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Aims: The primary safety and efficacy endpoints of the randomized FIRE AND ICE trial have recently demonstrated non-inferiority of cryoballoon vs. radiofrequency current (RFC) catheter ablation in patients with drug-refractory symptomatic paroxysmal atrial fibrillation (AF). The aim of the current study was to assess outcome parameters that are important for the daily clinical management of patients using key secondary analyses. Specifically, reinterventions, rehospitalizations, and quality-of-life were examined in this randomized trial of cryoballoon vs. RFC catheter ablation.
Methods and results: Patients (374 subjects in the cryoballoon group and 376 subjects in the RFC group) were evaluated in the modified intention-to-treat cohort. After the index ablation, log-rank testing over 1000 days of follow-up demonstrated that there were statistically significant differences in favour of cryoballoon ablation with respect to repeat ablations (11.8% cryoballoon vs. 17.6% RFC; P = 0.03), direct-current cardioversions (3.2% cryoballoon vs. 6.4% RFC; P = 0.04), all-cause rehospitalizations (32.6% cryoballoon vs. 41.5% RFC; P = 0.01), and cardiovascular rehospitalizations (23.8% cryoballoon vs. 35.9% RFC; P < 0.01). There were no statistical differences between groups in the quality-of-life surveys (both mental and physical) as measured by the Short Form-12 health survey and the EuroQol five-dimension questionnaire. There was an improvement in both mental and physical quality-of-life in all patients that began at 6 months after the index ablation and was maintained throughout the 30 months of follow-up.
Conclusion: Patients treated with cryoballoon as opposed to RFC ablation had significantly fewer repeat ablations, direct-current cardioversions, all-cause rehospitalizations, and cardiovascular rehospitalizations during follow-up. Both patient groups improved in quality-of-life scores after AF ablation.
Clinical trial registration: ClinicalTrials.gov identifier: NCT01490814.
Summary: This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5–2 times higher and risk of discontinuation was significantly lower (P < 0.0001) with denosumab.
Introduction: Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse.
Methods: From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan–Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use.
Results: Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [n = 21,154] vs 20.9 % [i.v. ibandronate; n = 20,472] and 24.8 % [i.v. zoledronic acid; n = 3966] and 16.7–17.5 % [oral bisphosphonates; n = 114,401]; all P < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96–2.02, respectively; all P < 0.0001).
Conclusions: Two-year persistence with denosumab was 1.5–2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab than with bisphosphonates. A more detailed understanding of factors affecting medication-taking behavior may improve persistence and thereby reduce rates of fracture.
More than 30% of the world's population are anemic with serious economic consequences including reduced work capacity and other obstacles to national welfare and development. Red blood cell transfusion is the mainstay to correct anemia, but it is also 1 of the top 5 overused procedures. Patient blood management (PBM) is a proactive, patient-centered, and multidisciplinary approach to manage anemia, optimize hemostasis, minimize iatrogenic blood loss, and harness tolerance to anemia. Although the World Health Organization has endorsed PBM in 2010, many hospitals still seek guidance with the implementation of PBM in clinical routine. Given the use of proven change management principles, we propose simple, cost-effective measures enabling any hospital to reduce both anemia and red blood cell transfusions in surgical and medical patients. This article provides comprehensive bundles of PBM components encompassing 107 different PBM measures, divided into 6 bundle blocks acting as a working template to develop institutions' individual PBM practices for hospitals beginning a program or trying to improve an already existing program. A stepwise selection of the most feasible measures will facilitate the implementation of PBM. In this manner, PBM represents a new quality and safety standard.
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent lymphoma, but can transform into diffuse large B cell lymphoma (DLBCL), showing a more aggressive clinical behavior. Little is known about these cases on the molecular level. Therefore, the aim of the present study was to characterize DLBCL transformed from NLPHL (LP-DLBCL) by gene expression profiling (GEP). GEP revealed an inflammatory signature pinpointing to a specific host response. In a coculture model resembling this host response, DEV tumor cells showed an impaired growth behavior. Mechanisms involved in the reduced tumor cell proliferation included a downregulation of MYC and its target genes. Lack of MYC expression was also confirmed in 12/16 LP-DLBCL by immunohistochemistry. Furthermore, CD274/PD-L1 was upregulated in DEV tumor cells after coculture with T cells or monocytes and its expression was validated in 12/19 cases of LP-DLBCL. Thereby, our data provide new insights into the pathogenesis of LP-DLBCL and an explanation for the relatively low tumor cell content. Moreover, the findings suggest that treatment of these patients with immune checkpoint inhibitors may enhance an already ongoing host response in these patients.
Purpose: Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols.
Design: Of 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy.
Results: In MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis.
Conclusion: The MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases.
Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. Notably, 69% of ara-C-resistant samples show a good to fair response to BV6. Furthermore, combination treatment with ara-C and BV6 exerts additive effects in most samples. Whole-genome gene expression profiling identifies cell death, TNFR1 and NF-κB signaling among the top pathways that are activated by BV6 in BV6-sensitive, but not in BV6-resistant cases. Furthermore, sensitivity of primary AML blasts to BV6 correlates with significantly elevated expression levels of TNF and lower levels of XIAP in diagnostic samples, as well as with NPM1 mutation. In a large set of primary AML samples, these data provide novel insights into factors regulating Smac mimetic response in AML and have important implications for the development of Smac mimetic-based therapies and related diagnostics in AML.
The multifunctional protein p21Cip1/CDKN1A (p21) is an important and universal Cdk-interacting protein. Recently, we have reported that p21 is involved in the regulation of the mitotic kinase Cdk1/cyclin B1 and critical for successful mitosis and cytokinesis. In the present work we show that S130 of p21 is phosphorylated by Cdk1/cyclin B1 during mitosis, which reduces p21’s stability and binding affinity to Cdk1/cyclin B1. Interfering with this phosphorylation results in extended mitotic duration and defective chromosome segregation, indicating that this regulation ensures proper mitotic progression. Given that p53, the major transcriptional activator of p21, is the most frequently mutated gene in human cancer and that deregulated Cdk1 associates with the development of different types of cancer, this work provides new insight into the understanding of how deregulated p21 contributes to chromosomal instability and oncogenesis.
Impact of Polo-like kinase 1 inhibitors on human adipose tissue-derived mesenchymal stem cells
(2016)
Polo-like kinase 1 (Plk1) has been established as one of the most promising targets for molecular anticancer intervention. In fact, various Plk1 inhibitors have been identified and characterized. While the data derived from the bench are prospective, the clinical outcomes are less encouraging by showing modest efficacy. One of the explanations for this discrepancy could be unintendedly targeting of non-malignant cells by Plk1 inhibitors. In this work, we have addressed the effect of Plk1 inhibition in adipose tissue-derived mesenchymal stem cells (ASCs). We show that both visceral and subcutaneous ASCs display monopolar spindles, reduced viability and strong apoptosis induction upon treatment with BI 2536 and BI 6727, the Plk1 kinase domain inhibitors, and with Poloxin, the regulatory Polo-box domain inhibitor. While Poloxin triggers quickly apoptosis, BI 2536 and BI 6727 result in mitotic arrest in ASCs. Importantly, survived ASCs exhibit DNA damage and a pronounced senescent phenotype. In addition, Plk1 inhibition impairs ASCs’ motility and homing ability. These results show that Plk1 inhibitors target slowly proliferating ASCs, an important population of anti-inflammation and immune modulation. The toxic effects on primary cells like ASCs could be partially responsible for the reported moderate antitumor activity in patients treated with Plk1 inhibitors.
