associated with inhibiting apoptosis in local esophageal tissues of EoE subjects as compared to controls. Eotaxin and FGF signaling pathways share activation through the ERK pathway; together, they could act to increase eosinophil activation and prolong the half-life of eosinophils in local tissues of the esophagus in EoE subjects.</p

A Randomized Trial to Identify Accurate and Cost-Effective Fidelity Measurement Methods for Cognitive-Behavioral Therapy: Project FACTS Study Protocol

Background: This randomized trial will compare three methods of assessing fidelity to cognitive-behavioral therapy (CBT) for youth to identify the most accurate and cost-effective method. The three methods include self-report (i.e., therapist completes a self-report measure on the CBT interventions used in session while circumventing some of the typical barriers to self-report), chart-stimulated recall (i.e., therapist reports on the CBT interventions used in session via an interview with a trained rater, and with the chart to assist him/her) and behavioral rehearsal (i.e., therapist demonstrates the CBT interventions used in session via a role-play with a trained rater). Direct observation will be used as the gold-standard comparison for each of the three methods. Methods/design: This trial will recruit 135 therapists in approximately 12 community agencies in the City of Philadelphia. Therapists will be randomized to one of the three conditions. Each therapist will provide data from three unique sessions, for a total of 405 sessions. All sessions will be audio-recorded and coded using the Therapy Process Observational Coding System for Child Psychotherapy-Revised Strategies scale. This will enable comparison of each measurement approach to direct observation of therapist session behavior to determine which most accurately assesses fidelity. Cost data associated with each method will be gathered. To gather stakeholder perspectives of each measurement method, we will use purposive sampling to recruit 12 therapists from each condition (total of 36 therapists) and 12 supervisors to participate in semi-structured qualitative interviews. Discussion: Results will provide needed information on how to accurately and cost-effectively measure therapist fidelity to CBT for youth, as well as important information about stakeholder perspectives with regard to each measurement method. Findings will inform fidelity measurement practices in future implementation studies as well as in clinical practice. Trial registration: NCT02820623, June 3rd, 2016

The Vehicle, Fall 1970

Vol. 13, No. 1 Table of Contents A Thought Written in a Locked RoomJudy Huntpage 1 The Eggshell MoonWilliam Probeckpage 2 PoemBarb Parkerpage 3 4/5, May, 1970J. Michael Sainpage 5 A TreeRichard Stickannpage 6 both or noneMichelle Hallpage 6 The TrainSteve Sestinapage 8 Attempted DiscoveryDonald R. Johnsonpage 16 Island of SmokeVerna L. Jonespage 18 AwakeRobert Bladepage 19 PoemMary Klinkerpage 19 In ChurchMuriel Poolpage 21 PoemBarb Parkerpage 21 PoemMichelle Hallpage 22 Pod\u27nerVerna L. Jonespage 23 Rain and Other ThingsCarol Staniecpage 24 PoemAnn Graffpage 24 Examination of StudentdomMelvin Zaloudekpage 26 Women\u27s LiberationTonya Mortonpage 27 Morning Reflections on the Evening NewsPrudence Herberpage 29 Art and Photography Credits Jim Diaspage 4 Mike Dorseypages 7, 20 David Griffithpages 8, 17, 25 Cover PhotographyMark McKinneyhttps://thekeep.eiu.edu/vehicle/1024/thumbnail.jp

Malaria illness mediated by anaemia lessens cognitive development in younger Ugandan children

BACKGROUND: Asymptomatic falciparum malaria is associated with poorer cognitive performance in African schoolchildren and intermittent preventive treatment of malaria improves cognitive outcomes. However, the developmental benefits of chemoprevention in early childhood are unknown. Early child development was evaluated as a major outcome in an open-label, randomized, clinical trial of anti-malarial chemoprevention in an area of intense, year-round transmission in Uganda. METHODS: Infants were randomized to one of four treatment arms: no chemoprevention, daily trimethoprim–sulfamethoxazole, monthly sulfadoxine–pyrimethamine, or monthly dihydroartemisinin–piperaquine (DP), to be given between enrollment (4–6 mos) and 24 months of age. Number of malaria episodes, anaemia (Hb < 10) and neurodevelopment [Mullen Scales of Early Learning (MSEL)] were assessed at 2 years (N = 469) and at 3 years of age (N = 453); at enrollment 70 % were HIV-unexposed uninfected (HUU) and 30 % were HIV-exposed uninfected (HEU). RESULTS: DP was highly protective against malaria and anaemia, although trial arm was not associated with MSEL outcomes. Across all treatment arms, episodes of malarial illness were negatively predictive of MSEL cognitive performance both at 2 and 3 years of age (P = 0.02). This relationship was mediated by episodes of anaemia. This regression model was stronger for the HEU than for the HUU cohort. Compared to HUU, HEU was significantly poorer on MSEL receptive language development irrespective of malaria and anaemia (P = 0.01). CONCLUSIONS: Malaria with anaemia and HIV exposure are significant risk factors for poor early childhood neurodevelopment in malaria-endemic areas in rural Africa. Because of this, comprehensive and cost/effective intervention is needed for malaria prevention in very young children in these settings

