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Introduction: Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA). Objective: These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study. Methods: Patients with active PsA and psoriasis in SPIRIT-H2H (N = 566) were categorised into two sets of four response groups irrespective of treatment allocation (approved dosages of ixekizumab or adalimumab): patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52 weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes. Results: Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis ≤ 4, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points. Conclusion: High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity.
Purpose: To investigate short-term (3 months follow-up) changes in visual quality following Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy (FED). Methods: In this prospective institutional case series, 51 patients that underwent DMEK for FED were included. Assessment included the Quality of Vision (QoV) questionnaire preoperatively, at 1 month, and 3 months after surgery. Secondary outcome measures were anterior segment parameters acquired by Scheimpflug imaging, corrected distance visual acuity (CDVA), and endothelial cell density (ECD). Results: Glare, hazy vision, blurred vision, and daily fluctuation in vision were the symptoms mostly reported preoperatively. All symptoms demonstrated a significant reduction of item scores for severity, frequency, and bothersome in the course after DMEK (P < 0.01). Glare and fluctuation in vision remained to some extent during the follow-up period (median score = 1). Preoperatively, corneal densitometry correlated moderately to weakly with severity of hazy vision (rs = 0.39; P = 0.03) and frequency (rs = 0.26; P = 0.02) as well as severity (rs = 0.27; P = 0.03) of blurry vision. CDVA and central corneal thickness (CCT) did not correlate with visual complains. Conclusions: Following DMEK for FED, patient-reported visual symptoms assessed by the QoV questionnaire represent a useful tool providing valuable information on the impact of DMEK on visual quality that cannot be directly estimated by morphological parameters and visual acuity only.
Background: Due to the coronavirus disease 2019 (COVID-19) pandemic, interventions in the upper airways are considered high-risk procedures for otolaryngologists and their colleagues. The purpose of this study was to evaluate limitations in hearing and communication when using a powered air-purifying respirator (PAPR) system to protect against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission and to assess the benefit of a headset. Methods: Acoustic properties of the PAPR system were measured using a head and torso simulator. Audiological tests (tone audiometry, Freiburg speech test, Oldenburg sentence test (OLSA)) were performed in normal-hearing subjects (n = 10) to assess hearing with PAPR. The audiological test setup also included simulation of conditions in which the target speaker used either a PAPR, a filtering face piece (FFP) 3 respirator, or a surgical face mask. Results: Audiological measurements revealed that sound insulation by the PAPR headtop and noise, generated by the blower-assisted respiratory protection system, resulted in significantly deteriorated hearing thresholds (4.0 ± 7.2 dB hearing level (HL) vs. 49.2 ± 11.0
Objectives: To evaluate the predictive value of volumetric bone mineral density (BMD) assessment of the lumbar spine derived from phantomless dual-energy CT (DECT)-based volumetric material decomposition as an indicator for the 2-year occurrence risk of osteoporosis-associated fractures. Methods: L1 of 92 patients (46 men, 46 women; mean age, 64 years, range, 19–103 years) who had undergone third-generation dual-source DECT between 01/2016 and 12/2018 was retrospectively analyzed. For phantomless BMD assessment, dedicated DECT postprocessing software using material decomposition was applied. Digital files of all patients were sighted for 2 years following DECT to obtain the incidence of osteoporotic fractures. Receiver operating characteristic (ROC) analysis was used to calculate cut-off values and logistic regression models were used to determine associations of BMD, sex, and age with the occurrence of osteoporotic fractures. Results: A DECT-derived BMD cut-off of 93.70 mg/cm3 yielded 85.45% sensitivity and 89.19% specificity for the prediction to sustain one or more osteoporosis-associated fractures within 2 years after BMD measurement. DECT-derived BMD was significantly associated with the occurrence of new fractures (odds ratio of 0.8710, 95% CI, 0.091–0.9375, p < .001), indicating a protective effect of increased DECT-derived BMD values. Overall AUC was 0.9373 (CI, 0.867–0.977, p < .001) for the differentiation of patients who sustained osteoporosis-associated fractures within 2 years of BMD assessment. Conclusions: Retrospective DECT-based volumetric BMD assessment can accurately predict the 2-year risk to sustain an osteoporosis-associated fracture in at-risk patients without requiring a calibration phantom. Lower DECT-based BMD values are strongly associated with an increased risk to sustain fragility fractures.