Although the mechanistic target of rapamycin (mTOR) inhibitor, everolimus, has improved the outcome of patients with renal cell carcinoma (RCC), improvement is temporary due to the development of drug resistance. Since many patients encountering resistance turn to alternative/complementary treatment options, an investigation was initiated to evaluate whether the natural compound, sulforaphane (SFN), influences growth and invasive activity of everolimus-resistant (RCCres) compared to everolimus-sensitive (RCCpar) RCC cell lines in vitro. RCC cells were exposed to different concentrations of SFN and cell growth, cell proliferation, apoptosis, cell cycle, cell cycle regulating proteins, the mTOR-akt signaling axis, adhesion to human vascular endothelium and immobilized collagen, chemotactic activity, and influence on surface integrin receptor expression were investigated. SFN caused a significant reduction in both RCCres and RCCpar cell growth and proliferation, which correlated with an elevation in G2/M- and S-phase cells. SFN induced a marked decrease in the cell cycle activating proteins cdk1 and cyclin B and siRNA knock-down of cdk1 and cyclin B resulted in significantly diminished RCC cell growth. SFN also modulated adhesion and chemotaxis, which was associated with reduced expression of the integrin subtypes α5, α6, and β4. Distinct differences were seen in RCCres adhesion and chemotaxis (diminished by SFN) and RCCpar adhesion (enhanced by SFN) and chemotaxis (not influenced by SFN). Functional blocking of integrin subtypes demonstrated divergent action on RCC binding and invasion, depending on RCC cell sensitivity to everolimus. Therefore, SFN administration could hold potential for treating RCC patients with established resistance towards everolimus.
EUSOBI and 30 national breast radiology bodies support mammography for population-based screening, demonstrated to reduce breast cancer (BC) mortality and treatment impact. According to the International Agency for Research on Cancer, the reduction in mortality is 40 % for women aged 50–69 years taking up the invitation while the probability of false-positive needle biopsy is <1 % per round and overdiagnosis is only 1–10 % for a 20-year screening. Mortality reduction was also observed for the age groups 40–49 years and 70–74 years, although with “limited evidence”. Thus, we firstly recommend biennial screening mammography for average-risk women aged 50–69 years; extension up to 73 or 75 years, biennially, is a second priority, from 40–45 to 49 years, annually, a third priority. Screening with thermography or other optical tools as alternatives to mammography is discouraged. Preference should be given to population screening programmes on a territorial basis, with double reading. Adoption of digital mammography (not film-screen or phosphor-plate computer radiography) is a priority, which also improves sensitivity in dense breasts. Radiologists qualified as screening readers should be involved in programmes. Digital breast tomosynthesis is also set to become “routine mammography” in the screening setting in the next future. Dedicated pathways for high-risk women offering breast MRI according to national or international guidelines and recommendations are encouraged.
We assessed the prognostic value of hypoxia (carbonic anhydrase 9; CA9), vessel density (CD31), with macrophages (CD68) and B cells (CD20) that can interact and lead to immune suppression and disease progression using scanning and histological mapping of whole-mount FFPE pancreatectomy tissue sections from 141 primarily resectable pancreatic ductal adenocarcinoma (PDAC) samples treated with surgery and adjuvant chemotherapy. Their expression was correlated with clinicopathological characteristics, and overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of stroma density (haematoxylin-eosin) and activity (alpha-smooth muscle actin). The median OS was 21 months after a mean follow-up of 20 months (range, 2–69 months). The median tumor surface area positive for CA9 and CD31 was 7.8% and 8.1%, respectively. Although total expression of these markers lacked prognostic value in the entire cohort, nevertheless, high tumor compartment CD68 expression correlated with worse PFS (p = 0.033) and DMFS (p = 0.047). Also, high CD31 expression predicted for worse OS (p = 0.004), PFS (p = 0.008), LPFS (p = 0.014) and DMFS (p = 0.004) in patients with moderate density stroma. High stromal and peripheral compartment CD68 expression predicted for significantly worse outcome in patients with loose and moderate stroma density, respectively. Altogether, in contrast to the current notion, hypoxia levels in PDAC appear to be comparable to other malignancies. CD31 and CD68 constitute prognostic markers in patient subgroups that vary according to tumor compartment and stromal density. Our study provides important insight on the pathophysiology of PDAC and should be exploited for future treatments.
Background: Few studies have evaluated the impact of pre-treatment drug resistance (PDR) on response to combination antiretroviral treatment (cART) in children. The objective of this joint EuroCoord-CHAIN-EPPICC/PENTA project was to assess the prevalence of PDR mutations and their association with virological outcome in the first year of cART in children.
Methods: HIV-infected children <18 years initiating cART between 1998 and 2008 were included if having at least one genotypic resistance test prior to cART initiation. We used the World Health Organization 2009 resistance mutation list and Stanford algorithm to infer resistance to prescribed drugs. Time to virological failure (VF) was defined as the first of two consecutive HIV-RNA > 500 copies/mL after 6 months cART and was assessed by Cox proportional hazards models. All models were adjusted for baseline demographic, clinical, immunology and virology characteristics and calendar period of cART start and initial cART regimen.
Results: Of 476 children, 88 % were vertically infected. At cART initiation, median (interquartile range) age was 6.6 years (2.1–10.1), CD4 cell count 297 cells/mm3 (98–639), and HIV-RNA 5.2 log10copies/mL (4.7–5.7). Of 37 children (7.8 %, 95 % confidence interval (CI), 5.5–10.6) harboring a virus with ≥1 PDR mutations, 30 children had a virus resistant to ≥1 of the prescribed drugs. Overall, the cumulative Kaplan-Meier estimate for virological failure was 19.8 % (95 %CI, 16.4–23.9). Cumulative risk for VF tended to be higher among children harboring a virus with PDR and resistant to ≥1 drug prescribed than among those receiving fully active cART: 32.1 % (17.2–54.8) versus 19.4 % (15.9–23.6) (P = 0.095). In multivariable analysis, age was associated with a higher risk of VF with a 12 % reduced risk per additional year (HR 0.88; 95 %CI, 0.82–0.95; P < 0.001).
Conclusions: PDR was not significantly associated with a higher risk of VF in children in the first year of cART. The risk of VF decreased by 12 % per additional year at treatment initiation which may be due to fading of PDR mutations over time. Lack of appropriate formulations, in particular for the younger age group, may be an important determinant of virological failure.
Influence of the sFlt-1/PlGF ratio on clinical decision-making in women with suspected preeclampsia
(2016)
Objective: To evaluate the influence of the soluble fms-like tyrosine kinase 1/placental growth factor ratio in physicians’ decision making in pregnant women with signs and symptoms of preeclampsia in routine clinical practice.
Methods: A multicenter, prospective, open, non-interventional study enrolled pregnant women presenting with preeclampsia signs and symptoms in several European perinatal care centers. Before the soluble fms-like tyrosine kinase 1/placental growth factor ratio result was known, physicians documented intended clinical procedures using an iPad® application (data locked/time stamped). After the result was available, clinical decisions were confirmed or revised and documented. An independent adjudication committee evaluated the appropriateness of decisions based on maternal/fetal outcomes. Clinician decision making with regard to hospitalization was the primary outcome.
Results: In 16.9% of mothers (20/118) the hospitalization decision was changed after knowledge of the ratio. In 13 women (11.0%), the initial decision to hospitalize was changed to no hospitalization. In seven women (5.9%) the revised decision was hospitalization. All revised decisions were considered appropriate by the panel of adjudicators (McNemar test; p < 0.0001).
