Activation of Cell-Intrinsic Signaling in CAR-T Cells via a Chimeric IL7R Domain.

Chimeric antigen receptor (CAR) T cells can effectively treat leukemias, but sustained antitumor responses can be hindered by a lack of CAR T-cell persistence. Cytotoxic effector T cells are short-lived, and establishment of CAR-T cells with memory to ensure immune surveillance is important. Memory T cells depend on cytokine support, with IL7 activation of the IL7 receptor (IL7R) being critical. However, IL7R surface expression is negatively regulated by exposure to IL7. We aimed to support CAR T-cell persistence by equipping CAR-T cells with a sustained IL7Rα signal. We engineered T cells to constitutively secrete IL7 or to express an anti-acute myeloid leukemia-targeted IL7Rα-chimeric cytokine receptor (CCR) and characterized the phenotype of these cell types. Canonical downstream signaling was activated in CCR-T cells with IL7R activation. When coexpressed with a cytotoxic CAR, functionality of both the CCR and CAR was maintained. We designed hybrid CAR-CCR and noted membrane proximity of the intracellular domains as vital for signaling. These data show cell-intrinsic cytokine support with canonical signaling, and functionality can be provided via expression of an IL7Rα domain whether independently expressed or incorporated into a cytotoxic CAR for use in anticancer therapy. SIGNIFICANCE: To improve the phenotype of tumor-directed T-cell therapy, we show that provision of cell-intrinsic IL7R-mediated signaling is preferable to activation of cells with exogenous IL7. We engineer this signaling via independent receptor engineering and incorporation into a CAR and validate maintained antigen-specific cytotoxic activity.

Human Immunodeficiency Virus and Clonal Hematopoiesis.

The evolution of antiretroviral therapies (ART) has tremendously improved the life expectancy of people living with human immunodeficiency virus (HIV) (PLWH), which is currently similar to the general population. However, as PLWH are now living longer, they exhibit various comorbidities such as a higher risk of cardiovascular disease (CVD) and non-acquired immunodeficiency syndrome (AIDS)-defined malignancies. Clonal hematopoiesis (CH) is the acquisition of somatic mutations by the hematopoietic stem cells, rendering them survival and growth benefit, thus leading to their clonal dominance in the bone marrow. Recent epidemiologic studies have highlighted that PLWH have a higher prevalence of CH, which in turn is associated with increased CVD risk. Thus, a link between HIV infection and a higher risk for CVD might be explained through the induction of inflammatory signaling in the monocytes carrying CH mutations. Among the PLWH, CH is associated with an overall poorer control of HIV infection; an association that requires further mechanistic evaluation. Finally, CH is linked to an increased risk of progression to myeloid neoplasms including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), which are associated with particularly poor outcomes among patients with HIV infection. These bidirectional associations require further molecular-level understanding, highlighting the need for more preclinical and prospective clinical studies. This review summarizes the current literature on the association between CH and HIV infection.

Publication dynamics in gastroenterology and hepatology over the last decade in Greece: a SCImago-based study.

BACKGROUND: There is evidence that the financial crisis has deleteriously affected scientific output. We aimed to assess the dynamics of Greek publications in gastroenterology and hepatology over the last ten years. METHODS: Data were collected from SCImago. The average annual growth rate (AAGR) of total and citable documents published in Greece in the field of gastroenterology and hepatology was compared with that of cardiology, surgery, and radiology. In addition, it was compared with the corresponding rates in Belgium, Ireland and Portugal. RESULTS: The annual number of Greek publications (total and citable documents) remained relatively unchanged in the field of gastroenterology and hepatology from 2006-2011. During the following years, we detected a negative AAGR, with values of -12%, -3.3%, -9.5% and -5.4% for gastroenterology-hepatology, cardiology, surgery and radiology, respectively. During the same period, the AAGR of the citable documents of the respective specialties was -8.6%, -3.7%, -9.8%, and -5.1%. Comparison of the 4 European countries in the field of gastroenterology and hepatology revealed that publications from Portugal rose massively (AAGR +24.6% and +20.6% for total and citable documents, respectively), almost reaching the number of Greek publications in 2015. The number of publications from Belgium and Ireland remained essentially unchanged after 2011, with AAGR values of -0.7%, and -2.1% for total and -1.1% and -1.4% for citable documents, respectively. CONCLUSION: The publication output in the field of gastroenterology and hepatology decreased significantly after the outbreak of the financial crisis in Greece, not only in relation to other medical specialties, but also compared to the output of other European countries with or without fiscal austerity measures.

Monitoring of colonoscopy quality indicators in an academic endoscopy facility reveals adherence to international recommendations.

BACKGROUND: We monitor colonoscopy service quality biannually, by measuring sedation administration, colonoscopy completion, adenoma detection and early complications rates (CR). We herein present our audit results for the years 2013 and 2015. METHODS: In our endoscopy facility, five rotating senior gastroenterologists perform colonoscopies, on a daily basis. We measured the quality indicators in three cohorts: A, intention for total colonoscopy cases; B, cohort A excluding bowel obstruction cases; C, colorectal cancer (CRC) screening cases. RESULTS: In 2015, overall sedation administration rate (SAR) was 93.0% (91.6-94.4%), achieving our target to give conscious sedation to >90% of patients undergoing colonoscopy in all three cohorts. Colonoscopy completion rate (CCR) increased significantly (P<0.0001) from 94.8% (93.4-96.2%) to 98.1% (97.3-98.9%) in cohort B and numerically from 96.6% (94.4-98.8%) to 98.6% (97.4-99.7%) in cohort C, at the same periods. In cohort C, adenoma detection rates (ADR) were similar-27.1% (21.7-32.5%) and 27% (22.7-31.3%)-in the two periods. There were only two serious early complications: one cardiorespiratory event and one perforation in 2013 and 2015, respectively. While significant variability regarding SAR (ranging from 80% to 100%) was detected among the participating endoscopists, all but one of them constantly achieved [judged by the lower confidence interval (CI) of the quality indicator] CCRs higher than the recommended by international guidelines. On the contrary ADR was variable among endoscopists during the studied periods. CONCLUSIONS: Although there is certain variability in endoscopists' performance, the overall colonoscopy quality indicators meet or exceed the internationally recommended standards, in our endoscopy facility.