Ubiquitination and Ubiquitin-Like Modifications in Multiple Myeloma: Biology and Therapy

Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination and SUMOylation play key roles in essential pathways in multiple myeloma, including NFκB signaling, epigenetic regulation, as well as DNA damage repair. Drugs modulating the ubiquitin-proteasome system, such as proteasome inhibitors and thalidomide analogs, are approved and highly effective drugs in multiple myeloma. In this review, we focus on ubiquitin and ubiquitin-like modifications in the biology and current developments of new treatments for multiple myeloma

Schwannoma of the Hypoglossal Nerve Mimicking Carotid Body Paraganglioma

Carotid body paragangliomas (CBPs) clinically present as highly vascularized cervical masses with a pathognomonic localization at the carotid artery bifurcation. Following ultrasonography and MRI/CT imaging, surgical resection with optional preoperative embolization is considered as the treatment of choice in most cases. We herein present the case of a 60-year-old female with characteristic clinical signs and imaging findings of a right-sided CBP who finally went to surgical treatment. Intraoperatively, the tumor showed an adherent growth to the hypoglossal nerve that had to be partially resected, resulting in a postoperative nerve palsy. Histological examination of the resected tumor revealed the unexpected diagnosis of a hypoglossal nerve schwannoma. To the best of our knowledge, we herein present the third case reported in the literature of a unilateral hypoglossal schwannoma located at the carotid bifurcation mimicking clinical symptoms, imaging and intraoperative findings of a CBP

European Working Conditions Survey 2024: Cognitive Pretest

Eurofound is preparing to transition the European Working Conditions Survey (EWCS) from a computer-assisted personal interview (CAPI) to self-administered online data collection. GESIS was contracted to adapt the CAPI master questionnaire, translate the adapted online questionnaire into German and Polish, and cognitively pretest the online questionnaire using cross-cultural cognitive interviews and web probing. The main goal of cognitive testing was assessing the comparability of the adapted online questionnaire to the original face-to-face questionnaire. Further objectives were testing whether the online questionnaire is suitable for cross-cultural research and applies gender-sensitive language

Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding

Introduction Prothrombin complex concentrates are recommended for rapid reversal of vitamin K anticoagulants. As they normalize levels of vitamin K dependent clotting factors and re-establish hemostasis, they may also be used as adjunctive therapy in patients with major bleeding. The aim of this study was to retrospectively evaluate the efficacy of prothrombin complex concentrates in the surgical setting. Methods The case notes of 50 patients requiring urgent oral anticoagulation reversal (n = 12) or with severe perioperative coagulopathic bleeding (n = 38) who received an infusion of prothrombin complex concentrate (Beriplex P/N(R) 500) at the surgical department of the University of Munich Hospital, Germany were retrospectively reviewed. Efficacy of prothrombin complex concentrate application was evaluated using the Quick test, reported as an international normalized ratio, hemodynamic measurements and requirement for blood products. Safety assessments included whole blood hemoglobin levels and specific parameters of organ dysfunction. Results Baseline characteristics were comparable, except that mean baseline international normalized ratio and hemoglobin levels were significantly higher (P < 0.01) in anticoagulation reversal than in bleeding patients. In anticoagulation reversal, the international normalized ratio was significantly reduced (from 2.8 +/- 0.2 at baseline to 1.5 +/- 0.1, P < 0.001) after one prothrombin complex concentrate infusion (median dose 1500 IU; lower quartile 1,000, upper quartile 2,000). No major bleeding was observed during surgery after prothrombin complex concentrate administration. Only one patient received platelets and red blood cell transfusion after prothrombin complex concentrate administration. In bleeding patients, infusion of prothrombin complex concentrate (median dose 2,000 IU; lower quartile 2,000, upper quartile 3,000) significantly reduced the INR from 1.7 +/- 0.1 at baseline to 1.4 +/- 0.1 (P < 0.001). This decrease was unrelated to fresh frozen plasma or vitamin K administration. Bleeding stopped after prothrombin complex concentrate administration in 4/11 (36%) patients with surgical bleeding and 26/ 27 (96%) patients with diffuse bleeding. Hemoglobin levels increased significantly from baseline in bleeding patients (P < 0.05) and mean arterial pressure stabilized (P < 0.05). No thrombotic events or changes in organ function were reported in any patient. Conclusions Prothrombin complex concentrate application effectively reduced international normalized ratios in anticoagulation reversal, allowing surgical procedures and interventions without major bleeding. In bleeding patients, the improvement in coagulation after prothrombin complex concentrate administration was judged to be clinically significant