Key Points: Dual-energy CT–derived assessment of bone mineral density can identify patients at risk to sustain osteoporosis-associated fractures with a sensitivity of 85.45% and a specificity of 89.19%. The DECT-derived BMD threshold for identification of at-risk patients lies above the American College of Radiology (ACR) QCT guidelines for the identification of osteoporosis (93.70 mg/cm 3 vs 80 mg/cm 3 ).
To explore and describe attitudes and opinions towards suicidality in healthcare professionals (HCPs) working with oncological patients. Methods: A 48-item online questionnaire was developed and distributed to HCPs working with cancer patients. Three hundred fifty-four answered questionnaires were analyzed. Results: The majority of HCPs reported that they were able to understand why a cancer patient would commit suicide (87.8%) or would seek help from an assisted suicide organization (ASO; 83.9%). The understandable reasons were pain and physical impairments (51.4%), social isolation (19.8%), loss of control and autonomy (18.1%), terminal disease (17.2%), loss of meaning (15.3%), desperation (14.7%), and psychic distress (9.3%). Personal experiences with suicidality lead only 44.8% of HCPs to believe that thereby they would be better able to understand a patients’ wish for suicide. Religion was negatively associated with understanding of suicide and why a cancer patient would seek help from an ASO. Knowledge of suicidality was positively associated with why a cancer patient would seek help from an ASO. Conclusions: There is still little knowledge in oncology about the relation of HCPs’ attitudes toward suicidality in their patients and how those attitudes influence their behavior, especially care and treatment of patients. More research on this topic is needed. It stands to reason that more education about suicidality in cancer patients seems likely to improve understanding and attitudes and thereby influence care for cancer patients.
Das Übergangstraining : Maßnahme in der betrieblichen Wiedereingliederung im professionellen Tanz
(2021)
Neben der Vorbeugung von akuten und chronischen Schäden ist im professionellen Bühnentanz bei gesundheitlichen Problemen am Muskel-Skelett-System eine intensive – dem Berufssport vergleichbare – Rehabilitation unter Berücksichtigung tanzspezifischer Bewegungselemente von großer Bedeutung. In Kombination mit anderen, die Leistungsfähigkeit wiederherstellenden Maßnahmen ist das in diesem Beitrag erläuterte sog. Übergangstraining („transition dance class“) als Trainingsform im Rahmen der stufenweisen beruflichen Wiedereingliederung von zentraler Bedeutung, da es die Übergangsphase zwischen allgemeinen Maßnahmen einer Rehabilitation und dem Wiedererreichen der vollständigen Arbeitsfähigkeit im Tanzberuf darstellt.
Für die Funktion und das Überleben von Zellen ist die Aufrechterhaltung und Regulation der Redoxhomöostase durch Produktion und Elimination von radikalen Sauerstoffspezies (ROS) von entscheidender Bedeutung. In Tumorzellen finden sich höhere basale ROS-Level als in gesunden Zellen, was jedoch trotz des vermehrten oxidativen Stresses nicht zur Zelltodinduktion führt, da kompensatorisch antioxidative Mechanismen ebenfalls gesteigert sind. Vor allem zwei antioxidative Systeme sind hauptsächlich bei der Elimination von ROS involviert: das Glutathion (GSH)-System und das Thioredoxin (TRX)-System. Hierbei spielt eine beständige Regeneration von GSH, als auch von TRX, eine wichtige Rolle, da diese bei der Reduktion von Sauerstoffradikalen verbraucht werden. Im hepatozellulären Karzinom (HCC) ist die gestörte Redoxhomöostase mit gesteigerten ROS Leveln ein wichtiger Faktor in der Karzinogenese. Das HCC wird oft erst im fortgeschrittenen, nicht mehr kurativen Stadium diagnostiziert und ist resistent gegenüber nahezu allen Formen von Chemotherapien. Dies verdeutlich die immense Bedeutung der Erforschung der teilweise unverstandenen Tumorgenese, aber auch die Notwendigkeit für die Entwicklung von neuen Therapien.
