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We sought to obtain detailed information on the procedures and appraisal of screening for and diagnosing diabetic sensorimotor polyneuropathy (DSPN) in clinical practice.This cross-sectional survey included 574 physicians from 13 federal states across Germany who responded to a tripartite questionnaire.The vast majority of the respondents reported to screen for DSPN at least once a year (87 %), while 65 % reported to examine the feet of DSPN patients at least twice a year. However, only 28 % and 20 % of the respondents used questionnaires and scores to assess the severity of neuropathic symptoms and signs, respectively. The rates of participants reporting that they do not use a standardized testing procedure were 58 % for pressure sensation, 62 % for pain sensation, and 54 % for thermal sensation. The rates of respondents reporting that they do not deploy a standardized assessment were 41 % for vibration sensation, 73 % for pressure sensation, 77 % for pain sensation, and 66 % for thermal sensation. Half of the physicians oriented themselves towards clinical guidelines when diagnosing DSPN.Despite relatively high screening rates, the willingness to implement both standardized testing procedures and assessment and to follow guidelines is low among physicians when screening for and clinically diagnosing DSPN.

A consensus statement about indications for post-surgical radioiodine therapy (RIT) in differentiated thyroid cancer patients (DTC) was recently published by the European Thyroid Association (ETA) 1. This publication discusses indications for RIT on the basis of an individual risk assessment. Many of the conclusions of this consensus statement are well founded and accepted across the disciplines involved. However, especially from the perspective of nuclear medicine, as the discipline responsible for indicating and executing RIT, some of the recommendations may require further clarification with regard to their compatibility with established best practice and national standards of care. Assessment of the indications for RIT is strongly dependent on the weighing up of benefits and risks. On the basis of longstanding clinical experience in nuclear medicine, RIT represents a highly specific precision medicine procedure of proven efficacy with a favorable side-effect profile. This distinguishes RIT significantly from other adjuvant oncological therapies and has resulted in the establishment of this procedure as a usually well-tolerated, standard safety measure. With regard to its favorable risk/benefit ratio, this procedure should not be unnecessarily restricted, in the interest of offering reassurance to the patients. Both patients' interests and regional/national differences need to be taken into account. We would therefore like to comment on the recent consensus from the perspective of authors and to provide recommendations based on the respective published data.Die European Thyroid Association (ETA) hat vor Kurzem eine Konsenserklärung zu den Indikationen für die postoperative Radiojodtherapie (RIT) bei Patienten mit differenziertem Schilddrüsenkrebs veröffentlicht 1. In dieser Veröffentlichung werden die Indikationen für eine RIT auf der Grundlage einer individuellen Risikobewertung erörtert. Viele der Schlussfolgerungen dieser Konsenserklärung sind gut begründet und werden von allen beteiligten Disziplinen akzeptiert. Insbesondere aus der Sicht der Nuklearmedizin, die für die Indikationsstellung und Durchführung der RIT verantwortlich ist, bedürfen einige der Empfehlungen jedoch einer weiteren Klärung im Hinblick auf ihre Vereinbarkeit mit bewährten Verfahren und nationalen Versorgungsstandards. Die Beurteilung der Indikationen für eine RIT ist stark von der Abwägung von Nutzen und Risiken abhängig. Auf der Grundlage der langjährigen klinischen Erfahrung in der Nuklearmedizin stellt die RIT ein hochspezifisches Verfahren der Präzisionsmedizin mit nachgewiesener Wirksamkeit und günstigem Nebenwirkungsprofil dar. Dies unterscheidet die RIT deutlich von anderen adjuvanten onkologischen Therapien und hat dazu geführt, dass sich dieses Verfahren als eine in der Regel gut verträgliche, sichere Standardmaßnahme etabliert hat. In Anbetracht des günstigen Nutzen-Risiko-Verhältnisses sollte dieses Verfahren nicht unnötig eingeschränkt werden, um den Patienten Sicherheit zu geben. Dabei müssen sowohl die Interessen der Patienten als auch regionale/nationale Unterschiede berücksichtigt werden. Wir möchten daher den aktuellen Konsens aus Sicht der Autoren kommentieren und Empfehlungen auf der Basis der jeweils veröffentlichten Daten geben.

Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In our study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n = 67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA and histone H3 as compared to serum EVs from healthy volunteers (P value range

SARS CoV-2 antibody assays measure antibodies against the viral nucleoprotein (NP) or spike protein. The study examined if testing of antibodies against both antigens increases the diagnostic sensitivity. Sera (N=98) from infected individuals were tested with ELISAs based on the NP, receptor-binding domain (RBD), or both proteins. The AUROCs were 0.958 (NP), 0.991 (RBD), and 0.992 (NP/RBD). The RBD- and NP/RBD-based ELISAs showed better performance than the NP-based assay. Simultaneous testing for antibodies against NP and RBD increased the number of true and false positives. If maximum diagnostic sensitivity is required, the NP/RBD-based ELISA is preferable. Otherwise, the RBD-based ELISA is sufficient. Supplementary Information The online version contains supplementary material available at 10.1007/s10096-021-04284-5.

This study aimed to investigate the incidence and potentially modifiable risk factors of acute kidney injury (AKI) in patients with cardiac implantable electronic devices (CIED) admitted for removal of infected and non-infected transvenous leads.In this observational cohort study, data from 147 consecutive patients with CIED undergoing transvenous lead removal were analyzed. Study endpoint was AKI according to the KDIGO criteria. Multivariable logistic regression analysis was performed to identify independent risk factors for AKI.Lead removal was performed due to systemic infection (50.3%), isolated pocket infection (34.0%), pocket or lead perforation without infection (13.6%), and endocarditis (2.0%). Out of 147 patients, 34 (23.1%) developed AKI (82.4% stage 1, 8.8% stage 2, and 8.8% stage 3). There was no difference regarding incidence of AKI when separated by infectious vs. non-infectious lead status (25.5 vs. 25.0%) p = 0.605. Defibrillator lead type (HR 24.55, CI 2.41 - 249.97, p = 0.007), necessity to perform laser-assisted lead removal (HR 5.41, CI 1.12 - 26.13, p = 0.035), and time from initial implantation to lead removal (HR 1.01, CI 1.00 - 1.02, p = 0.013) were independent risk factors for AKI. Also, AKI was associated with in-hospital mortality (HR 8.44, CI 2.08 - 34.33, p = 0.003).Almost a quarter of patients undergoing transvenous lead removal developed AKI. Independent modifiable risk factors for AKI were identified. The role of procedure-related risk factors for AKI, such as lead type and use of laser, needs further evaluation in these patients.

Purpose Transforming growth factor β (TGFβ) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFβ activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed. Methods and Materials We evaluated positron emission tomography (PET) to image 89Zr -fresolimumab, a humanized TGFβ neutralizing monoclonal antibody, as a means to detect TGFβ activation in intracranial tumor models. Pathway activity of TGFβ was validated by immunodetection of phosphorylated SMAD2 and the TGFβ target, tenascin. The contribution of TGFβ to radiation response was assessed by Kaplan-Meier survival analysis of mice bearing intracranial murine tumor models GL261 and SB28 glioblastoma and brain-adapted 4T1 breast cancer (4T1-BrA) treated with TGFβ neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy). Results 89Zr-fresolimumab PET imaging detected engineered, physiological, and radiation-induced TGFβ activation, which was confirmed by immunostaining of biological markers. GL261 glioblastoma tumors had a greater PET signal compared with similar-sized SB28 glioblastoma tumors, whereas the widespread PET signal of 4T1-BrA intracranial tumors was consistent with their highly dispersed histologic distribution. Survival of mice bearing intracranial tumors treated with 1D11 neutralizing antibody alone was similar to that of mice treated with control antibody, whereas 1D11 improved survival when given in combination with focal radiation. The extent of survival benefit of a combination of radiation and 1D11 was associated with the degree of TGFβ activity detected by PET. Conclusions This study demonstrates that 89Zr-fresolimumab PET imaging detects radiation-induced TGFβ activation in tumors. Functional imaging indicated a range of TGFβ activity in intracranial tumors, but TGFβ blockade provided survival benefit only in the context of radiation treatment. This study provides further evidence that radiation-induced TGFβ activity opposes therapeutic response to radiation.