Complete remission of an early-stage laryngeal cancer under combined pembrolizumab and chemotherapy treatment of a synchronous lung adenocarcinoma

Background: Anti-PD1-Checkpoint inhibition (CI) is an established treatment of recurrent and/or metastatic head and neck cancer. A potential beneft from CI in early-stage disease that is usually treated by radiation or surgery has not been investigated so far and is currently not addressed in clinical trials. Case presentation: A 58-year-old man was diagnosed with a cT2 supraglottic laryngeal cancer and a synchronous metastasized adenocarcinoma of the lung. As the patient refused any treatment of his laryngeal cancer, he received combined immune-chemotherapy according to the KEYNOTE-189 protocol. After 4 cycles of pembrolizumab/carboplatin/pemetrexed, the patient showed a complete remission of his laryngeal cancer with a clear shrinkage of the mediastinal and hilar lung cancer metastases. After 21 cycles of maintenance therapy, the lung adenocarcinoma shows a stable disease status with no signs of any residual or recurrent laryngeal cancer. Conclusions: Anti-PD1-CI may be a treatment option also for early-stage HNSCC with excellent functional outcome when established therapies are not available

Banken unter Druck: Gibt es Auswege aus der neuen Bankenkrise?

Durch die globale Finanz- und Wirtschaftskrise geraten Europas Banken immer mehr unter Druck. So hat die desolate Verfassung der Staatsfinanzen der südeuropäischen Länder nach Ansicht von Stephan Paul und Christian Farruggio, Ruhr-Universität Bochum, die Krise in den Bankensektor »zurückgebracht«, denn diese halten immer noch in großem Umfang öffentliche Schuldtitel. Die von der Politik favorisierten Vorschläge zur Beseitigung der Bankenkrise lösen aber leider nicht die derzeitigen Probleme, da sie sich vor allem auf die Höhe des regulatorischen Eigenkapitals von Banken beziehen. Stattdessen müsse im Rahmen einer proaktiven Kontrolle der Aufsicht intensiver geprüft werden, welche Risiken Banken eingehen. Gerhard Schick und Jan Weder, Bündnis 90/Die Grünen, sehen es als wichtig an, die Banken- und Schuldenkrisen separat zu lösen, wobei die Stabilisierung der Banken hierfür ein elementarer Baustein sei. Leider habe es die Politik versäumt, sich neue Optionen zwischen den beiden Extremen »Retten« und »Nicht-Retten« zu verschaffen. Jochen Zimmermann, Universität Bremen, möchte an den Anreizstrukturen und dem Geschäftsmodell der großen Privatbanken ansetzen, und zwar in mehrfacher Hinsicht: durch die Trennung von Staat und Kreditwirtschaft, durch weiträumige Verbote derivativer Geschäfte und die Stärkung des Zusammenhangs von Handlung und Haftung. Harald Hau, Universität Genf und Swiss Finance Institute, und Bernd Lucke, Indiana University, Bloomington, und Universität Hamburg, sehen Europa vor der Wahl zwischen hoher Infla­tion oder dem möglichen Staatsbankrott einzelner Staaten der Eurozone.Bankenkrise, Finanzmarkt, Eigenkapital, Bankrisiko, Konjunkturpolitik, Inflation, Staatsbankrott, Europa

Effects of a novel, transdiagnostic, hybrid ecological momentary intervention for improving resilience in youth (EMIcompass):Protocol for an exploratory randomized controlled Trial