In der hier dargestellten experimentellen Arbeit gingen wir deshalb der Frage nach, ob die alleinige Inhibierung der antioxidativen Schutzmechanismen durch sog. ROS Modulatoren ausreicht, um eine Zelltodinduktion in humanen HCC-Zelllinien herbeizuführen und damit eine potenzielle neue Therapiestrategie aufzuzeigen.
Wir konnten zeigen, dass die simultane Inhibierung dieser zwei antioxidativen Hauptmechanismen im HCC durch die Kombination von Auranofin (TXR-Inhibitor) mit Buthionine-Sulfoximin (BSO, Glutathion-Inhibitor) und Erastin (indirekter Glutathion-Inhibitor) mit BSO zur ROS-abhängigen Zelltodinduktion im HCC in vitro führt. Interessant ist, dass die gesteigerten ROS-Level jedoch nicht den Zelltod im HCC induzierten, wenn nur eines der beiden antioxidativen Systeme inhibiert wurde. Offenbar ist die Tumorzelle in der Lage durch Hochregulierung anderer antioxidativer Systeme das induzierte ROS zu neutralisieren. Unsere Untersuchungen zum Wirkmechanismus der Zelltodinduktion durch die Kombinationsbehandlungen Auranofin + BSO bzw. Erastin + BSO identifizierten unerwarteterweise eine Caspasen-unabhängige, nicht-apoptotische Zelltodform, die sog Ferroptose, welche durch ROS-Produktion und Lipidperoxidierung charakterisiert ist.
Weitere Experimente konnten untermauern, dass mit der Induktion der Ferroptose durch die selektive ROS-Modulation die Apoptoseresistenz der HCC Zellen umgangen werden kann.
Mechanistisch kann diese erstmals 2012 beschriebene eisenabhängige Zelltodform, Ferroptose, durch zwei verschiedene Signalwege induziert werden: Erstens durch den kanonischen Pfad, bei welchem die Inhibierung der Glutathionperoxidase 4 (GPX4), einem Protein, welches die Zellmembran vor Lipidperoxidation schützt, eine zentrale Rolle spielt, und zweitens durch den nicht-kanonischen Pfad, welcher durch eine Anhäufung von zweiwertigem Eisen u. a. durch Aktivierung von Hämoxygenasen (HO), vermittelt durch den Transkriptionsfaktor Nuclear factor erythroid 2-related factor 2 (Nrf2), gekennzeichnet ist. Wir konnten feststellen, dass in unseren Kombinationsbehandlungen beide Pfade involviert sind und eine Herunterregulierung von GPX4 als auch eine Akkumulation von Nrf2 und Hämoxygenase-1 (HO-1) besteht.
Zusammenfassend konnte unsere Arbeit zeigen, dass mittels pharmakologischer Adressierung zweier antioxidativer Systeme die Therapieresistenz der HCC-Zellen umgangen werden kann, und dass die Induktion der Ferroptose zukünftig eine vielversprechende Therapieoption im HCC darstellen könnte.
