Non-lethal proteasome inhibition activates pro-tumorigenic pathways in multiple myeloma cells

Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle‐cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non‐lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib‐like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non‐lethal (IC10) doses of the PIs revealed inhibitor‐ and cell type‐specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro‐tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro‐tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse.Bio-organic Synthesi

Die bikuspide Aortenklappe

Zusammenfassung Die bikuspide Aortenklappe ist der häufigste kongenitale Herzfehler und gleichzeitig die häufigste angeborene Fehlbildung der Aortenklappe bei Erwachsenen. In dieser Übersichtsarbeit werden die verschiedenen Aspekte der bikuspiden Aortenklappe einschließlich ihrer Komplikationen unter klinischen Gesichtspunkten dargestellt. Abstract The bicuspid aortic valve is the most common congenital heart disease as also the most common congenital malformation of the aortic valve. Due to altered hemodynamics, anatomy and geometry of the valve apparatus there is a high risk of complications, with the most common of them the aortic valve stenosis. Echocardiography is primarily considered as the gold standard for the diagnosis. However computed tomography and magnetic resonance tomography belong to the diagnostic armamentarium for precise diagnosis, risk stratification and defining the therapeutic approaches. Operative aortic valve replacement has been ultimately the gold standard therapy for the bicuspid aortic valve, although in the last years, transaortic valve replacement emerge as an alternative option with excellent results

Plasma enhanced decomposition of propylene on activated carbon fibers

Activated carbons with uniform size micropores appear to have the highest potential for improvement of their molecular sieving properties by employing chemical vapor deposition techniques. In this work RF plasma was used to enhance propylene cracking and to examine its effect on the pore structure, chemical surface groups and selective CO2 adsorption of a commercial activated carbon fiber. Plasma treatment of carbon fibers was carried out under various experimental conditions. Raman, FTIR and XPS spectroscopy were used to evaluate the modifications on the fibers surface. SEM was also used for the observation of fibers surface before and after plasma treatment

CT angiography with three-dimensional techniques for the early diagnosis of intracranial aneurysms. Comparison with intra-arterial DSA and the surgical findings

Introduction: Cerebral CT angiography (CTA) is an established method applied to both the detection and treatment planning of intracranial aneurysms. The aim of our study was to compare CTA and digital subtraction angiography (DSA) findings with the surgical results mainly in patients with acute SAH and to evaluate the clinical usefulness of CTA. Materials and methods: During the last 2 years, 82 consecutive patients were admitted under clinical symptoms and signs suggestive of harboring an intracranial aneurysm. CT angiography performed immediately afterwards the plain CT, while DSA was performed within the first 48 h of admission. All aneurysms detected were confirmed during surgery or endovascular embolization. Repeat DSA was performed in all patients having both the initial CTA and the DSA 15 days after the onset of symptoms negative. CT angiograms and conventional angiographies were studied by a consensus of two radiologists for each technique, who performed aneurysm detection, morphological features characterization and evaluation of the technique. Results: Surgical or/and endovascular treatment was performed in 45 patients and 53 aneurysms were confirmed. Using 3D-CT angiography, we detected 47 aneurysms in 42 patients. Conventional angiography depicted 43 aneurysms in 39 patients. The sensitivity of CTA for the detection of all aneurysms versus surgery was 88.7%, the specificity 100%, the positive predictive value (PPV) 100%, the negative predictive value (NPV) 80.7% and the accuracy 92.3%. Accordingly, the sensitivity of DSA was 87.8%, the specificity 98%, the PPV 97.7%, the NPV 89.1% and the accuracy 92.9%. Considering aneurysms mm, CTA showed a sensitivity ranging from 93.3 to 100%, equal to that of DSA. Conclusion: Cerebral CT angiography has an equal sens..

Hepcidin in iron overload disorders

Hepcidin is the principal regulator of iron absorption in humans. The pepticle inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload. Indeed, hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in HFE, transferrin receptor 2, hemojuvelin, and the hepcidin gene itself. We measured urinary hepcidin in patients with other genetic causes of iron overload. Hepcidin was found to be suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1 and was undetectable in patients with juvenile hemochromatosis with HAMP mutations. Of interest, urine hepcidin levels were significantly elevated in 2 patients with hemochromatosis type 4. These findings extend the spectrum of iron disorders with hepcidin deficiency and underscore the critical importance of the hepcidin-ferroportin interaction in iron homeostasis. (c) 2005 by The American Society of Hematology

A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease

Objectives Rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). We aimed to assess long-term efficacy and safety of RTX in SSc compared to standard treatment. Methods A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1–7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10). Results Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7 year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups. Conclusions Our data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Randomized controlled studies are highly needed. © 2017 Elsevier Inc

Non-lethal proteasome inhibition activates pro-tumorigenic pathways in multiple myeloma cells

Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle-cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non-lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib-like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non-lethal (IC10) doses of the PIs revealed inhibitor- and cell type-specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro-tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro-tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse. © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley &amp; Sons Ltd and Foundation for Cellular and Molecular Medicine