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BACKGROUND: Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level. METHODS: Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity. RESULTS: We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity. CONCLUSIONS: Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

Background: Systemic inflammation has a critical role in the development of symptomatic coronary artery disease (CAD). Identification of inflammatory pathways may provide a platform for novel therapeutic approaches. We sought to determine whether there are differences in circulating cytokine profiles between patients with CAD and disease-free controls as well as according to the severity of the disease. Methods: Case-control study's population consisted of 452 patients who underwent diagnostic invasive coronary angiography due to clinical indications. We measured the serum concentrations of 48 circulating cytokines. Extent of CAD was assessed using the SYNTAX Score in 116 patients. Cytokine differences between groups were tested using Mann-Whitney U test and associations with CAD were explored using a logistic regression model. Results: Overall, 310 patients had angiographically verified CAD whereas 142 had no angiographically-detected coronary atherosclerosis. In multivariable logistic regression models adjusted for age, sex, hypertension, atrial fibrillation, history of smoking and treatment for diabetes and hyperlipidemia, increased levels of interleukin 9 (OR 1.359, 95%CI 1.046–1.766, p = 0.022), IL-17 (1.491, 95%CI 1.115–1.994, p = 0.007) and tumor necrosis factor alpha (TNF-α) (OR 1.440, 95%CI 1.089–1.904, p = 0.011) were independently associated with CAD. Patients with SYNTAX Score>22 had increased levels of stromal cell-derived factor 1 alfa (SDF-1α), beta-nerve growth factor (β-NGF), IL-3 and decreased level of IL-17 compared to those with score ≤22 when adjusted for smoking and use of beta-blockers. Conclusions: Patients with CAD have distinct circulating cytokine profiles compared to disease-free controls. Distinct cytokines may have pivotal roles at different stages of coronary atherosclerosis. ClinicalTrials.gov Identifier: NCT03444259 (https://clinicaltrials.gov/study/NCT03444259).

BackgroundMobilization of certain immune cells may improve the ability of the immune system to combat tumor cells, but the effect of acute exercise on mobilizing immune cells has been sparsely investigated in cancer patients. Therefore, we examined how acute exercise influences circulating immune cells in breast cancer patients.MethodsNineteen newly diagnosed breast cancer patients aged 36–68 performed 30 minutes of moderate-intensity exercise with a cycle ergometer. Blood samples were collected at various time points: at rest, at 15 (E15) and 30 minutes (E30) after onset of the exercise, and at 30 and 60 minutes post-exercise. We analyzed several immune cell subsets using flow cytometry.ResultsAcute exercise increased the number of total leukocytes, neutrophils, lymphocytes, monocytes, basophils, total T-cells, CD4+ T-cells, T helper (Th) 2-cells, Th 17-cells, CD8+ T-cells, CD4-CD8- T-cells, CD56+ natural killer (NK) cells, and CD14-CD16+ monocytes. Many of the changes were transient. Proportions of NK-cells and CD8+ T-cells increased, while the proportion of myeloid derived suppressor cells (MDSCs) reduced, and proportion of regulatory T-cells remained unchanged by exercise. Several associations were detected between cell mobilizations and disease state. For instance, tumor size correlated negatively with NK cell mobilization at E15, and progesterone receptor positivity correlated negatively with CD8+ T-cell mobilization.ConclusionThe findings show that the proportions of CD8+ T-cells and NK cells increased and the proportion of MDSCs proportion decreased in breast cancer patients after 30-minute exercise, suggesting a change in the profile of circulating immune cells towards more cytotoxic/anti-tumorigenic. The mobilization of some immune cells also appears to be related to the disease state.

