Repeated lipoprotein apheresis and immune response: Effects on different immune cell populations

BACKGROUND Atherosclerosis is considered a chronic inflammation of arterial vessels with the involvement of several immune cells causing severe cardiovascular diseases. Lipoprotein apheresis (LA) improves cardiovascular conditions of patients with severely disturbed lipid metabolism. In this context, little is known about the impact of LA on various immune cell populations, especially over time. METHODS Immune cells of 18 LA-naïve patients starting weekly LA treatment were analyzed before and after four apheresis cycles over the course of 24 weeks by flow cytometry. RESULTS AND CONCLUSIONS An acute lowering effect of LA on T cell and natural killer (NK) cell subpopulations expressing CD69 was observed. The non-classical and intermediate monocyte subsets as well as HLA-DR$^{+}$ 6-sulfo LacNAc$^{+}$ monocytes were significantly reduced during the apheresis procedure. We conclude that LA has the capacity to alter various immune cell subsets. However, LA has mainly short-term effects than long-term consequences on proportions of immune cells

Staphylococcus aureus nasal colonization among dental health care workers in Northern Germany (StaphDent study)

Methicillin-resistant Staphylococcus aureus (MRSA) can colonize dental patients and students, however, studies on the prevalence of MRSA and methicillin-susceptible S. aureus (MSSA) among dental health care workers (DHCW) including use of personal protective equipment (PPE) are scarce. We conducted an observational study (StaphDent study) to (I) determine the prevalence of MRSA and MSSA colonization in DHCW in the region of Mecklenburg Western-Pomerania, Germany, (II) resolve the MSSA population structure to gain hints on possible transmission events between co-workers, and (III) clarify use of PPE. Nasal swabs were obtained from dentists (n?=?149), dental assistants (n?=?297) and other dental practice staff (n?=?38). Clonal relatedness of MSSA isolates was investigated using spa typing and, in some cases, whole genome sequencing (WGS). PPE use was assessed by questionnaire. While 22.3% (108/485) of the participants were colonized with MSSA, MRSA was not detected. MSSA prevalence was not associated with size of dental practices, gender, age, or duration of employment. The identified 61 spa types grouped into 17 clonal complexes and four sequence types. Most spa types (n?=?51) were identified only once. In ten dental practices one spa type occurred twice. WGS data analysis confirmed a close clonal relationship for 4/10 isolate pairs. PPE was regularly used by most dentists and assistants. To conclude, the failure to recover MRSA from DHCW reflects the low MRSA prevalence in this region. Widespread PPE use suggests adherence to routine hygiene protocols. Compared to other regional HCW MRSA rates the consequent usage of PPE seems to be protective

Genome-Wide Association Study and Functional Characterization Identifies Candidate Genes for Insulin-Stimulated Glucose Uptake

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in \u3e55,000 participants from three ancestry groups. We identified ten new loci (P \u3c 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits

Short- and long-term effects of lipoprotein apheresis on plasma hormones in patients with therapy-resistant dyslipidemia

BACKGROUND AND AIMS Lipoprotein apheresis (LA) is a highly effective method to improve the clinical and metabolic situation in patients with therapy-resistant disorders of lipid metabolism. Cholesterol is the substrate for the synthesis of all steroid hormones. If repeated massive reduction of LDL-cholesterol may interfere with human adrenal steroidogenesis, and could become clinically relevant is unknown, so far. Thus, the aim of this study was to determine possible short- and long-term effects of LA on blood plasma levels of ACTH, cortisol, aldosterone, DHEAS, renin and testosterone. METHODS In total, 39 patients, treated with one of four LA techniques were studied: 1. Lipid Filtration (LF; n = 7), 2. Dextran Sulfate Adsorption (DSA; n = 7), 3. Membrane Filtration Optimised Novel Extracorporeal Treatment (MONET; n = 8), and 4. Direct Absorption of Lipoproteins (DALI; n = 15). Hormone levels were analyzed before and after five LA sessions with an interval of 20 weeks covering a total observation time of two years. In addition patients were comprehensively characterized by clinical and laboratory data. RESULTS Patients treated with LA revealed an acute reduction of steroid hormones and ACTH, independent of apheresis technology but no long-term insufficiency in steroidogenesis was observed. Plasma renin levels were stable in LF patients and were highly elevated in patients under DSA, MONET and DALI apheresis throughout the observation period. CONCLUSIONS In summary, these data suggest that although different LA techniques considerably differ in their acute effects on hormone levels during LA, they did not alter long-term hormone levels sustainably

Allosteric inhibition of HER2 by Moesin-mimicking compounds targets HER2-positive cancers and brain metastases

International audienceTherapies targeting the tyrosine kinase receptor HER2 have significantly improved survival of HER2+ cancer patients. However, both de novo and acquired resistance remain a challenge, particularly in the brain metastatic setting. Here we report that, unlike other HER tyrosine kinase receptors, HER2 possesses a binding motif in its cytosolic juxtamembrane region that allows interaction with members of the ezrin/radixin/moesin (ERM) family. Under physiological conditions, this interaction controls the localization of HER2 in ERM-enriched domains and stabilizes HER2 in a catalytically repressed state. In HER2+ breast cancers, low expression of moesin correlated with increased HER2 expression. Restoring expression of ERM proteins in HER2+ breast cancer cells was sufficient to revert HER2 activation and inhibit HER2-dependent proliferation. A high-throughput assay recapitulating the HER2/ERM interaction allowed for screening of about 1500 approved drugs. From this screen, Zuclopenthixol, an anti-psychotic drug that behaved as a moesin-mimicking compound, was found to directly bind the juxtamembrane region of HER2 and specifically inhibit HER2 activation in HER2+ cancers, as well as activation of oncogenic mutated and truncated forms of HER2. Zuclopenthixol efficiently inhibited HER2-positive breast tumor progression in vitro and in vivo and, more importantly, showed significant activity on HER2-positive brain tumor progression. Collectively, these data reveal a novel class of allosteric HER2 inhibitors, increasing the number of approaches to consider for intervention on HER2+ breast cancers and brain metastases

Post COVID and Apheresis - Where are we Standing?

A continual increase in cases of Long/Post COVID constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggest that up to 20% of people with confirmed SARS-CoV-2 suffer from clinically relevant symptoms of Long/Post COVID several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea, and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Post/COVID. Thus, numerous patients are currently treated with apheresis. However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Post/COVID from centers across Germany