Cardiac implantable electronic devices (CIED) have become an indispensable part in everyday clinical practice in cardiology. The indications for CIED implantation are based on the guidelines of the European Heart Rhythm Association (EHRA). Nevertheless, numbers of CIED implantations in Europe are subject to considerable differences. We hypothesized that reimbursements linked to the respective health systems may influence implantation behavior.Based on the EHRA White Book 2017, CIED implantation data as well as socioeconomic key figures were collected, in particular gross domestic product (GDP) and share of gross domestic product spent on healthcare. Implantation numbers for pacemakers, implantable cardioverter defibrillators and cardiac resynchronization treatment as well as all in total were assessed, compared with the health care expenditures and visualized using heat maps.Total implantation numbers per 100,000 inhabitants varied from 196.53 (Germany) to 2.81 (Kosovo). Higher implantation numbers correlated moderately with a higher GDP (r = 0.456, p 0.002) and higher health expenditure (r = 0.586, p 0.001). The annual financial resources per inhabitant were also subject to fluctuations ranging from 9476 $ (Switzerland) to 140 $ (Ukraine); however, there were countries with high financial means, such as Switzerland or Scandinavian countries, which showed significantly lower implantation rates.There were considerable differences in CIED implantations in Europe. These seem to be explained in part by socioeconomic disparities within Europe. Also, a potential influence by the respective remuneration system is likely.

Background Cutaneous melanoma exhibits heterogeneous metastatic patterns and prognosis. In this regard, liver metastasis, which is detected in ~ 10–20% of stage 4 patients, came to the fore of melanoma research, as it recently evolved as decisive indicator of treatment resistance to immune checkpoint inhibition. Methods Hepatic metastases were induced by intrasplenic injection of five different murine melanoma cell lines. The efficiencies of hepatic colonization, morphologic patterns, gene expression profiles and degree of vascularization were analyzed and Sorafenib was applied as anti-angiogenic treatment. Results WT31 melanoma showed the highest efficiency of hepatic colonization, while intermediate efficiencies were observed for B16F10 and RET, and low efficiencies for D4M and HCmel12. RNAseq-based gene expression profiles of high and intermediate metastatic melanomas in comparison to low metastatic melanomas indicated that this efficiency predominantly associates with gene clusters involved in cell migration and angiogenesis. Indeed, heterogeneous vascularization patterns were found in the five models. Although the degree of vascularization of WT31 and B16F10 metastases differed, both showed a strong response to Sorafenib with a successful abrogation of the vascularization. Conclusion Our data indicate that molecular heterogeneity of melanomas can be associated with phenotypic and prognostic features of hepatic metastasis paving the way for organ-specific anti-angiogenic therapeutic approaches.

The thyroid gland is among the organs at the greatest risk of cancer from ionizing radiation. Epidemiological evidence from survivors of radiation therapy, atomic bombing, and the Chernobyl reactor accident, clearly shows that radiation exposure in childhood can cause thyroid cancer and benign thyroid nodules. Radiation exposure also may induce hypothyroidism and autoimmune reactions against the thyroid, but these effects are less well-documented. The literature includes only a few, methodologically weak animal studies regarding genetic/molecular mechanisms underlying hypothyroidism and thyroid autoimmunity after radiation exposure. Rather, evidence about radiation-induced hypothyroidism and thyroid autoimmunity derives mainly from follow-up studies in patients treated with external beam radiotherapy (EBRT) or iodine-131, and from epidemiological studies in the atomic bombing or nuclear accident survivors. Historically, hypothyroidism after external irradiation of the thyroid in adulthood was considered not to develop below a 10–20 Gy dose threshold. Newer data suggest a 10 Gy threshold after EBRT. By contrast, data from patients after iodine-131 “internal radiation therapy” of Graves´ disease indicate that hypothyroidism rarely occurs below thyroid doses of 50 Gy. Studies in children affected by the Chernobyl accident indicate that the dose threshold for hypothyroidism may be considerably lower, 3–5 Gy, aligning with observations in A-bomb survivors exposed as children. The reasons for these dose differences in radiosensitivity are not fully understood. Other important questions about the development of hypothyroidism after radiation exposure e.g., in utero, about the interaction between autoimmunity and hypofunction, and about the different effects of internal and external irradiation still must be answered.