Conclusions: The use of the soluble fms-like tyrosine kinase 1/placental growth factor test influenced clinical decision making towards appropriate hospitalization in a considerable proportion of women with suspected preeclampsia. This is the first study to demonstrate the impact of angiogenic biomarkers on decision making in a routine clinical practice.
Background: Hemodynamic instability is frequent and outcome-relevant in critical illness. The understanding of complex hemodynamic disturbances and their monitoring and management plays an important role in treatment of intensive care patients. An increasing number of treatment recommendations and guidelines in intensive care medicine emphasize hemodynamic goals, which go beyond the measurement of blood pressures. Yet, it is not known to which extent the infrastructural prerequisites for extended hemodynamic monitoring are given in intensive care units (ICUs) and how hemodynamic management is performed in clinical practice. Further, it is still unclear which factors trigger the use of extended hemodynamic monitoring.
Methods: In this multicenter, 1-day (November 7, 2013, and the preceding 24 h) cross-sectional study, we retrieved data on patient monitoring from ICUs in Germany, Austria, and Switzerland by means of a web-based case report form. One hundred and sixty-one intensive care units contributed detailed information on availability of hemodynamic monitoring. In addition, detailed information on hemodynamic monitoring of 1789 patients that were treated on due date was collected, and independent factors triggering the use of extended hemodynamic monitoring were identified by multivariate analysis.
Results: Besides basic monitoring with electrocardiography (ECG), pulse oximetry, and blood pressure monitoring, the majority of patients received invasive arterial (77.9 %) and central venous catheterization (55.2 %). All over, additional extended hemodynamic monitoring for assessment of cardiac output was only performed in 12.3 % of patients, while echocardiographic examination was used in only 1.9 %. The strongest independent predictors for the use of extended hemodynamic monitoring of any kind were mechanical ventilation, the need for catecholamine therapy, and treatment backed by protocols. In 71.6 % of patients in whom extended hemodynamic monitoring was added during the study period, this extension led to changes in treatment.
Conclusions: Extended hemodynamic monitoring, which goes beyond the measurement of blood pressures, to date plays a minor role in the surveillance of critically ill patients in German, Austrian, and Swiss ICUs. This includes also consensus-based recommended diagnostic and monitoring applications, such as echocardiography and cardiac output monitoring. Mechanical ventilation, the use of catecholamines, and treatment backed by protocol could be identified as factors independently associated with higher use of extended hemodynamic monitoring.
Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug’s mechanism of action.
Background: Community acquired viruses (CRVs) may cause severe disease in cancer patients. Thus, efforts should be made to diagnose CRV rapidly and manage CRV infections accordingly.
Methods: A panel of 18 clinicians from the Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology have convened to assess the available literature and provide recommendations on the management of CRV infections including influenza, respiratory syncytial virus, parainfluenza virus, human metapneumovirus and adenovirus.
Results: CRV infections in cancer patients may lead to pneumonia in approximately 30% of the cases, with an associated mortality of around 25%. For diagnosis of a CRV infection, combined nasal/throat swabs or washes/aspirates give the best results and nucleic acid amplification based-techniques (NAT) should be used to detect the pathogen. Hand hygiene, contact isolation and face masks have been shown to be of benefit as general infection management. Causal treatment can be given for influenza, using a neuraminidase inhibitor, and respiratory syncytial virus, using ribavirin in addition to intravenous immunoglobulins. Ribavirin has also been used to treat parainfluenza virus and human metapneumovirus, but data are inconclusive in this setting. Cidofovir is used to treat adenovirus pneumonitis.
Conclusions: CRV infections may pose a vital threat to patients with underlying malignancy. This guideline provides information on diagnosis and treatment to improve the outcome.
Background: Shortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12.
Methods: In this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0–F2 fibrosis, patients with HCV-RNA <25 IU/mL (detectable/undetectable) at Week 2, and undetectable HCV-RNA at Weeks 4 and 8, stopped all treatment at Week 12. All other patients continued PR for a further 12 weeks. Baseline factors significantly associated with SVR12 were identified through logistic regression.
Results: Of 163 patients who participated in the study, 123 (75%) qualified for 12-week treatment; of these, 81 (66%) achieved SVR12. Baseline factors positively associated with SVR12 rates in patients receiving the 12-week regimen were: IL28B CC genotype: (94% SVR12); HCV RNA ≤800,000 IU/mL (82%); F0–F1 fibrosis (74%). Among all 163 patients, 94% experienced ≥1 adverse event (AE), 4% a serious AE, and 2.5% discontinued due to an AE. Reduced impairment in patient-reported outcomes was observed in the 12-week vs >12-week regimen.
Conclusions: Overall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen.
Trial Registration: ClinicalTrials.gov NCT01846832
Background: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Growing evidence indicates that tumor-initiating cells (TICs) are responsible for tumor growth and progression. Conventional chemotherapeutics do not sufficiently eliminate TICs, leading to tumor relapse. We aimed to gain insight into TIC biology by comparing the transcriptome of primary TIC cultures and their normal stem cell counterparts to uncover expression differences.
Methods: We established colonosphere cultures derived from the resection of paired specimens of primary tumor and normal mucosa in patients with CRC. These colonospheres, enriched for TICs, were used for differential transcriptome analyses to detect new targets for a TIC-directed therapy. Effects of target inhibition on CRC cells were studied in vitro and in vivo.
Results: Pathway analysis of the regulated genes showed enrichment of genes central to PI3K/AKT and Wnt-signaling. We identified CD133 as a marker for a more aggressive CRC subpopulation enriched with TICs in SW480 CRC cells in an in vivo cancer model. Treatment of CRC cells with the selective AKT inhibitor MK-2206 caused a decrease in cell proliferation, particularly in the TIC fraction, resulting in a significant reduction of the stemness capacity to form colonospheres in vitro and to initiate tumor formation in vivo. Consequently, MK-2206 treatment of mice with established xenograft tumors exhibited a significant deceleration of tumor progression. Primary patient-derived tumorsphere growth was significantly inhibited by MK-2206.
Conclusion: This study reveals that AKT signaling is critical for TIC proliferation and can be efficiently targeted by MK-2206 representing a preclinical therapeutic strategy to repress colorectal TICs.
Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69 ± .06 for the cohort without IT and .69 ± .10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21 ± .05, 3-year CITRM, .10 ± .04; IT patients: 3-year CIR, .18 ± .09, 3-year CITRM .13 ± .07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL.
Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.
Natural Killer (NK) cells are active against Aspergillus fumigatus, which in turn is able to impair the host defense. Unfortunately, little is known on the mutual interaction of NK cells and A. fumigatus. We coincubated human NK cells with A. fumigatus hyphae and assessed the gene expression and protein concentration of selected molecules. We found that A. fumigatus up-regulates the gene expression of pro-inflammatory molecules in NK cells, but inhibited the release of these molecules resulting in intracellular accumulation and limited extracellular availability. A. fumigatus down-regulatedmRNA levels of perforin in NK cells, but increased its intra- and extracellular protein concentration. The gene expression of stress related molecules of A. fumigatus such as heat shock protein hsp90 was up-regulated by human NK cells. Our data characterize for the first time the immunosuppressive effect of A. fumigatus on NK cells and may help to develop new therapeutic antifungal strategies.