Hintergrund: Seit mehr als 50 Jahren werden in Deutschland Herzschrittmacher-Implantationen durchgeführt, mittlerweile mit mehr als 100.000 Implantationen pro Jahr. Obwohl es sich um einen gängigen Eingriff handelt, existieren wenig prospektiv randomisierte Studien zu technischen Aspekten der Implantation, insbesondere dem Wundverschluss am Ende der Operation. Ziel der vorliegenden Arbeit war es, an einem Kollektiv von Patienten unerwünschte Ereignisse und kosmetische Ergebnisse, in Abhängigkeit des beim Hautverschluss verwendeten Nahtmaterials (resorbierbarer bzw. nicht-resorbierbarer Faden), miteinander zu vergleichen.
Methoden: In einem Zeitraum von Juli 2018 bis April 2019 wurden Patienten mit geplanter de novo Herzschrittmacher-Implantation ohne Defibrillationstherapie prospektiv in die Studie eingeschlossen und anhand einer Randomisierungliste in zwei Probandengruppen eingeteilt: nicht-resorbierbares Nahtmaterial (Gruppe Prolene®) bzw. resorbierbares Nahtmaterial (Gruppe Monocryl®).
Ein Tag (Beobachtungszeitpunkt 1), sechs Wochen (Beobachtungszeitpunkt 2) und ein Jahr post-OP (Beobachtungszeitpunkt 3) erfolgte die Beurteilung der Narbe bezüglich des kosmetischen Ergebnisses und klinisch relevanter, unerwünschter Ereignisse. Zur kosmetischen Beurteilung diente die Wundbreite in mm, eine auftretende Kelloidbildung und die „Patient and Observer Scar Assessment Scale“ (POSA-Score). Dieser wurde zu Beobachtungszeitpunkt 1 seitens des Patienten auf zwei Fragen (Schmerzhaftigkeit, Juckreiz) reduziert. Die erhobenen klinisch relevanten Parameter waren Nachblutungen, Infektionen, Insuffizienz der Naht und Revisions-OP aufgrund eines Lokalbefundes.
Ergebnisse: Es konnten 114 Patienten in die Studie eingeschlossen werden. Zu Beobachtungszeitpunkt 2 und Beobachtungszeitpunkt 3 belief sich die Anzahl auf jeweils 92 Probanden. Zu allen drei Beobachtungszeitpunkten konnte zwischen beiden Gruppen weder ein signifikanter Unterschied im kosmetischen Ergebnis noch im Auftreten klinisch relevanter Ereignisse festgestellt werden.
Schlussfolgerung: Anhand der vorliegenden Studie scheint das verwendete Nahtmaterial keinen großen Einfluss auf das kosmetische Ergebnis der Narbe, sowie auf das Auftreten von unerwünschten Ereignissen zu haben. Eine multizentrische prospektiv randomisierte Studie mit größerer Patientenanzahl ist notwendig, um die hier erhobenen Daten zu verifizieren.
HINTERGRUND: Asthma ist die häufigste chronische Krankheit bei Kindern und Jugendlichen, wobei bei einem Großteil bereits erste Exazerbationen im Vorschulalter auftreten. Diese sind meist mit stationären Aufenthalten verbunden, jedoch gibt es nur wenige detaillierte zeitliche und demografische Untersuchungen dieser besonders schweren Asthmakohorte. Ebenso gibt es kaum Untersuchungen über die Verteilung der Asthmaphänotypen in dieser Altersgruppe.
METHODEN: Es erfolgte eine retrospektive Analyse von 572 Krankenhausaufenthalten im Universitätsklinikum für Kinder- und Jugendmedizin Frankfurt mit der ICD Diagnose Asthma (J.45) zwischen dem 1. Januar 2008 und dem 31. Dezember 2017 bei Kindern im Alter 1-5 Jahren. Die Aufteilung erfolgte in drei Phänotypen. Allergisches Asthma (RAST und/oder Prick-Test positiv), eosinophiles Asthma (Eosinophilie >300/µl und RAST/Prick-Test negativ) und nicht-allergisches Asthma (Eosinophilie ≤300/µl und RAST/Prick-Test negativ). Akut schweres Asthma wurde definiert als akute Dyspnoe, Tachypnoe, Sauerstoffbedarf und/oder systemische Steroidtherapie. Analysiert wurden u.a. Alter, Geschlecht, Liegezeit, Therapie und Re-Hospitalisierungsrate.
