Activation of the PP2A-B56α heterocomplex synergizes with venetoclax therapies in AML through BCL2 and MCL1 modulation.

Venetoclax combination therapies are becoming the standard of care in acute myeloid leukemia (AML). However, the therapeutic benefit of these drugs in older/unfit patients is limited to only a few months, highlighting the need for more effective therapies. Protein phosphatase 2A (PP2A) is a tumor suppressor phosphatase with pleiotropic functions that becomes inactivated in ∼70% of AML cases. PP2A promotes cancer cell death by modulating the phosphorylation state in a variety of proteins along the mitochondrial apoptotic pathway. We therefore hypothesized that pharmacological PP2A reactivation could increase BCL2 dependency in AML cells and, thus, potentiate venetoclax-induced cell death. Here, by using 3 structurally distinct PP2A-activating drugs, we show that PP2A reactivation synergistically enhances venetoclax activity in AML cell lines, primary cells, and xenograft models. Through the use of gene editing tools and pharmacological approaches, we demonstrate that the observed therapeutic synergy relies on PP2A complexes containing the B56α regulatory subunit, of which expression dictates response to the combination therapy. Mechanistically, PP2A reactivation enhances venetoclax-driven apoptosis through simultaneous inhibition of antiapoptotic BCL2 and extracellular signal-regulated kinase signaling, with the latter decreasing MCL1 protein stability. Finally, PP2A targeting increases the efficacy of the clinically approved venetoclax and azacitidine combination in vitro, in primary cells, and in an AML patient-derived xenograft model. These preclinical results provide a scientific rationale for testing PP2A-activating drugs with venetoclax combinations in AML.

Flow cytometric characterization of cecal appendix lymphocyte subpopulations in children: a pilot study.

INTRODUCTION: Scientific literature regarding the characterization of lymphocyte subpopulations of the cecal appendix is sparse, with few precedents limited to immunohistochemical techniques. METHODS: We conducted a prospective pilot study to characterize lymphocyte subpopulations of the cecal appendix in children. Participants were divided into three groups: (1) patients without histological acute appendiceal inflammation, (2) patients with histological uncomplicated acute appendicitis, and (3) patients with histological complicated acute appendicitis (gangrenous, perforated). A fresh sample of the base of the appendix was taken from all patients and a flow cytometric study was performed. Quantitative variables were compared using Kruskal-Wallis test and Mann-Whitney U test. RESULTS: This study included 57 patients divided into Group 1 (n = 5), Group 2 (n = 37), and Group 3 (n = 15). Median values (IQR) of the percentage of B-lymphocytes were 67.8 [66.8-68.1] in group 1, 61.15 [53.74-66.4] in group 2, and 52.1 [33-62.02] in group 3 (p = 0.02). Median values (IQR) of the percentage of NK-lymphocytes were 0.26 [0.2-0.3] in group 1, 0.55 [0.37-0.66] in group 2, and 0.84 [0.35-1.45] in group 3 (p = 0.008). Median values (IQR) of the percentage of T-lymphocytes were 31.9 [31.7-33.1] in group 1, 37.68 [32.15-45.69] in group 2, and 46.9 [37.03-67] in group 3 (p = 0.02). Pair comparisons of groups 2 and 3 also showed significant differences in the percentage of B lymphocytes (p = 0.03) and NK-lymphocytes (p = 0.02). CONCLUSIONS: Significant differences in lymphocyte subpopulations were identified according to the histologic grade of the cecal appendix. More specifically, a lower percentage of B-lymphocytes and a higher percentage of T- and NK-lymphocytes were observed in cases of acute appendicitis. These findings must be confirmed and their etiopathogenic, diagnostic, and prognostic implications elucidated in future studies with larger sample sizes.

[Paraneoplastic hemolytic anemia associated with prostate cancer. A case report].

Paraneoplastic syndromes are a group of tumor-related symptoms not directly attributable to tumors or metastasis. Symptoms are caused by secretion of substances by the tumor or the production of antibodies from immune cross-reactivity between tumor and normal tissues. Among hematological paraneoplastic syndromes, cancer-associated hemolytic anemias associated are rare, particularly in solid tumors. We present the case of a patient with localized bladder (high-grade infiltrating papillary carcinoma pT1) and prostate (Gleason 7) cancer who developed warm antibody autoimmune hemolytic anemia during radiation therapy for prostate cancer. It was resolved with prednisone (1 mg/Kg/day, tapering schedule). To the best of our knowledge, this is the first time an autoimmune hemolytic anemia is described in the literature as a paraneoplastic syndrome in such early stages of tumor disease.

Effect of the application of the "Patient blood management" programme on the approach to elective hip and knee arthroplasties. / Efecto de la aplicación del programa Patient blood management en el abordaje de las artroplastias de cadera y rodilla programada.

BACKGROUND AND OBJECTIVES: The "Patient Blood Management" (PBM) programmes have demonstrated their value in the continuous improvement of care practice, due to continuous systematic reviewing of results and their dynamic and multidisciplinary updating in accordance with new clinical evidence. Our goal is to demonstrate the effectiveness of simple protocols, applicable in second level hospitals. PATIENTS AND METHODS: 702 patients undergoing scheduled arthroplasty from 2011 to 2018 were retrospectively analysed. During this period, the evolution of transfusion rates and anaemia and bleeding management were recorded in the patients' computerised clinical histories. RESULTS: Stages and transfusion rates were: Year 2011-2012, "Universal self-donation programme": 62.4%; year 2013, "Optimization of preoperative haemoglobin and universal self-donation withdrawal", 22.5%; year 2015, "Stopping the use of cell-savers and drains", 13.2%; and year 2017, "Introduction of routine tranexamic acid", 3.6%. A significant reduction in the transfusion rate and volume (P<.001) and the average hospital stay (8 to 6 days) (P<.001) was achieved. In multivariate models, transfused patients have a .5-day stay and there is a trend towards a reduction in complications, being fewer in patients receiving tranexamic acid (OR .44). CONCLUSION: A simple progressive and multidisciplinary PBM programme, with continued re-evaluation, has allowed a reduction in transfusion rates and average hospital stay.