Increased activity of lipoprotein-associated phospholipase A2 in non-severe asthma

Background Given increased risk of cardiovascular events in asthma we hypothesized that lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme involved in atherosclerosis, is associated with proinflammatory and prothrombotic blood alterations in this disease. Methods In 164 adult asthmatics (63 with severe asthma) we measured plasma Lp-PLA2 activity using the PLAC test. We determined its relations to inflammation and prothrombotic blood alterations. Results In asthma, Lp-PLA2 was inversely related to the age (β = −0.1 [−0.18 to −0.02]) and was lower in women (n = 122 [74%], 205 [182–242] vs. 243 [203–262] nmol/min/ml, p = 0.001). Interestingly, Lp-PLA2 correlated negatively with the asthma severity score (β = −0.15 [−0.23 to −0.07]), being 10.3% higher in those with non-severe (mild or moderate) asthma (n = 101, 62%) as compared to the severe disease subtype (224 [191–261] vs. 203 [181–229], p = 0.006 after adjustment for potential confounders). Lp-PLA2 activity was positively related to the levels of low-density lipoprotein (β = 0.1 [0.02–0.18]), triglycerides (β = 0.11 [0.03–0.19]) and glucose (β = 0.1 [0.02–0.18]) and inversely to the tumor necrosis factor α (β = −0.27 [−0.35 to −0.2]), high sensitivity C-reactive protein (β = −0.1 [−0.19 to −0.02]) and fibrinogen (β = −0.12 [−0.21 to −0.03]), as well as prothrombin (β = −0.16 [−0.24 to −0.08]), and parameters describing thrombin generation potential, such as endogenous thrombin potential (β = −0.14 [−0.21 to −0.06]) and peak thrombin generated (β = −0.2 [−0.28 to −0.12]). Conclusions Elevated Lp-PLA2 activity in non-severe asthmatics suggests increased atherosclerotic risk in this group. Lower Lp-PLA2 activity accompanied by its inverse relationship to inflammatory or prothrombotic blood biomarkers observed in turn in severe asthmatics might be related to the pathogenesis of more severe asthma phenotype

The role of neoadjuvant chemotherapy in the management of advanced ovarian cancer in geriatric patients

It is increasingly common for ovarian cancer to affect older women, with over half of all cases involving patients aged 65 years and older. Unfortunately, elderly patients with ovarian malignancy tend to be treated less aggressively than younger patients, with less extensive surgery and less intensive chemotherapy regimens. This is due to a variety of factors, such as overall medical fitness and the function of specific organs. Moreover, multiple morbidities are typical for geriatric patients and affect their eligibility for certain forms of cancer therapy as well as their treatment outcomes, which are commonly less satisfactory than in younger patients. Additionally, for fear of complications, treating physicians sometimes limit the extent of the necessary surgery, or adjust chemotherapy doses, even though such a course of management tends to be largely misguided. One available management option is neoadjuvant chemotherapy followed by a surgical treatment known as interval debulking surgery. This type of combination therapy is associated with fewer postoperative complications, thus increasing the patient's chances of receiving a full course of adjuvant treatment. The decision to begin treatment with neoadjuvant chemotherapy tends to restrict later surgical therapy; however, under certain circumstances, this therapy can be a valid therapeutic option and, in fact, facilitate surgery. Prior to initiating therapy in elderly patients, their eligibility for combination therapy must be evaluated and the geriatric assessment of their performance and condition must be considered during the course of interdisciplinary preoperative management

ERAP1 and HLA-C*06 are strongly associated with the risk of psoriasis in the population of northern Poland

Introduction: HLA-C*06 is a major psoriasis genetic risk marker. Recent reports have been focused on the role of different polymorphisms within genes involved in the functioning of the epidermal barrier and antigen processing in the pathogenesis of psoriasis. Data on the association between genetic variants of LCE3B_LCE3C, CSTA, ERAP1, ZAP70 and this dermatosis in the population from Eastern Europe are lacking. Aim: To compare the association between known genetic risk markers and psoriasis in a cohort of northern Polish patients with psoriasis and healthy controls. Material and methods: Based on previous studies’ results, five susceptibility loci: HLA-C, LCE3C_LCE3B, ERAP1, ZAP70 and CSTA were selected for genotyping in 148 patients with chronic plaque psoriasis and 146 healthy controls. Each patient with this disease was clinically assessed with the Psoriasis Area and Severity Index. Results: The study population showed a significant association of psoriasis and a single nucleotide polymorphism in the ERAP1 – rs26653 (p = 3.11 × 10–5) and HLA-C*06 allele (p = 1.02 × 10–11) when compared with the control group. The presence of HLA-C*06 or rs26653 G allele significantly increased the risk of psoriasis by 2.4 times or twice, respectively. Carrying rs26653 C allele considerably decreased the risk of psoriasis by 1.5 times. Conclusions: In the context of pathogenesis of psoriasis, our findings might give the evidence on disturbances in the proteolytic processing of N-terminal fragments of antigens presented via major histocompatibility complex class I to T cells

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials

A practical approach to the ESC 2022 cardio-oncology guidelines. Comments by a team of experts: cardiologists and oncologists

The 2022 European Society of Cardiology (ESC) guidelines [1] are a comprehensive document, prepared jointly by experts in cardiology and oncology. In the case of an oncological patient, it is necessary to individualize care in relation to the cardiological condition, the stage of the cancer and the type of potential anti-cancer therapy. Cardiac care optimisation should be undertaken before the start of oncological therapy, and continued during oncological therapy, as well as long-term after its completion [2]. The published ESC Guidelines were supplemented with a practical comments of a team of polish cardiology and oncology experts

The 2012 Russian Foreign Agent Law : An evaluation of the legitimacy of the Foreign Agent Law with reference to freedom of association and expression as specified in the European Convention on Human Rights

This paper analyzes the legitimacy of the newly adopted Russian Foreign Agent Law, which compels all politically active non-governmental organizations (NGOs) that receive foreign funding to register as ‘foreign agents’ with the Ministry of Justice (MoJ). The Russian authorities have viewed foreign funded NGOs as threats to their national security. Stricter regulatory control is justified with the need for supervisory oversight of their activities, prevent interference in the affairs of the state and to protect against attempts to exercise foreign influence. This thesis seeks to establish what implications such registration has for the operations of NGOs, and assesses the legitimacy of the provisions with reference to freedom of association and expression as prescribed in the European Convention on Human Rights (ECHR), in addition to their right to seek and secure resources. The research of this paper is qualitative in nature, principally based on a desk study and supplemented with some semi-structured interviews. The methodological approach can be described as an external approach of law, meaning the examination of how legal rules move into social reality through their application and interpretation in a given social, historical and political context. The results of this study show that the ‘foreign agent’ status restricts the organizations’ freedom of association and expression by discrediting them in the eyes of the public, consequently limiting their ability work efficiently in society. It demonstrates that the vagueness of the law provides too much discretionary power to the MoJ, consequently opening up for arbitrary application of the law. Ensuring organizational transparency and protection against attempts to exercise foreign influence do not constitute legitimate aims as prescribed in the limitation clauses of the ECHR, and the proportionality assessment indicates that the law was not necessary in the context in which it came about. The provisions of the law are thus clearly directed at restricting the independence and authority of NGOs. This study therefore demonstrates how States are increasingly establishing legal obstacles in order to limit the influence of civil society actors critical of the government