Objective: Patients undergoing heart surgery are at high risk of postoperative fluid accumulation due to long procedures and cardiopulmonary bypass. In the present study, we sought to investigate the prevalence of postoperative fluid accumulation and its relation to adverse events in patients undergoing cardiac surgery. Methods: CAREBANK is prospective, single-center cohort study focusing on the adverse events after cardiac surgery. The study population was divided into 2 groups based on 5% postoperative weight gain. All the in-hospital adverse events are registered on the database. The end points of the present study were length of hospital stay, length of intensive care unit stay, occurrence of new-onset atrial fibrillation after hospital major bleeding episodes major cardiac events, cerebrovascular events, and death. Three-month and 1-year follow-up data also include all major adverse events. Results: Altogether 1001 adult cardiac surgery patients were enrolled. The most frequent operations were coronary artery bypass grafting (56.3%). Five hundred fifty-four out of 939 (59.0%) patients had ≥5% weight gain during index hospitalization. Patients with a weight gain ≥5% were more likely to be women, have lower body mass index, had heart failure, and more often had preoperative atrial fibrillation. In-hospital period fluid accumulation was associated with reoperation due bleeding and longer total hospital stay. At 3 months' follow-up, weight gain 5% or more was associated with increased occurrence of new-onset atrial fibrillation, this was not reflected in the occurrence of strokes, transient ischemic attacks, or myocardial infarctions. Conclusions: Postoperative fluid excess is associated with adverse outcomes in cardiac surgery. Women, low-weight patients, and patients with cardiac failure or atrial fibrillation are prone to perioperative fluid accumulation.

Abstract Background Idiopathic pulmonary fibrosis (IPF) has an unknown aetiology and limited treatment options. A recent meta-analysis identified three novel causal variants in the TERT, SPDL1, and KIF15 genes. This observational study aimed to investigate whether the aforementioned variants cause clinical phenotypes in a well-characterised IPF cohort. Methods The study consisted of 138 patients with IPF who were diagnosed and treated at the Helsinki University Hospital and genotyped in the FinnGen FinnIPF study. Data on > 25 clinical parameters were collected by two pulmonologists who were blinded to the genetic data for patients with TERT loss of function and missense variants, SPDL1 and KIF15 missense variants, and a MUC5B variant commonly present in patients with IPF, or no variants were separately analysed. Results The KIF15 missense variant is associated with the early onset of the disease, leading to progression to early-age transplantation or death. In patients with the KIF15 variant, the median age at diagnosis was 54.0 years (36.5–69.5 years) compared with 72.0 years (65.8–75.3 years) in the other patients (P = 0.023). The proportion of KIF15 variant carriers was 9- or 3.6-fold higher in patients aged

Abstract The role of exercise in cancer prevention and control is increasingly recognized, and based on preclinical studies, it is hypothesized that mobilization of leukocytes plays an important role in the anti-tumor effect. Thus, we examined how 10-min acute exercise modulates immune cells in newly diagnosed breast cancer patients. Blood samples were taken at rest, immediately after exercise and 30 min after exercise and phenotypic characterization of major leukocyte subsets was done using 9-color flow cytometry. Total leukocyte count increased by 29%, CD8+ T cell count by 34%, CD19+ B cell count by 18%, CD56+CD16+ NK cell count by 130%, and CD14+CD16+ monocyte count by 51% immediately after acute exercise. Mobilization of CD45+, CD8+, CD19+, and CD56+CD16+ cells correlated positively with exercising systolic blood pressure, heart rate percentage of age predicted maximal heart rate, rate pressure product, and mean arterial pressure. Our findings indicate that a single bout of acute exercise of only 10 min can cause leukocytosis in breast cancer patients. Mobilization of leukocytes appear to be directly related to the intensity of exercise. It is possible that the positive effect of exercise on oncologic outcome might be partly due to immune cell mobilization as documented in the present study.

Abstract Background The use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). The use of intravenous Interferon beta (IFN β) for the treatment of ARDS was recently tested in a phase III ARDS trial (INTEREST), in which more than half of the patients simultaneously received glucocorticoids. Trial results showed deleterious effects of glucocorticoids when administered together with IFN β, and therefore, we aimed at finding the reason behind this. Methods We first sequenced the genes encoding the IFN α/β receptor of the patients, who participated in the INTEREST study (ClinicalTrials.gov Identifier: NCT02622724 , November 24, 2015) in which the patients were randomized to receive an intravenous injection of IFN β-1a (144 patients) or placebo (152 patients). Genetic background was analyzed against clinical outcome, concomitant medication, and pro-inflammatory cytokine levels. Thereafter, we tested the influence of the genetic background on IFN α/β receptor expression in lung organ cultures and whether, it has any effect on transcription factors STAT1 and STAT2 involved in IFN signaling. Results We found a novel disease association of a SNP rs9984273, which is situated in the interferon α/β receptor subunit 2 (IFNAR2) gene in an area corresponding to a binding motif of the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates with higher IFNAR expression, more rapid decrease of IFN γ and interleukin-6 (IL-6) levels and better outcome in IFN β treated patients with ARDS, while the major allele associates with a poor outcome especially under concomitant IFN β and glucocorticoid treatment. Moreover, the minor allele of rs9984273 associates with a less severe form of coronavirus diseases (COVID-19) according to the COVID-19 Host Genetics Initiative database. Conclusions The distribution of this SNP within clinical study arms may explain the contradictory results of multiple ARDS studies and outcomes in COVID-19 concerning type I IFN signaling and glucocorticoids. Graphical abstract