We have recently shown that caspase-8 is a new substrate of Polo-like kinase 3 (Plk3) that phosphorylates the protein on residue T273 thereby promoting its pro-apoptotic function. In the present study we aimed to investigate the clinical relevance of Plk3 expression and phosphorylation of caspase-8 at T273 in patients with anal squamous cell carcinoma (SSC) treated with 5-fluorouracil and mitomycin C-based chemoradiotherapy (CRT). Immunohistochemical detection of the markers was performed in pretreatment biopsy specimens of 95 patients and was correlated with clinical/histopathologic characteristics including HPV-16 virus load/p16INK4a expression and cumulative incidence of local and distant failure, cancer specific survival (CSS), and overall survival (OS). We observed significant positive correlations between Plk3 expression, pT273 caspase-8 signal, and levels of HPV-16 virus DNA load/p16INK4a detection. Patients with high scores of Plk3 and pT273 caspase-8 showed increased local control (p = 0.011; p = 0.001), increased CSS (p = 0.011; p = 0.013) and OS (p = 0.024; p = 0.001), while the levels of pT273 caspase-8 were significantly associated (p = 0.033) with distant metastases. In multivariate analyses Plk3 expression remained significant for local failure (p = 0.018), CSS (p = 0.016) and OS (p = 0.023). Moreover, a combined HPV16 DNA load and Plk3 or pT273 caspase-8 variable revealed a significant correlation to decreased local failure (p = 0.001; p = 0.009), increased CSS (p = 0.016; p = 0.023) and OS (p = 0.003; p = 0.003). In conclusion these data indicate that elevated levels of Plk3 and pT273 caspase-8 are correlated with favorable clinical outcome in patients with anal SCC treated with concomitant CRT.
Renal cell carcinoma alters endothelial receptor expression responsible for leukocyte adhesion
(2016)
Renal cell carcinoma (RCC) escapes immune recognition. To elaborate the escape strategy the influence of RCC cells on endothelial receptor expression and endothelial leukocyte adhesion was evaluated. Human umbilical vein endothelial cells (HUVEC) were co-cultured with the RCC cell line, Caki-1, with and without tumor necrosis factor (TNF)-alpha. Intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelial (E)-selectin, standard and variants (V) of CD44 were then analysed in HUVEC, using flow cytometry and Western blot analysis. To determine which components are responsible for HUVEC-Caki-1 interaction causing receptor alteration, Caki-1 membrane fragments versus cell culture supernatant were applied to HUVECS. Adhesion of peripheral blood lymphocytes (PBL) and polymorphonuclear neutrophils (PMN) to endothelium was evaluated by co-culture adhesion assays. Relevance of endothelial receptor expression for adhesion to endothelium was determined by receptor blockage. Co-culture of RCC and HUVECs resulted in a significant increase in endothelial ICAM-1, VCAM-1, E-selectin, CD44 V3 and V7 expression. Previous stimulation of HUVECs with TNF-alpha and co-cultivation with Caki-1 resulted in further elevation of endothelial CD44 V3 and V7 expression, whereas ICAM-1, VCAM-1 and E-selectin expression were significantly diminished. Since Caki-1 membrane fragments also caused these alterations, but cell culture supernatant did not, cell-cell contact may be responsible for this process. Blocking ICAM-1, VCAM-1, E-selectin or CD44 with respective antibodies led to a significant decrease in PBL and PMN adhesion to endothelium. Thus, exposing HUVEC to Caki-1 results in significant alteration of endothelial receptor expression and subsequent endothelial attachment of PBL and PMN.
Purpose: Few individuals that are latently infected with M. tuberculosis latent tuberculosis infection(LTBI) progress to active disease. We investigated risk factors for LTBI and active pulmonary tuberculosis (PTB) in Germany.
Methods: Healthy household contacts (HHCs), health care workers (HCWs) exposed to M. tuberculosis and PTB patients were recruited at 18 German centres. Interferon-γ release assay (IGRA) testing was performed. LTBI risk factors were evaluated by comparing IGRA-positive with IGRA-negative contacts. Risk factors for tuberculosis were evaluated by comparing PTB patients with HHCs.
Results: From 2008–2014, 603 HHCs, 295 HCWs and 856 PTBs were recruited. LTBI was found in 34.5% of HHCs and in 38.9% of HCWs. In HCWs, care for coughing patients (p = 0.02) and longstanding nursing occupation (p = 0.04) were associated with LTBI. In HHCs, predictors for LTBI were a diseased partner (odds ratio 4.39), sexual contact to a diseased partner and substance dependency (all p < 0.001). PTB was associated with male sex, low body weight (p < 0.0001), alcoholism (15.0 vs 5.9%; p < 0.0001), glucocorticoid therapy (7.2 vs 2.0%; p = 0.004) and diabetes (7.8 vs. 4.0%; p = 0.04). No contact developed active tuberculosis within 2 years follow-up.
Conclusions: Positive IGRA responses are frequent among exposed HHCs and HCWs in Germany and are poor predictors for the development of active tuberculosis.
Measuring NADPH oxidase (Nox)-derived reactive oxygen species (ROS) in living tissues and cells is a constant challenge. All probes available display limitations regarding sensitivity, specificity or demand highly specialized detection techniques. In search for a presumably easy, versatile, sensitive and specific technique, numerous studies have used NADPH-stimulated assays in membrane fractions which have been suggested to reflect Nox activity. However, we previously found an unaltered activity with these assays in triple Nox knockout mouse (Nox1-Nox2-Nox4-/-) tissue and cells compared to wild type. Moreover, the high ROS production of intact cells overexpressing Nox enzymes could not be recapitulated in NADPH-stimulated membrane assays. Thus, the signal obtained in these assays has to derive from a source other than NADPH oxidases. Using a combination of native protein electrophoresis, NADPH-stimulated assays and mass spectrometry, mitochondrial proteins and cytochrome P450 were identified as possible source of the assay signal. Cells lacking functional mitochondrial complexes, however, displayed a normal activity in NADPH-stimulated membrane assays suggesting that mitochondrial oxidoreductases are unlikely sources of the signal. Microsomes overexpressing P450 reductase, cytochromes b5 and P450 generated a NADPH-dependent signal in assays utilizing lucigenin, L-012 and dihydroethidium (DHE). Knockout of the cytochrome P450 reductase by CRISPR/Cas9 technology (POR-/-) in HEK293 cells overexpressing Nox4 or Nox5 did not interfere with ROS production in intact cells. However, POR-/- abolished the signal in NADPH-stimulated assays using membrane fractions from the very same cells. Moreover, membranes of rat smooth muscle cells treated with angiotensin II showed an increased NADPH-dependent signal with lucigenin which was abolished by the knockout of POR but not by knockout of p22phox. In conclusion: the cytochrome P450 system accounts for the majority of the signal of Nox activity chemiluminescence based assays.
Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases.
Bone losses are common as a consequence of unloading and also in patients with chronic obstructive pulmonary disease (COPD). Although hypoxia has been implicated as an important factor to drive bone loss, its interaction with unloading remains unresolved. The objective therefore was to assess whether human bone loss caused by unloading could be aggravated by chronic hypoxia.
In a cross-over designed study, 14 healthy young men underwent 21-day interventions of bed rest in normoxia (NBR), bed rest in hypoxia (HBR), and hypoxic ambulatory confinement (HAmb). Hypoxic conditions were equivalent to 4000 m altitude. Bone metabolism (NTX, P1NP, sclerostin, DKK1) and phospho-calcic homeostasis (calcium and phosphate serum levels and urinary excretion, PTH) were assessed from regular blood samples and 24-hour urine collections, and tibia and femur bone mineral content was assessed by peripheral quantitative computed tomography (pQCT).
