Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy

Regulatory T cells (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3+CD25highCD4+ Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival. We observed a pronounced increase in Treg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating Tregs resembled thymic-derived natural Tregs (nTregs), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by Treg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of Treg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of Tregs in later treatment cycles and a short Treg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive Tregs that may be targeted for improved anti-leukemic efficiency

Kvinnliga kockar, sämre soppa? - En diskursanalytisk kulturstudie av svenska matlagningsprogram

Studien är en granskning av språk och beteende hos kockar i svensk televisions matlagningsprogram. Vi undersöker kockarnas sätt att laga mat, deras språk och hur de presenteras utifrån sitt kön. Studieobjektets relevans styrks, av att TV-mediet spelar en stor roll i västerländsk kultur och då matlagning i hemmet alltid har setts som kvinnans roll medan mannen har fått rollen som kock på den professionella arenan. Dessutom har få studier om matlagning och genus publicerats, ännu mindre om kockars matlagning i relation till genus i svensk television. Därför hoppas vi ha tillfört något nytt forskningsmässigt sett inom studiet av medie- och kommunikationsvetenskap. Syftet med vår studie är att skapa insikt i om kockar i det svenska TV-mediet reproducerar synen, eller diskursen, där mannen är den professionella kocken och kvinnan är kocken i hemmet. För att få kunskap om den kultur som kockarna lever och arbetar inom har vi bland annat använt oss av Billy Ehn & Oskar Löfgrens kulturanalys. Om diskursen uttrycks i praktiken har vi undersökt med hjälp av Norman Faircloughs kritiska diskursanalys. Efter gjord analys såg vi att när män lagar mat i svensk television presenteras de ofta utifrån den klassiska bilden av mannen. De ses som kunniga, spontana, tävlingsinriktade och de som lagar mat för att visa sin expertis. Kvinnan presenteras utifrån den klassiska kvinnliga bilden, hon är känslosam, utseendefixerad och den som lagar mat till familj eller vänner. Mannen framställs som den professionella kocken och kvinnan som kocken i hemmet. Vi ser detta som tydliga och oroväckande resultat, diskursen uttrycks i praktiken. Nyckelord; kritisk diskursanalys, kulturanalys, genus, matlagningsprogram, TV-kockar Fredric Thörnqvist, Rebecca Thorén Lunds Universitet, Enheten för Medie- och kommunikationsvetenskap, 2009-201

Short time to blood culture positivity in Enterococcus faecalis infective endocarditis

Time to blood culture positivity (TTP) is an indirect measure of bacterial concentration in blood. A short TTP has been linked to the presence of infective endocarditis (IE) and to poor prognosis in Staphylococcus aureus bacteremia. We analyze factors influencing TTP in bacteremia with Enterococcus faecalis. This retrospective observational study of medical records included adults diagnosed with monomicrobial E. faecalis bacteremia between 2015 and 2018 in the Skåne region (Sweden). For each episode, the shortest TTP was recorded. Median TTP was compared between patients grouped based on age, sex, comorbidity, site of acquisition, and focus of infection. Using a dichotomized TTP (shorter or longer than 12 h), a multivariable logistic regression for factors associated to TTP was performed. The association between TTP and IE or mortality was evaluated. Three hundred sixty-seven episodes with monomicrobial E. faecalis bacteremia with the corresponding TTP were identified. Median TTP for the entire cohort was 11.6 (IQR 9.9–14.1) h and a significantly shorter TTP was noted for episodes which represented IE (n = 55, 9.4 (IQR 6.4–10.6) h). Only IE remained associated with a short TTP (≤ 12 h) in binary logistic regression analysis. Factors associated with IE were investigated and TTP was associated with IE also when adjusted for age, gender, comorbidity, and nosocomial acquisition. There was no association between TTP and mortality. A low TTP is associated with IE in E. faecalis bacteremia and could be used as a help in determining the need for echocardiography in patients with this condition