ERGEBNISSE: Von 572 Krankenhausaufenthalten mit der Diagnose Asthma erfüllten 205 Patienten die Definition eines akut schweren Asthmas. Von diesen 205 Kindern wurden bereits n=55 (26,8%) vor der stationären Aufnahme mit einem inhalativen Steroid (ICS) behandelt. Die phänotypische Charakterisierung ergab folgende Verteilung: 49% wiesen Allergisches Asthma, 15% Asthma mit atopischer Dermatitis, 10% eosinophiles nicht-allergisches Asthma und 26% nicht-allergisches Asthma. Von diesen Patienten wurden 71.7% mit ICS und 15,1% mit Montelukast als Monotherapie entlassen. Die Rate der Notfallvorstellung (Notfallambulanz und Re-Hospitalisierung) innerhalb von 12 Monaten nach Entlassung war mit n=42 (20,5%) hoch. Die Zahl der Eosinophilen (> 300 µl) hatte keinen Einfluss auf die Re-Hospitalisierung. Es zeigte sich eine hohe Verschreibung von Antibiotika bei Asthma-Patienten (143 (69,8%) der 205 Patienten) während des stationären Aufenthalts, wobei nur 42 Patienten (20,5%) einen CRP-Wert über 2 mg/dl aufwiesen.
Schlussfolgerung: Obwohl die Asthmaprävalenz bei Schulkindern höher ist, leiden Vorschulkinder im Alter von 1-5 Jahren häufiger an schweren Asthma-Exazerbationen mit Hospitalisierung. Trotz protektiver Therapie mit ICS oder Montelukast ist die Re-Hospitalisierungsrate hoch. Die bisherigen Therapiekonzepte reichen in dieser Altersgruppe anscheinend nicht aus, um Patienten mit schwerem Asthma im Vorschulalter ausreichend zu kontrollieren. Neue Therapiekonzepte wie die Triple-Therapie mit Zugabe des Long-Acting Muscarin Rezeptors (Tiotropium) sollten dringend evaluiert werden.
Cancer stem cells (CSCs) are nowadays one of the major focuses in tumor research since this subpopulation was revealed to be a great obstacle for successful treatment. The identification of CSCs in pediatric solid tumors harbors major challenges because of the immature character of these tumors. Here, we present CD34, CD90, OV-6 and cell-surface vimentin (csVimentin) as reliable markers to identify CSCs in hepatoblastoma cell lines. We were able to identify CSC characteristics for the subset of CD34+CD90+OV-6+csVimentin+-co-expressing cells, such as pluripotency, self-renewal, increased expression of EMT markers and migration. Treatment with Cisplatin as the standard chemotherapeutic drug in hepatoblastoma therapy further revealed the chemo-resistance of this subset, which is a main characteristic of CSCs. When we treated the cells with the Hsp90 inhibitor 17-AAG, we observed a significant reduction in the CSC subset. With our study, we identified CSCs of hepatoblastoma using CD34, CD90, OV-6 and csVimentin. This set of markers could be helpful to estimate the success of novel therapeutic approaches, as resistant CSCs are responsible for tumor relapses.