Aims/Introduction Despite its major clinical impact, distal symmetric polyneuropathy remains frequently undiagnosed and undertreated in clinical practice. We previously reported in the PROTECT Study that 70% of type 2 diabetes patients with distal symmetric polyneuropathy were unaware of having the latter condition. Materials and Methods In the present follow up after 2.5 ± 0.7 years, 122 and 85 participants with and without type 2 diabetes, respectively, completed questionnaires to obtain information about the further course of disease and its management. Results At follow up, 49 and 48% of the respondents with type 2 diabetes and without diabetes, respectively, reported that the intensity of paresthesia or numbness in the feet increased, whereas for burning and pain in the feet the corresponding percentages were 56 and 61%. However, 33 and 40% of the respondents with type 2 diabetes and without diabetes, respectively, reporting neuropathic symptoms at follow up did not receive any pharmacotherapy. Pharmacotherapy of neuropathic symptoms at follow up among participants with type 2 diabetes and without diabetes included mainly World Health Organization Step 1 analgesics (17% each; excluding acetylsalicylic acid), pregabalin/gabapentin (20 and 12%), vitamin B complex (13 and 22%), benfotiamine (13 and 2%), opioids (7 and 12%), antidepressants (4 and 5%) and α‐lipoic acid (4 and 2%). Conclusions These findings point to insufficient care, inadequate treatment adherence or limited efficacy of treatments in patients with polyneuropathy, suggesting that effective measures should be implemented to correct these healthcare deficits., This survey shows that despite increasing intensity of neuropathic symptoms, a significant proportion of participants with and without diabetes did not receive any pharmacotherapy for these symptoms or received agents, such as World Health Organization Step 1 analgesics, which are not recommended by evidence‐based guidelines. These data suggest insufficient care, inadequate treatment adherence or limited effectiveness of treatments in patients with polyneuropathy.