Urinary NTX excretion increased (P < 0.001) to a similar extent in NBR and HBR (P = 0.69) and P1NP serum levels decreased (P = 0.0035) with likewise no difference between NBR and HBR (P = 0.88). Serum total calcium was increased during bed rest by 0.059 (day D05, SE 0.05 mM) to 0.091 mM (day D21, P < 0.001), with no additional effect by hypoxia during bed rest (P = 0.199). HAmb led, at least temporally, to increased total serum calcium, to reduced serum phosphate, and to reduced phosphate and calcium excretion.
In conclusion, hypoxia did not aggravate bed rest-induced bone resorption, but led to changes in phospho-calcic homeostasis likely caused by hyperventilation. Whether hyperventilation could have mitigated the effects of hypoxia in this study remains to be established.
Latent transforming growth factor beta binding protein 4 (LTBP4) belongs to the fibrillin/LTBP family of proteins and plays an important role as a structural component of extracellular matrix (ECM) and local regulator of TGFβ signaling. We have previously reported that Ltbp4S knock out mice (Ltbp4S −/−) develop centrilobular emphysema reminiscent of late stage COPD, which could be partially rescued by inactivating the antioxidant protein Sestrin 2 (Sesn2). More recent studies showed that Sesn2 knock out mice upregulate Pdgfrβ-controlled alveolar maintenance programs that protect against cigarette smoke induced pulmonary emphysema. Based on this, we hypothesized that the emphysema of Ltbp4S −/− mice is primarily caused by defective Pdgfrβ signaling. Here we show that LTBP4 induces Pdgfrβ signaling by inhibiting the antioxidant Nrf2/Keap1 pathway in a TGFβ-dependent manner. Overall, our data identified Ltbp4 as a major player in lung remodeling and injury repair.
Sequence type 131 (ST131) is one of the predominant Escherichia coli lineages among extraintestinal pathogenic E. coli (ExPEC) that causes a variety of diseases in humans and animals and frequently shows multidrug resistance. Here, we report the first genome sequence of an ST131-ExPEC strain from poultry carrying the plasmid-encoded colistin resistance gene mcr-1.
Background: Cancer screening participation rates in Germany differ depending on patients’ gender. International studies have found that patient–physician gender concordance fosters recommendation and conducting of cancer screening, and especially cancer screening for women.
Objectives: We aimed to ascertain whether gender concordance influences general practitioners' (GPs’) rating of the usefulness of cancer screening, as well as their recommendations and readiness to conduct cancer screening in general practice in Germany.
Methods: For an exploratory cross-sectional survey, 500 randomly selected GPs from all over Germany were asked to fill in a questionnaire on cancer screening in general practice between March and June 2015. We asked them to rate the usefulness of each cancer screening examination, how frequently they recommended and conducted them and whether they viewed GPs or specialists as responsible for carrying them out. We used multiple logistic regression to analyse gender effect size by calculating odds ratios.
Results: Our study sample consisted of 139 GPs of which 65% were male. Male and female GPs did not differ significantly in their rating of the general usefulness of any of the specified cancer screening examinations. Male GPs were 2.9 to 6.8 times as likely to consider GPs responsible for recommending and conducting PSA testing and digital rectal examinations and were 3.7 to 7.9 times as likely to recommend and conduct these examinations on a regular basis.
Conclusion: Patient–physician gender concordance made it more likely that male-specific cancer screenings would be recommended and conducted, but not female-specific screenings.
Congenital sensory deprivation can lead to reorganization of the deprived cortical regions by another sensory system. Such cross-modal reorganization may either compete with or complement the “original“ inputs to the deprived area after sensory restoration and can thus be either adverse or beneficial for sensory restoration. In congenital deafness, a previous inactivation study documented that supranormal visual behavior was mediated by higher-order auditory fields in congenitally deaf cats (CDCs). However, both the auditory responsiveness of “deaf” higher-order fields and interactions between the reorganized and the original sensory input remain unknown. Here, we studied a higher-order auditory field responsible for the supranormal visual function in CDCs, the auditory dorsal zone (DZ). Hearing cats and visual cortical areas served as a control. Using mapping with microelectrode arrays, we demonstrate spatially scattered visual (cross-modal) responsiveness in the DZ, but show that this did not interfere substantially with robust auditory responsiveness elicited through cochlear implants. Visually responsive and auditory-responsive neurons in the deaf auditory cortex formed two distinct populations that did not show bimodal interactions. Therefore, cross-modal plasticity in the deaf higher-order auditory cortex had limited effects on auditory inputs. The moderate number of scattered cross-modally responsive neurons could be the consequence of exuberant connections formed during development that were not pruned postnatally in deaf cats. Although juvenile brain circuits are modified extensively by experience, the main driving input to the cross-modally (visually) reorganized higher-order auditory cortex remained auditory in congenital deafness.
Periods of rhythmic slow-wave activity during physiological slow-wave sleep or induced by anesthesia are characterized by a waxing and waning of spontaneous neuronal firing coordinated between cortex and thalamus. This activity is generated in the cortex but influences neuronal excitability and stimulus–response properties of neuronal networks throughout the brain (Steriade et al., 1993; Stroh et al., 2013; McGinley et al., 2015b). The corresponding low-frequency component of field potential recordings reflects alternating active states, in which cells are depolarized and synaptic activity is high, and silent states with hyperpolarized membrane potentials and low synaptic activity (Steriade et al., 2001; Timofeev et al., 2001). In contrast, waking is generally associated with continuous depolarization of cortical neurons, resulting in persistent activity (Destexhe et al., 2007; Sheroziya and Timofeev, 2015) and suppression of silent states (Steriade et al., 2001; McGinley et al., 2015b). In their recent study, Sheroziya and Timofeev (2015) demonstrated that moderate cortical cooling (to 29–31°C) of lightly ketamine/xylazin (ket/xyl) anesthetized or non-anesthetized mice reversibly diminished silent states and induced a persistent active state of the cortex. Mild heating (to 39–40°C), in contrast, increased rhythmicity of slow waves. Under deep ket/xyl anesthesia, cortical cooling disrupted slow waves and promoted bursts of activity correlated with thalamic firing. Local cooling of somatosensory cortex was shown to be sufficient to induce a shift from slow-wave to wide-spread persistent cortical activity, extending to the thalamus as well as the contralateral hemisphere. These results suggest that cortical temperature change can be used as a bidirectional and reversible tool for investigating global brain state fluctuations, and provide evidence that the thalamocortical network rapidly reacts upon local depolarization of a small neuronal population with wide-spread shifts of brain state. ...
Background: Cytokine-induced-killer (CIK) cells are a promising immunotherapeutic approach for impending relapse following hematopoietic stem cell transplantation (HSCT). However, there is a high risk for treatment failure associated with severe graft versus host disease (GvHD) necessitating pharmaceutical intervention post-transplant. Whether immunosuppression with mycophenolate mofetil (MMF) or Ciclosporin A (CsA) influences the cytotoxic effect of CIK cell immunotherapy is still an open issue.
Methods: CIK cells were generated from PBMC as previously described followed by co-incubation with mycophenolic acid (MPA) or CsA. Proliferation, cytotoxicity and receptor expression were investigated following short- (24 h), intermediate- (3 days) and long-term (7 days) MPA incubation with the intention to simulate the in vivo situation when CIK cells were given to a patient with relevant MPA/CsA plasma levels.
