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Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which is often
caused by recurrent emboli. These are also frequently found in patients with myeloproliferative
diseases. While myeloproliferative diseases can be caused by gene defects, the genetic predisposition
to CTEPH is largely unexplored. Therefore, the objective of this study was to analyse these genes
and further genes involved in pulmonary hypertension in CTEPH patients. A systematic screening
was conducted for pathogenic variants using a gene panel based on next generation sequencing.
CTEPH was diagnosed according to current guidelines. In this study, out of 40 CTEPH patients
4 (10%) carried pathogenic variants. One patient had a nonsense variant (c.2071A>T p.Lys691*)
in the BMPR2 gene and three further patients carried the same pathogenic variant (missense variant,
c.1849G>T p.Val617Phe) in the Janus kinase 2 (JAK2) gene. The latter led to a myeloproliferative
disease in each patient. The prevalence of this JAK2 variant was significantly higher than expected
(p < 0.0001). CTEPH patients may have a genetic predisposition more often than previously thought.
The predisposition for myeloproliferative diseases could be an additional risk factor for CTEPH
development. Thus, clinical screening for myeloproliferative diseases and genetic testing may be
considered also for CTEPH patients.
Molecular Mechanisms of Bortezomib Action: Novel Evidence for the miRNA−mRNA Interaction Involvement
(2020)
Bortezomib is an anti-tumor agent, which inhibits 26S proteasome degrading ubiquitinated
proteins. While apoptotic transcription-associated activation in response to bortezomib has been
suggested, mechanisms related to its influence on post-transcriptional gene silencing mediated
regulation by non-coding RNAs remain not fully elucidated. In the present study, we examined
changes in global gene and miRNA expression and analyzed the identified miRNA–mRNA interactions
after bortezomib exposure in human neuroblastoma cells to define pathways affected by this agent in
this type of cells. Cell viability assays were performed to assess cytotoxicity of bortezomib. Global gene
and miRNA expression profiles of neuroblastoma cells after 24-h incubation with bortezomib were
determined using genome-wide RNA and miRNA microarray technology. Obtained results were
then confirmed by qRT-PCR and Western blot. Further bioinformatical analysis was performed
to identify affected biological processes and pathways. In total, 719 genes and 28 miRNAs were
downregulated, and 319 genes and 61 miRNAs were upregulated in neuroblastoma cells treated with
bortezomib. Possible interactions between dysregulated miRNA/mRNA, which could be linked to
bortezomib-induced neurotoxicity, affect neurogenesis, cellular calcium transport, and neuron death.
Bortezomib might exert toxic effects on neuroblastoma cells and regulate miRNA–mRNA interactions
influencing vital cellular functions. Further studies on the role of specific miRNA–mRNA interactions
are needed to elucidate mechanisms of bortezomib action.
The benefit of regular physical activity and exercise training for the prevention of cardiovascular and metabolic diseases is undisputed. Many molecular mechanisms mediating exercise effects have been deciphered. Personalised exercise prescription can help patients in achieving their individual greatest benefit from an exercise-based cardiovascular rehabilitation programme. Yet, we still struggle to provide truly personalised exercise prescriptions to our patients. In this position paper, we address novel basic and translational research concepts that can help us understand the principles underlying the inter-individual differences in the response to exercise, and identify early on who would most likely benefit from which exercise intervention. This includes hereditary, non-hereditary and sex-specific concepts. Recent insights have helped us to take on a more holistic view, integrating exercise-mediated molecular mechanisms with those influenced by metabolism and immunity. Unfortunately, while the outline is recognisable, many details are still lacking to turn the understanding of a concept into a roadmap ready to be used in clinical routine. This position paper therefore also investigates perspectives on how the advent of ‘big data’ and the use of animal models could help unravel inter-individual responses to exercise parameters and thus influence hypothesis-building for translational research in exercise-based cardiovascular rehabilitation.
Aims
Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.
Methods and results
An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.
Conclusion
Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Acquired inherited and/or somaticmutations drive its development. In order to prevent the formation of these mutations, precise and immediaterepair of any DNA damage is indispensable. Non-homologous end-joining (NHEJ) is the key mechanism of DNAdouble-strand break repair. Here, we report that miR-502 targets two components in pancreatic cell lines, Ku70and XLF of the C-NHEJ. Interestingly, we also observed an attenuated cell cycle response to gamma ionizingradiation (γ-IR) via diminished phosphorylation of checkpoint kinase 1 (Chk1) on serine 345 in these cell lines.Altogether, pancreatic cells showed increased susceptibility toγ-IR via direct inhibition of DNA double-strandbreak repair and attenuation of the cell cycle response.