Abstract Renal cell carcinoma (RCC) accounts for 90% of all renal cancers and is considered highly immunogenic. Although many studies have reported the circulating peripheral cytokine profiles, the signatures between the tumor tissue and matching healthy adjacent renal tissue counterparts have not been explored. We aimed to comprehensively investigate the cytokine landscape of RCC tumors and its correlation between the amount and phenotype of the tumor infiltrating lymphocytes (TILs). We analyzed the secretion of 42 cytokines from the tumor (n = 46), adjacent healthy kidney tissues (n = 23) and matching plasma samples (n = 33) with a Luminex-based assay. We further explored the differences between the tissue types, as well as correlated the findings with clinical data and detailed immunophenotyping of the TILs. Using an unsupervised clustering approach, we observed distinct differences in the cytokine profiles between the tumor and adjacent renal tissue samples. The tumor samples clustered into three distinct profiles based on the cytokine expressions: high (52.2% of the tumors), intermediate (26.1%), and low (21.7%). Most of the tumor cytokines positively correlated with each other, except for IL-8 that showed no correlation with any of the measured cytokine expressions. Furthermore, the quantity of lymphocytes in the tumor samples analyzed with flow cytometry positively correlated with the chemokine-family of cytokines, CXCL10 (IP-10) and CXCL9 (MIG). No significant correlations were found between the tumor and matching plasma cytokines, suggesting that circulating cytokines poorly mirror the tumor cytokine environment. Our study highlights distinct cytokine profiles in the RCC tumor microenvironment and provides insights to potential biomarkers for the treatment of RCC.

Enhancing our understanding of lymphatic anatomy from the microscopic to the anatomical scale is essential to discern how the structure and function of the lymphatic system interacts with different tissues and organs within the body and contributes to health and disease. The knowledge of molecular aspects of the lymphatic network is fundamental to understand the mechanisms of disease progression and prevention. Recent advances in mapping components of the lymphatic system using state of the art single cell technologies, the identification of novel biomarkers, new clinical imaging efforts, and computational tools which attempt to identify connections between these diverse technologies hold the potential to catalyze new strategies to address lymphatic diseases such as lymphedema and lipedema. This manuscript summarizes current knowledge of the lymphatic system and identifies prevailing challenges and opportunities to advance the field of lymphatic research as discussed by the experts in the workshop.

Background: Studies have shown that acute exercise can mobilize several leukocyte subpopulations in healthy individuals. Our aim was to investigate whether a 10-min acute exercise has an effect on immune cell proportions in lymphoma patients.Methods: This study included seven lymphoma patients referred to curative oncologic therapy. Three had Hodgkin and four non-Hodgkin lymphoma, one was female, and their mean age was 51. Patients underwent a 10-min acute exercise on a bicycle ergometer at moderate exercise intensity. Whole blood samples were taken at rest, immediately after exercise, and 30 min after exercise. Leukocyte subpopulation levels were determined using flow cytometry.Results: Proportions of total NK cells and CD56+CD16+ NK cells of total leukocytes increased immediately after exercise and decreased back to baseline at 30 min post-exercise. Proportion of CD8+ T cells of total T cells increased and proportion of CD4+ T cells of total T cells decreased immediately after exercise, and both returned to baseline at 30 min post-exercise. There was no change in the proportions of B cells, granulocytes, or monocytes. Exercising diastolic blood pressure correlated positively with changes in total NK cell and CD56+CD16+ NK cell proportions, and exercising mean arterial pressure correlated positively with change in CD56+CD16+ NK cell proportion.Conclusion: Our findings indicate that a single acute exercise bout of only 10 min can cause leukocytosis in lymphoma patients, particularly on cytotoxic T cells and NK cells, which are the most important immune cells fighting against cancer.