Results: Short-term MPA treatment led to unchanged proliferation capacity and barely had any effect on viability and cytotoxic capability in vitro. The composition of CIK cells with respect to T-, NK-like T- and NK cells remained stable. Intermediate MPA treatment lacked effects on NKG2D, FasL and TRAIL receptor expression, while an influence on proliferation and viability was detectable. Furthermore, long-term treatment significantly impaired proliferation, restricted viability and drastically reduced migration-relevant receptors accompanied by an alteration in the CD4/CD8 ratio. CD3+CD56+ cells upregulated receptors relevant for CIK cell killing and migration, whereas T cells showed the most interference through significant reductions in receptor expression. Interestingly, CsA treatment had no significant influence on CIK cell viability and the cytotoxic potential against K562.
Conclusions: Our data indicate that if immunosuppressant therapy is indispensable, efficacy of CIK cells is maintained at least short-term, although more frequent dosing might be necessary.
Alle lebenden Organismen sind in der Lage, sich an den re-gelmäßigen Wechsel von Licht und Dunkelheit und den zeitli-che Veränderungen im Takt der Jahreszeiten anzupassen. Die-se Synchronisierung der Aktivitäts- und Ruhephasen, sowie von physiologischen Stoffwechselprozessen an die vorgegebe-nen tageszeitlichen und saisonalen Zyklen findet beim Säu-getier in der inneren Uhr im Nucleus Suprachiasmaticus (SCN) statt. Das Licht, als wichtigster Zeitgeber für die Synchronisation der inneren Uhr, findet Eingang zum SCN über die Retina und den retinohypothalamischen Trakt (RTH), der Glutamat als Neurotransmitter nutzt. Ist dieses System fehlerhaft, führt dies zu Störung der oben beschriebenen Anpassungsprozesse. Dies hat eine gestörte Homöostase des Organismus zu Folge, aus denen sich wiederum Veränderungen im Tag/Nacht- Rhythmus, Schlafstörungen und depressive Ver-stimmungen ergeben können. Die genannten Symptome decken sich mit den Frühsymptomen den neurodegenerativen Erkran-kung Morbus Parkinson.
Ziel der vorliegenden Arbeit war es, Störungen im photoneu-roendokrinen System, insbesondere Veränderungen in der Re-tina an den photosensitiven Ganglienzellen mit dem Photo-pigment Melanopsin und dem SCN bei transgene Mäuse mit dem humanen alpha-Synuclein zu untersuchen. Hierbei wurden transgene Mäuse mit dem gesunden humanen alpha-Synuclein (Wildtyp) und transgene Mäuse mit der für Parkinson spezi-fischen Mutation im alpha-Synuclein Ala53Thr (A53T) vergli-chen.
Die immunochemischen Untersuchungen an Retina und SCN zei-gen einen signifikanten Anstieg der alpha-Synuclein Immun-reaktion bei der A53T Maus im Vergleich zum Wildtyp.
Parallel dazu wurden Unterschiede in Bezug auf das Photo-pigment Melanopsin zwischen den beiden Gruppen untersucht. Melanopsin ist lichtsensitiv und trägt, durch Übermittlung der aktuellen Lichtverhältnisse über den retinohypothalami-schen Trakt zum SCN, zur Synchronisation der circadianen Rhythmik bei. Durch den in dieser Arbeit nachgewiesene Me-lanopsindefizit und des deutlich reduzierten Vglut2 im hy-pothalamischen Trakt der A53T Maus lässt sich die Hypothese ableiten, dass möglicherweise die Überexpression des mu-tierten alpha-Synuclein in der Retina einen Untergang von melanopsinhaltigen Ganglienzellen herbeiführt und dadurch die Synchronisation der inneren Uhr durch Licht gestört ist. Diese Hypothese wird durch die Aktivitätsprofile ge-stützt, die durch die Aufzeichnung der lokomotorischen Ak-tivität der Tiere erstellt wurden.
Da in beiden Gruppen unter Dauerdunkel (DD) ein endogener zirkadianer Rhythmus beobachtet werden konnte, lässt dies auf die Funktionstüchtigkeit der inneren Uhr im SCN schlie-ßen. Im anschließenden Versuch die endogene Rhythmik an exogenen Reize anzupassen, zeigte sich bei dem A53T Stamm eine fehlende Synchronisierung an vorgegebene Lichtverhält-nisse mit gesteigerter Tagaktivität und reduzierten Schlaf-phasen. Somit trägt der fehlerhaft verarbeitete Lichtreiz bei A53T Mutanten zur Destabilisierung des zirkadianen Rhythmus der Lokomotion bei. Trotz des gestörten glutama-tergen Signalweges im retinohypothalamischen Trakt konnten keine Unterschiede in der Expression der Homerproteine zwi-schen Wildtyp und A53T unter Standard-Photoperiode und nach Schlafdeprivation nachgewiesen werden.
Die vorliegenden Befunde liefern Erkenntnisse zur Entste-hung der Frühsymptome bei Morbus Parkinson. Dies könnte neue Ansatzpunkte für die Therapie und Linderung von Schlafstörungen sowie Veränderungen im Tag/Nachtrhythmus liefern.
Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8
(2016)
Upon interaction of the CD95 receptor with its ligand, sequential association of the adaptor molecule FADD (MORT1), pro-forms of caspases-8/10, and the caspase-8/10 regulator c-FLIP leads to the formation of a death-inducing signaling complex. Here, we identify polo-like kinase (Plk) 3 as a new interaction partner of the death receptor CD95. The enzymatic activity of Plk3 increases following interaction of the CD95 receptor with its ligand. Knockout (KO) or knockdown of caspase-8, CD95 or FADD prevents activation of Plk3 upon CD95 stimulation, suggesting a requirement of a functional DISC for Plk3 activation. Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. Stimulation of CD95 in cells expressing a non-phosphorylatable caspase-8-T273A mutant in a rescue experiment or in Plk3-KO cells generated by CRISPR/Cas9 reduces the processing of caspase-8 prominently. Low T273 phosphorylation correlates significantly with low Plk3 expression in a cohort of 95 anal tumor patients. Our data suggest a novel mechanism of kinase activation within the Plk family and propose a new model for the stimulation of the extrinsic death pathway in tumors with high Plk3 expression.
Objectives: This study aimed to analyse and compare differences in occupational stress, depressive symptoms, work ability and working environment among residents working in various medical specialties.
Methods: 435 German hospital residents in medical training working in 6 different medical specialties participated in a cross-sectional survey study. Physicians were asked about their working conditions and aspects of mental health and work ability. The Copenhagen Psychosocial Questionnaire, the Work Ability Index, the ICD-10 Symptom Rating and the Perceived Stress Questionnaire were used to measure working conditions, mental health and work ability.
Results: Results show that up to 17% of the physicians reported high levels of occupational distress and 9% reported high levels of depressive symptoms. 11% of the hospital physicians scored low in work ability. Significant differences between medical specialties were demonstrated for occupational distress, depressive symptoms, work ability, job demands and job resources. Surgeons showed consistently the highest levels of perceived distress but also the highest levels of work ability and lowest scores for depression. Depressive symptoms were rated with the highest levels by anaesthesiologists. Significant associations between physicians’ working conditions, occupational distress and mental health-related aspects are illustrated.
Conclusions: Study results demonstrated significant differences in specific job stressors, demands and resources. Relevant relations between work factors and physicians' health and work ability are discussed. These findings should be reinvestigated in further studies, especially with a longitudinal study design. This work suggests that to ensure physicians' health, hospital management should plan and implement suitable mental health promotion strategies. In addition, operational efficiency through resource planning optimisation and work process improvements should be focused by hospital management.
Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.
Purpose: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).
Methods: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).
Results: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).
Conclusion: Both PLD and capecitabine are effective first-line agents for MBC.