Objective: To evaluate the effect of an educational intervention on health beliefs and adherence of elderly people to fall prevention measures. Methods: This is a quasi-experimental study, carried out at the Senior Citizens' Center. Sixty-eight elderly completed the intervention. The intervention consisted of four meetings focused on beliefs about falls and prevention, and the evaluation occurred at baseline and 30 days after completion. Results: The elderly were predominantly women (83.82%), with one to four years of schooling (36.76%), with health problems (95.59%), and 48.53% had fallen. There was a significant increase in perceived susceptibility, severity, benefits, barriers, and total health belief score post educational intervention. By adding total to partial adherence, there was a significant increase in the adherence of the elderly to fall prevention measures after the educational intervention. Conclusion: Educational intervention was able to improve the beliefs and adherence of the elderly to fall prevention measures. RESUMEN Objetivo: Evaluar efecto de una intervención educativa en las creencias en salud y adhesión de ancianos a medidas preventivas de caídas. Métodos: Estudio cuasi experimental, realizado en Centro de Convivencia para Ancianos. Concluyeron Ia intervención 68 ancianos. La intervención consistió en cuatro encuentros con enfoque en creencias sobre caídas y prevención, y la evaluación ocurrió en la baseline y 30 días tras el término. Resultados: Predominaron entre los ancianos: mujeres (83,82%), un a cuatro años de estudio (36,76%), con problemas de salud (95,59%); y 48,53% tuvieron caída. Hubo aumento significativo en la percepción de susceptibilidad, de severidad, de benefícios, de barreras y escore total de creencias en salud postintervención educativa. Al sumar la adhesión total a parcial, hubo aumento significativo de adhesión de ancianos a medidas preventivas de caídas postintervención educativa. Conclusión: Intervención educativa fue capaz de mejorar Ias creencias y la adhesión de ancianos a medidas preventivas de caídas. RESUMO Objetivo: Avaliar o efeito de uma intervenção educativa nas crenças em saúde e na adesão de idosos às medidas preventivas de quedas. Métodos: Estudo quase experimental, realizado em Centro de Convivência para Idosos. Concluíram a intervenção 68 idosos. A intervenção consistiu em quatro encontros com foco nas crenças sobre quedas e prevenção, e a avaliação ocorreu na baseline e 30 dias após o término. Resultados: Predominaram entre os idosos: mulheres (83,82%), um a quatro anos de estudo (36,76%), com problemas de saúde (95,59%); e 48,53% tiveram queda. Houve aumento significante na percepção de suscetibilidade, da severidade, dos benefícios, das barreiras e no escore total de crenças em saúde pós-intervenção educativa. Ao somar a adesão total à parcial, houve aumento significante da adesão dos idosos às medidas preventivas de quedas pós-intervenção educativa. Conclusão: Intervenção educativa foi capaz de melhorar as crenças e a adesão dos idosos às medidas preventivas de quedas.

Background and purpose Aerobic glycolysis is a unique feature of tumour cells that entails several advantages for cancer progression such as resistance to apoptosis. The low MW compound, dichloroacetate, is a pyruvate dehydrogenase kinase inhibitor, which restores oxidative phosphorylation and induces apoptosis in a variety of cancer entities. However, its therapeutic effectiveness is limited by resistance mechanisms. This study aimed to examine the role of the anti-apoptotic hyaluronan (HA) matrix in this context and to identify a potential add-on treatment option to overcome this limitation. Experimental approach The metabolic connection between dichloroacetate treatment and HA matrix augmentation was analysed in vitro by quantitative PCR and affinity cytochemistry. Metabolic pathways were analysed using Seahorse, HPLC, fluorophore-assisted carbohydrate electrophoresis, colourimetry, immunoblots, and immunochemistry. The effects of combining dichloroacetate with the HA synthesis inhibitor 4-methylumbelliferone was evaluated in 2D and 3D cell cultures and in a nude mouse tumour xenograft regression model by immunoblot, immunochemistry, and FACS analysis. Key results Mitochondrial reactivation induced by dichloroacetate metabolically activated HA synthesis by augmenting precursors as well as O-GlcNAcylation. This process was blocked by 4-methylumbelliferone, resulting in enhanced anti-tumour efficacy in 2D and 3D cell culture and in a nude mouse tumour xenograft regression model. Conclusions and implications The HA rich tumour micro-environment represents a metabolic factor contributing to chemotherapy resistance. HA synthesis inhibition exhibited pronounced synergistic actions with dichloroacetate treatment on oesophageal tumour cell proliferation and survival in vitro and in vivo suggesting the combination of these two strategies is an effective anticancer therapy.