Christmas holiday triggers of myocardial infarction

Objectives: Christmas holidays have been associated with the highest incidence of myocardial infarction (MI). We wanted to assess possible triggers of MI during Christmas. Design: A nationwide, retrospective postal survey with case-control design. All individuals suffering an MI during the Christmas holidays 2018 and 2019 in Sweden were identified through the SWEDEHEART registry and a control group matched in age and gender with chronic coronary syndrome who did not seek medical attention during Christmas were asked for participation. Subjects completed a questionnaire asking them to rate 27 potential MI-triggers as having occurred more or less than usual. Results: A total of 189 patients suffering an MI on Christmas Eve, Christmas Day, or Boxing Day, and 157 patients in the control group responded to the questionnaire, representing response rates of 66% and 62%, respectively. Patients with MI on Christmas experienced more stress (37% vs. 21%, p =.002), depression (21% vs. 11%, p =.024), and worry (26% vs. 10%, p <.001) compared to the control group. The food and sweets consumption was increased in both groups, but to a greater extent in the control group (33% vs. 50%, p =.002 and 32% vs. 43%, p =.031). There were no increases in quarrels, anger, economic worries, or reduced compliance with medication. Conclusions: Patients suffering MI on Christmas holiday experienced higher levels of stress and emotional distress compared to patients with chronic coronary syndrome, possibly contributing to the phenomenon of holiday heart attack. Understanding what factors increase the number of MI on Christmas may help reduce the excess number of MIs and cardiovascular burden

NK cell expression of natural cytotoxicity receptors may determine relapse risk in older AML patients undergoing immunotherapy for remission maintenance

In a phase IV trial, eighty-four patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose human recombinant interleukin-2 (IL-2) to prevent relapse in the post-consolidation phase. Aspects of natural killer (NK) cell biology were analyzed before and during immunotherapy with focus on outcome in older patients. In younger (60 years old, n = 47), treatment with HDC/IL-2 resulted in an expansion of CD56bright and CD16+ NK cells in blood along with an increased NK cell expression of the natural cytotoxicity receptors (NCR) NKp30 and NKp46. In older patients, a high expression of NKp30 or NKp46 on CD16+ NK cells before and during therapy predicted leukemia-free and overall survival. These results suggest that NK cell functions determine relapse risk and survival in older AML patients and point to biomarkers of efficacy in protocols for remission maintenance

Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia.

In a phase IV trial, 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose human recombinant interleukin 2 (IL-2) for 18 months to prevent leukemic relapse. During cycles, the treatment resulted in expansion of CD56(bright) (CD3(-)/16(-)/56(bright)) and CD16(+) (CD3(-)/16(+)/56(+)) natural killer (NK) cells in the blood along with increased NK cell expression of the natural cytotoxicity receptors (NCRs) NKp30 and NKp46. Multivariate analyses correcting for age and risk group demonstrated that high CD56(bright) NK cell counts and high expression of NKp30 or NKp46 on CD16(+) NK cells independently predicted leukemia-free survival (LFS) and overall survival (OS). Our results suggest that the dynamics of NK cell subsets and their NCR expression may determine the efficiency of relapse-preventive immunotherapy in AML

NOX2-dependent immunosuppression in chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a myeloproliferative and myelodysplastic neoplasm with few treatment options and dismal prognosis. The role of natural killer (NK) cells and other antileukemic lymphocytes in CMML is largely unknown. We aimed to provide insight into the mechanisms of immune evasion in CMML with a focus on immunosuppressive reactive oxygen species (ROS) formed by the myeloid cell NADPH oxidase-2 (NOX2). The dominant population of primary human CMML cells was found to express membrane-bound NOX2 and to release ROS, which, in turn, triggered extensive PARP-1-dependent cell death in cocultured NK cells, CD8(+) T effector memory cells, and CD8(+) T effector cells. Inhibitors of ROS formation and scavengers of extracellular ROS prevented CMML cell-induced lymphocyte death and facilitated NK cell degranulation toward Ab-coated, primary CMML cells. In patients with CMML, elevation of immature cell counts (CD34(+)) in blood was associated with reduced expression of several NK cell-activating receptors. We propose that CMML cells may use extracellular ROS as a targetable mechanism of immune escape

Dynamics of cytotoxic T cell subsets during immunotherapy predicts outcome in acute myeloid leukemia.

Preventing relapse after chemotherapy remains a challenge in acute myeloid leukemia (AML). Eighty-four non-transplanted AML patients in first complete remission received relapse-preventive immunotherapy with histamine dihydrochloride and low-dose interleukin-2 in an international phase IV trial (ClinicalTrials.gov; NCT01347996). Blood samples were drawn during cycles of immunotherapy and analyzed for CD8+ (cytotoxic) T cell phenotypes in blood. During the first cycle of therapy, a re-distribution of cytotoxic T cells was observed comprising a reduction of T effector memory cells and a concomitant increase of T effector cells. The dynamics of T cell subtypes during immunotherapy prognosticated relapse and survival, in particular among older patients and remained significantly predictive of clinical outcome after correction for potential confounders. Presence of CD8+ T cells with specificity for leukemia-associated antigens identified patients with low relapse risk. Our results point to novel aspects of T cell-mediated immunosurveillance in AML and provide conceivable biomarkers in relapse-preventive immunotherapy