Loss of HIF-1α in macrophages attenuates AhR/ARNT-mediated tumorigenesis in a PAH-driven tumor model
(2016)
Activation of hypoxia-inducible factor (HIF) and macrophage infiltration of solid tumors independently promote tumor progression. As little is known how myeloid HIF affects tumor development, we injected the polycyclic aromatic hydrocarbon (PAH) and procarcinogen 3-methylcholanthrene (MCA; 100 μg/100 μl) subcutaneously into myeloid-specific Hif-1α and Hif-2α knockout mice (C57BL/6J) to induce fibrosarcomas (n = 16). Deletion of Hif-1α but not Hif-2α in macrophages diminished tumor outgrowth in the MCA-model. While analysis of the tumor initiation phase showed comparable inflammation after MCA-injection, metabolism of MCA was impaired in the absence of Hif-1α. An ex vivo macrophage/fibroblast coculture recapitulated reduced DNA damage after MCA-stimulation in fibroblasts of cocultures with Hif-1α LysM-/- macrophages compared to wild type macrophages. A loss of myeloid Hif-1α decreased RNA levels of arylhydrocarbon receptor (AhR)/arylhydrocarbon receptor nuclear translocator (ARNT) targets such as Cyp1a1 because of reduced Arnt but unchanged Ahr expression. Cocultures using Hif-1α LysM-/- macrophages stimulated with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA; 2 μg/ml) also attenuated a DNA damage response in fibroblasts, while the DNA damage-inducing metabolite DMBA-trans-3,4-dihydrodiol remained effective in the absence of Hif-1α. In chemical-induced carcinogenesis, HIF-1α in macrophages maintains ARNT expression to facilitate PAH-biotransformation. This implies a metabolic activation of PAHs in stromal cells, i.e. myeloid-derived cells, to be crucial for tumor initiation.
Shrew-1, also called AJAP1, is a transmembrane protein associated with E-cadherin-mediated adherence junctions and a putative tumor suppressor. Apart from its interaction with β-catenin and involvement in E-cadherin internalization, little structure or function information exists. Here we explored shrew-1 expression during postnatal differentiation of mammary gland as a model system. Immunohistological analyses with antibodies against either the extracellular or the cytoplasmic domains of shrew-1 consistently revealed the expression of full-length shrew-1 in myoepithelial cells, but only part of it in luminal cells. While shrew-1 localization remained unaltered in myoepithelial cells, nuclear localization occurred in luminal cells during lactation. Based on these observations, we identified two unknown shrew-1 transcript variants encoding N-terminally truncated proteins. The smallest shrew-1 protein lacks the extracellular domain and is most likely the only variant present in luminal cells. RNA analyses of human tissues confirmed that the novel transcript variants of shrew-1 exist in vivo and exhibit a differential tissue expression profile. We conclude that our findings are essential for the understanding and interpretation of future functional and interactome analyses of shrew-1 variants.
Motion analysis in the field of dentistry : a kinematic comparison of dentists and orthodontists
(2016)
Objectives: To conduct a kinematic comparison of occupational posture in orthodontists and dentists in their workplace.
Design: Observational study.
Setting: Dentist surgeries and departments of orthodontics at university medical centres in Germany.
Participants: A representative sample of 21 (10 female, 11 male) dentists (group G1) and 21 (13 female, 8 male) orthodontists (G2) with one male dropout in G2.
Outcome measures: The CUELA (computer-assisted acquisition and long-term analysis of musculoskeletal loads) system was used to analyse occupational posture. Parallel to the recording through the CUELA system, a software-supported analysis of the activities performed (I: treatment; II: office; III: other activities) was carried out. In line with ergonomic standards the measured body angles are categorised into neutral, moderate and awkward postures. Activities between the aforementioned groups are compared using the stratified van Elteren U test and the Wilcoxon–Mann–Whitney U test. All p values are subject to the Bonferroni–Holm correction. The level of significance is set at 5%.
Results: The percentage of time spent on activities in categories I–II–III was as follows: dentists 41%–23%–36% and orthodontists 28%–37%–35%. The posture analysis of both groups showed, for all percentiles (P5–95), angle values primarily in the neutral or moderate range. However, depending on the activity performed, between 5% and 25% of working hours were spent in unfavourable postures, especially in the head-and-neck area. Orthodontists have a greater tendency than dentists to perform treatment activities with the head and torso in unfavourable positions. The statistically significant differences between the two groups with regard to the duration and the relevance of the activities performed confirm this assumption for all three categories (p<0.01, p<0.05).
Conclusions: Generally, both groups perform treatment activities in postures that are in the neutral or medium range; however, dentists had slightly more unfavourable postures during treatment for a greater share of their work day.
The Asian tiger mosquito, Aedes albopictus (Diptera: Culicidae, SKUSE), is an important threat to public health due to its rapid spread and its potential as a vector. The eggs of Ae. albopictus are the most cold resistant life stage and thus, the cold hardiness of eggs is used to predict the future occurrence of the species in distribution models. However, the mechanism of cold hardiness has yet to be revealed. To address this question, we analyzed the layers of diapausing and cold acclimatized eggs of a temperate population of Ae. albopictus in a full factorial test design using transmission electron microscopy. We reviewed the hypotheses that a thickened wax layer or chorion is the cause of cold hardiness but found no evidence. As a result of the induced diapause, the thickness of the dark endochorion as a layer of high electron density and thus an assumed location for waxes was decreasing. We therefore hypothesized a qualitative alteration of the wax layer due to compaction. Cold acclimation was causing an increase in the thickness of the middle serosa cuticle indicating a detachment of serosa membrane from the endochorion as a potential adaptation strategy to isolate inoculating ice formations in the inter-membranous space.
Endometriosis and its global research architecture : an in-depth density-equalizing mapping analysis
(2016)
Background: Endometriosis is one of the most common gynecological diseases. It is still a chameleon in many aspects and urges intense research activities in the fields of diagnosis, therapy and prevention. Despite the need to foster research in this area, no in-depth analysis of the global architecture of endometriosis research exists yet.
Methods: We here used the NewQIS platform to conduct a density equalizing mapping study, using the Web of Science as database with endometriosis related entries between 1900 and 2009. Density equalizing maps of global endometriosis research encompassing country-specific publication activities, and semi-qualitative indices such as country specific citations, citation rates, h-Indices were created.
Results: In total, 11,056 entries related to endometriosis were found. The USA was leading the field with 3705 publications followed by the United Kingdom (952) and Japan (846). Concerning overall citations and country-specific h-Indices, the USA again was the leading nation with 74,592 citations and a modified h-Index of 103, followed by the UK with 15,175 citations (h-Index 57). Regarding the citation rate, Sweden and Belgium were at top positions with rates of 22.46 and 22.26, respectively. Concerning collaborative studies, there was a steep increase in numbers present; analysis of the chronological evolution indicated a strong increase in international collaborations in the past 10 years.
Conclusions: This study is the first analysis that illustrates the global endometriosis research architecture. It shows that endometriosis research is constantly gaining importance but also underlines the need for further efforts and investments to foster research and ultimately improve endometriosis management on a global scale.
Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins.
Background: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response.
Methods: This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively.
Results: Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed.
Conclusions: Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted.
Trial registration: This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.
Background: Lectures remain an important teaching method to present and structure knowledge to many students concurrently. Adequate measures are necessary to maintain the quality of the lectures. The aim of this study was to determine the impact on the lecture quality using written structured feedback and to compare the ratings of surgical lectures between students and surgical peers.