BACKGROUND: Most mental disorders first emerge in youth and, in their early stages, surface as subthreshold expressions of symptoms comprising a transdiagnostic phenotype of psychosis, mania, depression, and anxiety. Elevated stress reactivity is one of the most widely studied mechanisms underlying psychotic and affective mental health problems. Thus, targeting stress reactivity in youth is a promising indicated and translational preventive strategy for adverse mental health outcomes that could develop later in life and for improving resilience. Compassion-focused interventions offer a wide range of innovative therapeutic techniques that are particularly amenable to being implemented as ecological momentary interventions (EMIs), a specific type of mobile health intervention, to enable youth to access interventions in a given moment and context in daily life. This approach may bridge the current gap in youth mental health care. OBJECTIVE: This study aims to investigate the clinical feasibility, candidate underlying mechanisms, and initial signals of the efficacy of a novel, transdiagnostic, hybrid EMI for improving resilience to stress in youth—EMIcompass. METHODS: In an exploratory randomized controlled trial, youth aged between 14 and 25 years with current distress, a broad Clinical High At-Risk Mental State, or the first episode of a severe mental disorder will be randomly allocated to the EMIcompass intervention (ie, EMI plus face-to-face training sessions) in addition to treatment as usual or a control condition of treatment as usual only. Primary (stress reactivity) and secondary candidate mechanisms (resilience, interpersonal sensitivity, threat anticipation, negative affective appraisals, and momentary physiological markers of stress reactivity), as well as primary (psychological distress) and secondary outcomes (primary psychiatric symptoms and general psychopathology), will be assessed at baseline, postintervention, and at the 4-week follow-up. RESULTS: The first enrollment was in August 2019, and as of May 2021, enrollment and randomization was completed (N=92). We expect data collection to be completed by August 2021. CONCLUSIONS: This study is the first to establish feasibility, evidence on underlying mechanisms, and preliminary signals of the efficacy of a compassion-focused EMI in youth. If successful, a confirmatory randomized controlled trial will be warranted. Overall, our approach has the potential to significantly advance preventive interventions in youth mental health provision. TRIAL REGISTRATION: German Clinical Trials Register DRKS00017265; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017265 INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/2746

Differential nasal swab cytology represents a valuable tool for therapy monitoring but not prediction of therapy response in chronic rhinosinusitis with nasal polyps treated with Dupilumab

Introduction: Chronic Rhinosinusitis with nasal polyps (CRSwNP) is a common chronic disease with a high impact on patients’ quality of life. If conservative and surgical guideline treatment cannot sufficiently control disease burden, biologicals can be considered as a comparably new treatment option that has revolutionized CRSwNP therapy since the first approval of Dupilumab in 2019. With the aim to select patients who benefit from this new treatment and to find a marker for therapy monitoring, we investigated the cellular composition of nasal mucous membranes and inflammatory cells of patients suffering from CRSwNP and undergoing Dupilumab therapy using non-invasive nasal swab cytology. Methods: Twenty CRSwNP patients with the indication for Dupilumab therapy have been included in this prospective clinical study. In total, five study visits were conducted with ambulatory nasal differential cytology using nasal swabs starting with the beginning of therapy and followed by visits every 3 months for 12 months. First, these cytology samples were stained with the May-GrunwaldGiemsa method (MGG) and the percentage of ciliated cells, mucinous cells, eosinophil cells, neutrophil cells, and lymphocytes was analyzed. Secondly, an immunocytochemical (ICC) ECP-staining was performed to detect eosinophil granulocytes. Additionally, during each study visit the nasal polyp score, SNOT20 questionnaire, olfactometry, the total IgE concentration in peripheral blood as well as the eosinophil cell count in peripheral blood were recorded. The change of parameters was evaluated over one year and the correlation between clinical effectiveness and nasal differential cytology was analyzed. Results: In both MGG (p<0.0001) and ICC analysis (p<0.001) a significant decrease of eosinophils was seen under Dupilumab treatment. When patients were divided into a Eo-low- (<21%) and Eo-high- (≥21%) group according to the percentage eosinophils in nasal swab catology in the first study visit, the Eo-highgroup showed a greater change of eosinophils over time (D17.82) compared to the Eo-low-group (D10.67) but, however, no better response to therapy. The polyp score, SNOT20 questionnaire, and total IgE concentration in peripheral blood showed a significant decrease during the observation period (p<0.0001). Discussion: Nasal swab cytology as an easy-to-apply diagnostic method allows detection and quantification of the different cell populations within the nasal mucosa at a given time. The nasal differential cytology showed a significant decrease of eosinophils during Dupilumab therapy and can therefore be used as non-invasvive method for monitoring therapy success of this cost intensive therapy and potentially can allow an optimized individual therapy planning and management for CRSwNP patients. Since the validity of initial nasal swab eosinophil cell count as a predictive biomarker for therapy response was limited in our study, additional studies including larger number of participants will be necessary to further evaluate the potential benefits for clinical practice of this new diagnostic method