Funding Information: This work was supported by a grant by the state of North-Rhine Westphalia and the European Fonds for Regional Development EFRE.NRW 2014-2020 to HG. We are grateful for computational support and infrastructure provided by the “Zentrum für Informations- und Medientechnologie” (ZIM) at the Heinrich Heine University Düsseldorf and the computing time provided by the John von Neumann Institute for Computing (NIC) to HG on the supercomputer JUWELS at Jülich Supercomputing Centre (JSC) (user ID: HKF7, VSK33). Financial support by Deutsche Forschungsgemeinschaft (DFG) through funds (INST 208/704-1 FUGG to HG) to purchase the hybrid computer cluster used in this study, an Emmy-Noether- and Heisenberg fellowship to ME (ET 103/2 and ET 103/5), and GRK 2158/2 (project number 270650915) to HG is gratefully acknowledged. Funding Information: This work was supported by a grant by the state of North-Rhine Westphalia and the European Fonds for Regional Development EFRE.NRW 2014-2020 to HG. We are grateful for computational support and infrastructure provided by the “Zentrum für Informations- und Medientechnologie” (ZIM) at the Heinrich Heine University Düsseldorf and the computing time provided by the John von Neumann Institute for Computing (NIC) to HG on the supercomputer JUWELS at Jülich Supercomputing Centre (JSC) (user ID: HKF7, VSK33). Financial support by Deutsche Forschungsgemeinschaft (DFG) through funds (INST 208/704-1 FUGG to HG) to purchase the hybrid computer cluster used in this study, an Emmy-Noether- and Heisenberg fellowship to ME (ET 103/2 and ET 103/5), and GRK 2158/2 (project number 270650915) to HG is gratefully acknowledged. Publisher Copyright: © 2022, The Author(s). Acute myeloid leukemia (AML) is a malignant disease of immature myeloid cells and the most prevalent acute leukemia among adults. The oncogenic homo-tetrameric fusion protein RUNX1/ETO results from the chromosomal translocation t(8;21) and is found in AML patients. The nervy homology region 2 (NHR2) domain of ETO mediates tetramerization; this oligomerization is essential for oncogenic activity. Previously, we identified the first-in-class small-molecule inhibitor of NHR2 tetramer formation, 7.44, which was shown to specifically interfere with NHR2, restore gene expression down-regulated by RUNX1/ETO, inhibit the proliferation of RUNX1/ETO-depending SKNO-1 cells, and reduce the RUNX1/ETO-related tumor growth in a mouse model. However, no biophysical and structural characterization of 7.44 binding to the NHR2 domain has been reported. Likewise, the compound has not been characterized as to physicochemical, pharmacokinetic, and toxicological properties. Here, we characterize the interaction between the NHR2 domain of RUNX1/ETO and 7.44 by biophysical assays and show that 7.44 interferes with NHR2 tetramer stability and leads to an increase in the dimer population of NHR2. The affinity of 7.44 with respect to binding to NHR2 is Klig = 3.75 ± 1.22 µM. By NMR spectroscopy combined with molecular dynamics simulations, we show that 7.44 binds with both heteroaromatic moieties to NHR2 and interacts with or leads to conformational changes in the N-termini of the NHR2 tetramer. Finally, we demonstrate that 7.44 has favorable physicochemical, pharmacokinetic, and toxicological properties. Together with biochemical, cellular, and in vivo assessments, the results reveal 7.44 as a lead for further optimization towards targeted therapy of t(8;21) AML. publishersversion published

Background The joint Union International Contre le Cancer and American Joint Committee on Cancer (UICC/AJCC) Tumor, Node, Metastasis (TNM) staging system for differentiated thyroid cancer (DTC) involves a single age cutoff as a prognostic criterion. Because a single cutoff is a dichotomization of what might be a sliding scale, using multiple age cutoffs might result into a better stage definition. The aim of our study was to investigate if using a two-step age-based cutoff would improve the TNM staging system regarding disease-specific survival (DSS). Methods We retrospectively studied two cohorts of adult DTC patients from The Netherlands and Germany. DSS was analyzed for papillary (PTC) and follicular thyroid cancer (FTC) separately, investigating several two-step age-based cutoffs for those with distant metastases; below lower threshold classified as stage I, between lower and upper threshold as stage II, and above upper threshold as stage IV. Results We included 3074 DTC patients (77% PTC). For PTC, an age cutoff of 45 with 50 years had the best statistical model performance, while this was 25 with 40 years for FTC. However, differences with the optimal single age cutoffs of 50 years for PTC and 40 years for FTC were small. Conclusions The optimal two-step age-based cutoff to predict DSS is 45 with 50 years for PTC and 25 with 40 years for FTC, rather than 55 years currently used for DTC. Although these two-step age-based cutoffs were marginally better from a statistical point of view, from a clinical point of view, the recently defined optimal single age cutoffs of 50 years for PTC and 40 years for FTC might be preferable.