Methods: Prospective analysis of two consecutive surgical lecture series for undergraduate students at Goethe-University Medical School was performed before and after evaluation of the lecturers via independent written feedback from trained undergraduate students and surgeons. The 22-item feedback instrument covered three areas of performance: content, visualization, and delivery. Additional suggestions for improvement were provided from
both students and surgical peers who anonymously attended the lectures. The lecturers, experienced surgeons, as well as the student and peer raters were blinded in terms of the aim and content of the study. Their response to the feedback was collected using a web-based 13-item questionnaire. The Kendall’s-W coefficient was computed to calculate inter-rater reliability (IRR). Differences between ratings before and after feedback were analyzed using Student’s t-test for dependent samples. The Kolmogorov-Smirnov-test was used for independent samples.
Results: A total of 22 lectures from a possible 32 given by 13 lecturers were included and analyzed by at least three surgeons and two students. There were significant improvements in overall score as well as in the details of 9 of the 13 items were found. The average inter-rater reliability was 0.71. There were no differences in the ratings as a function of the rater’s level of expertise (peers vs. students). We found that 13/23 lecturers (56.5%) answered the questionnaire, and 92% strongly agreed that the written feedback was useful. 76.9% of the lecturers revised their lecture based on the written feedback requiring on average 112.5 min (range from 20 to 300 min).
Conclusions: Overall, this study indicates that structured written feedback provided by trained peers and students that is subsequently discussed by the lecturers concerned is a highly effective and efficient method to improve aspects of lecturing. We anticipate that structured written feedback by trained students that is discussed by the lecturers concerned will improve lecturing.
Keywords: Lecture, Feedback, Surgery, Peer-feedback, Evaluation, Undergraduate training
Gendermetrics.NET : a novel software for analyzing the gender representation in scientific authoring
(2016)
Background: Imbalances in female career promotion are believed to be strong in the field of academic science. A primary parameter to analyze gender inequalities is the gender authoring in scientific publications. Since the presently available data on gender distribution is largely limited to underpowered studies, we here develop a new approach to analyze authors’ genders in large bibliometric databases.
Results: A SQL-Server based multiuser software suite was developed that serves as an integrative tool for analyzing bibliometric data with a special emphasis on gender and topographical analysis. The presented system allows seamless integration, inspection, modification, evaluation and visualization of bibliometric data. By providing an adaptive and almost fully automatic integration and analysis process, the inter-individual variability of analysis is kept at a low level. Depending on the scientific question, the system enables the user to perform a scientometric analysis including its visualization within a short period of time.
Conclusion: In summary, a new software suite for analyzing gender representations in scientific articles was established. The system is suitable for the comparative analysis of scientific structures on the level of continents, countries, cities, city regions, institutions, research fields and journals.
Background: Environmental tobacco smoke (ETS) is associated with human morbidity and mortality, particularly chronic obstructive pulmonary disease (COPD and lung cancer. Although direct DNA-damage is a leading pathomechanism in active smokers, passive smoking is enough to induce bronchial asthma, especially in children. Particulate matter (PM) demonstrably plays an important role in this ETS-associated human morbidity, constituting a surrogate parameter for ETS exposure.
Methods: Using an Automatic Environmental Tobacco Smoke Emitter (AETSE) and an in-house developed, non-standard smoking regime, we tried to imitate the smoking process of human smokers to demonstrate the significance of passive smoking. Mean concentration (Cmean) and area under the curve (AUC) of particulate matter (PM2.5) emitted by 3R4F reference cigarettes and the popular filter-tipped and non-filter brand cigarettes “Roth-Händle” were measured and compared. The cigarettes were not conditioned prior to smoking. The measurements were tested for Gaussian distribution and significant differences.
Results: Cmean PM2.5 of the 3R4F reference cigarette: 3911 µg/m3; of the filter-tipped Roth-Händle: 3831 µg/m3; and of the non-filter Roth-Händle: 2053 µg/m3. AUC PM2.5 of the 3R4F reference cigarette: 1,647,006 µg/m3·s; of the filter-tipped Roth-Händle: 1,608,000 µg/m3·s; and of the non-filter Roth-Händle: 858,891 µg/m3·s.
Conclusion: The filter-tipped cigarettes (the 3R4F reference cigarette and filter-tipped Roth-Händle) emitted significantly more PM2.5 than the non-filter Roth-Händle. Considering the harmful potential of PM, our findings note that the filter-tipped cigarettes are not a less harmful alternative for passive smokers. Tobacco taxation should be reconsidered and non-smoking legislation enforced.
The Escherichia coli sensor kinase EnvZ modulates porin expression in response to various stimuli, including extracellular osmolarity, the presence of procaine and interaction with an accessory protein, MzrA. Two major outer membrane porins, OmpF and OmpC, act as passive diffusion-limited pores that allow compounds, including certain classes of antibiotics such as β-lactams and fluoroquinolones, to enter the bacterial cell. Even though the mechanisms by which EnvZ detects and processes the presence of various stimuli are a fundamental component of microbial physiology, they are not yet fully understood. Here, we assess the role of TM1 during signal transduction in response to the presence of extracellular osmolarity. Various mechanisms of transmembrane communication have been proposed including rotation of individual helices within the transmembrane domain, dynamic movement of the membrane-distal portion of the cytoplasmic domain and regulated intra-protein unfolding. To assess these possibilities, we have created a library of single-Cys-containing EnvZ proteins in order to facilitate sulfhydryl-reactivity experimentation. Our results demonstrate that the major TM1-TM1' interface falls along a single surface consisting of residue positions 19, 23, 26, 30 and 34. In addition, we show that Cys substitutions within the N- and C-terminal regions of TM1 result in drastic changes to EnvZ signal output. Finally, we demonstrate that core residues within TM1 are responsible for both TM1 dimerisation and maintenance of steady-state signal output. Overall, our results suggest that no major rearrangement of the TM1-TM1' interface occurs during transmembrane communication in response to extracellular osmolarity. We conclude by discussing these results within the frameworks of several proposed models for transmembrane communication.
Objective: To estimate health status utility (preference) weights for hereditary angioedema (HAE) during an attack and between attacks using data from the Hereditary Angioedema Burden of Illness Study in Europe (HAE-BOIS-Europe) survey. Utility measures quantitatively describe the net impact of a condition on a patient’s life; a score of 0.0 reflects death and 1.0 reflects full health.
Study design and methods: The HAE-BOIS-Europe was a cross-sectional survey conducted in Spain, Germany, and Denmark to assess the real-world experience of HAE from the patient perspective. Survey items that overlapped conceptually with the EuroQol 5-Dimensions (EQ-5D) domains (pain/discomfort, mobility, self-care, usual activities, and anxiety/depression) were manually crosswalked to the corresponding UK population-based EQ-5D utility weights. EQ-5D utilities were computed for each respondent in the HAE-BOIS-Europe survey for acute attacks and between attacks.
Results: Overall, a total of 111 HAE-BOIS-Europe participants completed all selected survey items and thus allowed for computation of EQ-5D-based utilities. The mean utilities for an HAE attack and between attacks were 0.44 and 0.72, respectively. Utilities for an acute attack were dependent on the severity of pain of the last attack (0.61 for no pain or mild pain, 0.47 for moderate pain, and 0.08 for severe pain). There were no significant differences across countries. Mean utilities derived from the study approach compare sensibly with other disease states for both acute attacks and between attacks.
Conclusion: The impacts of HAE translate into substantial health status disutilities associated with acute attacks as well as between attacks, documenting that the detrimental effects of HAE are meaningful from the patient perspective. Results were consistent across countries with regard to pain severity and in comparison to similar disease states. The results can be used to raise awareness of HAE as a serious disease with wide-ranging personal and social impacts.