Abstract
The frequency of mechanical circulatory support (MCS) device application has increased in recent years. Besides implantation in the emergency setting, such as circulatory arrest, MCS is also increasingly used electively to ensure hemodynamic stability in high‐risk patients, for example, during percutaneous coronary interventions (PCI), valve interventions or off‐pump coronary bypass surgery. Lifebridge (Zoll Medical GmbH, Germany) is a compact percutaneous MCS device widely used in daily clinical routine. The present study aimed to investigate the indications, feasibility, and outcomes after use of Lifebridge in cardiac interventions, evaluating a large‐scale multicenter database. A total of 60 tertiary cardiovascular centers were questioned regarding application and short‐term outcomes after the use of the Lifebridge system (n = 160 patients). Out of these 60 centers, eight consented to participate in the study (n = 39 patients), where detailed data were collected using standardized questionnaires. Demographic and clinical characteristics of the patient population, procedural as well as follow‐up data were recorded and analyzed. In 60 interrogated centers, Lifebridge was used in 74% of emergency cases and 26% in the setting of planned interventions. The subcohort interrogated in detail displayed the same distribution of application scenarios, while the main cardiovascular procedure was high‐risk PCI (82%). All patients were successfully weaned from the device and 92% (n = 36) of the patients studied in detail survived after 30 days. As assessed 30 days after insertion of the device, bleeding requiring red blood cell (RBC) transfusion constituted the main complication, occurring in 49% of cases. In our analysis of clinical data, the use of Lifebridge in cardiac intervention was shown to be feasible. Further prospective studies are warranted to identify patients who benefit from hemodynamic MCS support despite the increased rate of RBC transfusion due to challenges in access sites during cardiovascular procedures.
Abstract
Fatty acid products derived from cytochromes P450 (CYP) monooxygenase and lipoxygenase (LOX)/CYP ω/(ω‐1)‐hydroxylase pathways are a superclass of lipid mediators with potent bioactivities. Whether or not the chronic kidney disease (CKD) and hemodialysis treatments performed on end‐stage renal disease (ESRD) patients affect RBC epoxy fatty acids profiles remains unknown. Measuring the products solely in plasma is suboptimal. Since such determinations invariably ignore red blood cells (RBCs) that make up 3 kg of the circulating blood. RBCs are potential reservoirs for epoxy fatty acids that regulate cardiovascular function. We studied 15 healthy persons and 15 ESRD patients undergoing regular hemodialysis treatments. We measured epoxides derived from CYP monooxygenase and metabolites derived from LOX/CYP ω/(ω‐1)‐hydroxylase pathways in RBCs by LC–MS/MS tandem mass spectrometry. Our data demonstrate that various CYP epoxides and LOX/CYP ω/(ω‐1)‐hydroxylase products are increased in RBCs of ESRD patients, compared to control subjects, including dihydroxyeicosatrienoic acids (DHETs), epoxyeicosatetraenoic acids (EEQs), dihydroxydocosapentaenoic acids (DiHDPAs), and hydroxyeicosatetraenoic acids (HETEs). Hemodialysis treatment did not affect the majority of those metabolites. Nevertheless, we detected more pronounced changes in free metabolite levels in RBCs after dialysis, as compared with the total RBC compartment. These findings indicate that free RBC eicosanoids should be considered more dynamic or vulnerable in CKD.
Abstract
The RADPAC trial evaluated paclitaxel with everolimus in patients with advanced gastroesophageal cancer (GEC) who have progressed after therapy with a fluoropyrimidine/platinum‐containing regimen. Patients were randomly assigned to receive paclitaxel (80 mg/m2) on day 1, 8 and 15 plus everolimus (10 mg daily, arm B) d1‐d28 or placebo (arm A), repeated every 28 days. Primary end point was overall survival (OS). Efficacy was assessed in the intention‐to‐treat population and safety in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01248403. Between October 2011 and September 2015, 300 patients (median age: 62 years; median lines prior therapy: 2; 47.7% of patients had prior taxane therapy) were randomly assigned (arm A, 150, arm B, 150). In the intention to treat population, there was no significant difference in progression‐free survival (PFS; everolimus, 2.2 vs placebo, 2.07 months, HR 0.88, P = .3) or OS (everolimus, 6.1 vs placebo, 5.0 months, HR 0.93, P = .54). For patients with prior taxane use, everolimus improved PFS (everolimus, 2.7 vs placebo 1.8 months, HR 0.69, P = .03) and OS (everolimus, 5.8 vs placebo 3.9 months, HR 0.73, P = .07). Combination of paclitaxel and everolimus was associated with significantly more grade 3‐5 mucositis (13.3% vs 0.7%; P < .001). The addition of everolimus to paclitaxel did not improve outcomes in pretreated metastatic gastric/gastroesophageal junction (GEJ) cancer. Activity was seen in the taxane pretreated group. Additional biomarker studies are planned to look for subgroups that may have a benefit.