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Embrace me, my sweet embraceable you! Embrace me [first line of chorus]

Performers: Mickey Rooney, Judy Garland, Tommy Dorsey and his OrchestraPiano, Voice and Chord

I got rhythm, I got music, I got my man, who could ask [first line of chorus]

Performers: Mickey Rooney, Judy Garland, Tommy Dorsey and His OrchestraPiano, Voice and Chord

Malaria illness mediated by anaemia lessens cognitive development in younger Ugandan children.

Background Asymptomatic falciparum malaria is associated with poorer cognitive performance in African schoolchildren and intermittent preventive treatment of malaria improves cognitive outcomes. However, the developmental benefits of chemoprevention in early childhood are unknown. Early child development was evaluated as a major outcome in an open-label, randomized, clinical trial of anti-malarial chemoprevention in an area of intense, year-round transmission in Uganda. Methods Infants were randomized to one of four treatment arms: no chemoprevention, daily trimethoprim–sulfamethoxazole, monthly sulfadoxine–pyrimethamine, or monthly dihydroartemisinin–piperaquine (DP), to be given between enrollment (4–6 mos) and 24 months of age. Number of malaria episodes, anaemia (Hb \u3c 10) and neurodevelopment [Mullen Scales of Early Learning (MSEL)] were assessed at 2 years (N = 469) and at 3 years of age (N = 453); at enrollment 70 % were HIV-unexposed uninfected (HUU) and 30 % were HIV-exposed uninfected (HEU). Results DP was highly protective against malaria and anaemia, although trial arm was not associated with MSEL outcomes. Across all treatment arms, episodes of malarial illness were negatively predictive of MSEL cognitive performance both at 2 and 3 years of age (P = 0.02). This relationship was mediated by episodes of anaemia. This regression model was stronger for the HEU than for the HUU cohort. Compared to HUU, HEU was significantly poorer on MSEL receptive language development irrespective of malaria and anaemia (P = 0.01). Conclusions Malaria with anaemia and HIV exposure are significant risk factors for poor early childhood neurodevelopment in malaria-endemic areas in rural Africa. Because of this, comprehensive and cost/effective intervention is needed for malaria prevention in very young children in these settings

The Vehicle, Spring 1971

Vol. 13, No. 2 Table of Contents PoemVerna L. Jonespage 3 PoemSarah Knobelochpage 5 Please, Come AgainLinda Hakepage 6 HaikuMartha McIntyrepage 9 The Eight O\u27Clock TrainCandy Hoempage 10 Late HourMelvin Zaloudekpage 18 SomedayKaren Saxonpage 21 Opus XCecily Hawthornepage 22 Trading CardsWilliam R. Probeckpage 25 MadnessSam Strakapage 26 PoemKristine Kirkhampage 27 Sleepless NightsKen Brewerpage 28 Never SomedayMartha McIntyrepage 31 Art and Photography Credits Judy Novakpage 4 Self PortraitMike Dorseypage 8 My Siege of AltamontMike Dorseypage 16 Marsha Ludlampage 19 Verna L. Jonespage 20 Mark McKinneypage 24, 29, 30 Cover PaintingMike Dorsey Cover PhotographyMark McKinneyhttps://thekeep.eiu.edu/vehicle/1026/thumbnail.jp

The Vehicle, Fall 1970

Vol. 13, No. 1 Table of Contents A Thought Written in a Locked RoomJudy Huntpage 1 The Eggshell MoonWilliam Probeckpage 2 PoemBarb Parkerpage 3 4/5, May, 1970J. Michael Sainpage 5 A TreeRichard Stickannpage 6 both or noneMichelle Hallpage 6 The TrainSteve Sestinapage 8 Attempted DiscoveryDonald R. Johnsonpage 16 Island of SmokeVerna L. Jonespage 18 AwakeRobert Bladepage 19 PoemMary Klinkerpage 19 In ChurchMuriel Poolpage 21 PoemBarb Parkerpage 21 PoemMichelle Hallpage 22 Pod\u27nerVerna L. Jonespage 23 Rain and Other ThingsCarol Staniecpage 24 PoemAnn Graffpage 24 Examination of StudentdomMelvin Zaloudekpage 26 Women\u27s LiberationTonya Mortonpage 27 Morning Reflections on the Evening NewsPrudence Herberpage 29 Art and Photography Credits Jim Diaspage 4 Mike Dorseypages 7, 20 David Griffithpages 8, 17, 25 Cover PhotographyMark McKinneyhttps://thekeep.eiu.edu/vehicle/1024/thumbnail.jp