Background: Dual-source dual-energy computed tomography (DECT) offers the potential for opportunistic osteoporosis screening by enabling phantomless bone mineral density (BMD) quantification. This study sought to assess the accuracy and precision of volumetric BMD measurement using dual-source DECT in comparison to quantitative CT (QCT). Methods: A validated spine phantom consisting of three lumbar vertebra equivalents with 50 (L1), 100 (L2), and 200 mg/cm3 (L3) calcium hydroxyapatite (HA) concentrations was scanned employing third-generation dual-source DECT and QCT. While BMD assessment based on QCT required an additional standardised bone density calibration phantom, the DECT technique operated by using a dedicated postprocessing software based on material decomposition without requiring calibration phantoms. Accuracy and precision of both modalities were compared by calculating measurement errors. In addition, correlation and agreement analyses were performed using Pearson correlation, linear regression, and Bland-Altman plots. Results: DECT-derived BMD values differed significantly from those obtained by QCT (p < 0.001) and were found to be closer to true HA concentrations. Relative measurement errors were significantly smaller for DECT in comparison to QCT (L1, 0.94% versus 9.68%; L2, 0.28% versus 5.74%; L3, 0.24% versus 3.67%, respectively). DECT demonstrated better BMD measurement repeatability compared to QCT (coefficient of variance < 4.29% for DECT, < 6.74% for QCT). Both methods correlated well to each other (r = 0.9993; 95% confidence interval 0.9984–0.9997; p < 0.001) and revealed substantial agreement in Bland-Altman plots. Conclusions: Phantomless dual-source DECT-based BMD assessment of lumbar vertebra equivalents using material decomposition showed higher diagnostic accuracy compared to QCT.
We investigated the effects of sexual arousal induced by olfactory stimuli on the expression of neuromodulators, neurotransmitters and sexual steroid receptors in the suprachiasmatic nucleus (SCN, the circadian pacemaker of mammals) and other cerebral entities of Syrian hamsters (Mesocricetus auratus) compared to manual sleep deprivation and immobilization stress. The hamsters kept under a 12:12 hours (h) light:dark cycle were deprived of sleep by sexual stimulation, gentle manual handling or immobilization stress for 1 h at the beginning of the light phase and subsequently sacrificed at zeitgeber time 01:00, respectively; for comparison, hamsters were manually sleep deprived for 6 or 20 h or sacrificed after completing a full sleep phase. As demonstrated by immunohistochemistry, apart from various alterations after manual sleep deprivation, sexual stimulation caused down-regulation of arginine-vasopressin (AVP), vasointestinal peptide (VIP), serotonin (5-HT), substance P (SP), and met-enkephalin (ME) in the SCN. Somatostatin (SOM) was diminished in the medial periventricular nucleus (MPVN). In contrast, an increase in AVP was observed in the PVN, that of oxytocin (OXY) in the supraoptic nucleus (SON), of tyrosine-hydroxylase (TH) in the infundibular nucleus (IN), and dopamine beta-hydroxylase (DBH) in the A7 neuron population of the brain stem (A7), respectively. Testosterone in plasma was increased. The results indicate that sexual arousal extensively influences the neuropeptide systems of the SCN, suggesting an involvement of the SCN in reproductive behavior.
Rodent models of Parkinson’s disease are based on transgenic expression of mutant synuclein, deletion of PD genes, injections of MPTP or rotenone, or seeding of synuclein fibrils. The models show histopathologic features of PD such as Lewi bodies but mostly only subtle in vivo manifestations or systemic toxicity. The models only partly mimic a predominant loss of dopaminergic neurons in the substantia nigra. We therefore generated mice that express the transgenic diphtheria toxin receptor (DTR) specifically in DA neurons by crossing DAT-Cre mice with Rosa26 loxP-STOP-loxP DTR mice. After defining a well-tolerated DTx dose, DAT-DTR and DTR-flfl controls were subjected to non-toxic DTx treatment (5 × 100 pg/g) and subsequent histology and behavioral tests. DAT protein levels were reduced in the midbrain, and tyrosine hydroxylase-positive neurons were reduced in the substantia nigra, whereas the pan-neuronal marker NeuN was not affected. Despite the promising histologic results, there was no difference in motor function tests or open field behavior. These are tests in which double mutant Pink1−/−SNCAA53T Parkinson mice show behavioral abnormalities. Higher doses of DTx were toxic in both groups. The data suggest that DTx treatment in mice with Cre/loxP-driven DAT-DTR expression leads to partial ablation of DA-neurons but without PD-reminiscent behavioral correlates.
Peptide receptor radionuclide therapy (PRRT) of metastatic neuroendocrine tumors (NET) can be successfully repeated but may eventually be dose-limited. Since 177Lu-DOTATATE dose limitation may come from hematological rather than renal function, hematological peripheral blood stem cell backup might be desirable. Here, we report our initial experience of peripheral blood stem-cell collection (PBSC) in patients with treatment-related cytopenia and therefore high risk of bone-marrow failure. Five patients with diffuse bone-marrow infiltration of NET and relevant myelosuppression (≥grade 2) received PBSC before one PRRT cycle with 177Lu-DOTATATE (7.6 ± 0.8 GBq/cycle). Standard stem-cell mobilization with Granulocyte-colony stimulating factor (G-CSF) was applied, and successful PBSC was defined as a collection of >2 × 106/kg CD34+ cells. In case of initial failure, Plerixafor was administered in addition to G-CSF prior to apheresis. PBSC was successfully performed in all patients with no adverse events. Median cumulative activity was 44.8 GBq (range, 21.3–62.4). Three patients had been previously treated with PRRT, two of which needed the addition of Plerixafor for stem-cell mobilization. Only one of five patients required autologous peripheral blood stem-cell transplantation during the median follow up time of 28 months. PBSC collection seems to be feasible in NET with bone-marrow involvement and might be worth considering as a backup strategy prior to PRRT, in order to overcome dose-limiting bone-marrow toxicity.
Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.
The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. Most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation. However, the factors predisposing individuals to severe disease remain poorly understood. Here, we show that levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells, are elevated in SARS-CoV-2-infected Caco-2 cells, Calu-3 cells, and air−liquid interface cultures of primary human bronchial epithelial cells. Moreover, SARS-CoV-2 infection increases SIRPalpha levels, the binding partner of CD47, on primary human monocytes. Systematic literature searches further indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels. High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions that may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury. Hence, age-related and virus-induced CD47 expression is a candidate mechanism potentially contributing to severe COVID-19, as well as a therapeutic target, which may be addressed by antibodies and small molecules. Further research will be needed to investigate the potential involvement of CD47 and SIRPalpha in COVID-19 pathology. Our data should encourage other research groups to consider the potential relevance of the CD47/ SIRPalpha axis in their COVID-19 research.
A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0–3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-β signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.
Background: To test the effect of urological primary cancers (bladder, kidney, testis, upper tract, penile, urethral) on overall mortality (OM) after secondary prostate cancer (PCa). Methods: Within the Surveillance, Epidemiology and End Results (SEER) database, patients with urological primary cancers and concomitant secondary PCa (diagnosed 2004-2016) were identified and were matched in 1:4 fashion with primary PCa controls. OM was compared between secondary and primary PCa patients and stratified according to primary urological cancer type, as well as to time interval between primary urological cancer versus secondary PCa diagnoses. Results: We identified 5,987 patients with primary urological and secondary PCa (bladder, n = 3,287; kidney, n = 2,127; testis, n = 391; upper tract, n = 125; penile, n = 47; urethral, n = 10) versus 531,732 primary PCa patients. Except for small proportions of Gleason grade group and age at diagnosis, PCa characteristics between secondary and primary PCa were comparable. Conversely, proportions of secondary PCa patients which received radical prostatectomy were smaller (29.0 vs. 33.5%), while no local treatment rates were higher (34.2 vs. 26.3%). After 1:4 matching, secondary PCa patients exhibited worse OM than primary PCa patients, except for primary testis cancer. Here, no OM differences were recorded. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis. Conclusions: After detailed matching for PCa characteristics, secondary PCa patients exhibit worse survival, except for testis cancer patients. The survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary urological cancer diagnosis.