Metastatic spread of cancer cells into a pre-metastatic niche is highly dependent on a supporting microenvironment. Human bone marrow-derived mesenchymal stem cells (bmMSCs) contribute to the tumor microenvironment and promote cancer metastasis by inducing epithelial-to-mesenchymal transition and immune evasion. The underlying mechanisms, however, are incompletely understood. The glycosaminoglycan hyaluronan (HA) is a central component of the extracellular matrix and has been shown to harbor pro-metastatic properties. In this study we investigated the highly disseminating breast cancer and glioblastoma multiforme cell lines MDA-MB-321 and U87-MG which strongly differ in their metastatic potential to evaluate the impact of HA on tumor promoting features of bmMSC and their interaction with tumor cells. We show that adipogenic differentiation of bmMSC is regulated by the HA-matrix. This study reveals that MDA-MB-231 cells inhibit this process by the induction of HA-synthesis in bmMSCs and thus preserve the pro-tumorigenic properties of bmMSC. Furthermore, we show that adhesion of MDA-MB-231 cells to bmMSC is facilitated by the tumor cell-induced HA-rich matrix and is mediated by the HA-receptor LAYN. We postulate that invasive breast cancer cells modulate the HA-matrix of bmMSC to adapt the pre-metastatic niche. Thus, the HA-matrix provides a potential novel therapeutic target to prevent cancer metastasis.

Background: Differentiated thyroid cancer (DTC) is the only cancer entity for which the UICC/AJCC (Union for International Cancer Control and American Joint Committee on Cancer) TNM (tumor-node-metastasis) staging system involves an age cutoff as a prognostic criterion. However, the optimal age cutoff has not yet been determined in detail. The aim of our study was therefore to investigate the optimal age cutoff for the TNM staging system to predict disease-specific survival (DSS) with a focus on differences between patients with papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Methods: We retrospectively studied two large well-described cohorts of adult DTC patients from a Dutch and a German university hospital. DSS was analyzed for DTC overall, and for PTC and FTC separately, using several age cutoffs (per 5-year increment between 20 and 85 years and subsequently 1-year increments between 35 and 55 years), employing the histopathological criteria from the TNM staging system, eighth edition. Results: We included 3074 DTC patients (77% PTC and 23% FTC; mean age at diagnosis was 49 years). Median follow-up was seven years. For DTC and for PTC and FTC separately, the majority of the age cutoffs had a better statistical model performance than a model with no age cutoff. For DTC overall and for PTC, an age cutoff of 50 years had the best statistical model performance, while it was 40 years for FTC. Conclusions: In this large European population of DTC patients, when employing the histopathological criteria of the TNM system (eighth edition), the optimal age cutoff to predict DSS is 50 years rather than the 55 years currently in use. With the optimal age cutoff being 50 years for PTC and 40 years for FTC, there was a substantial difference in age cutoff for the respective histological entities. Therefore, implementation of different age cutoffs for PTC and FTC could improve the predictive value of the TNM staging system.

Without any doubt, high dose radiation exposure can induce hypothyroidism. However, there are open questions related to the mechanisms of its induction, corresponding dose thresholds and possible countermeasures. Therefore, this review addresses the aetiology, prevention and therapy of radiation induced hypothyroidism. External beam radiotherapy with several 10 Gy to the head and neck region and radioiodine therapy with several 100 Gy thyroid absorbed dose can destroy the thyroid gland and can induce autoantibodies against thyroid tissue. According to recent literature, clinical hypothyroidism is observed at threshold doses of ∼10 Gy after external beam radiotherapy and of ∼50 Gy after radioiodine therapy, children being more sensitive than adults. In children and adolescents exposed by the Chernobyl accident with mean thyroid absorbed doses of 500–800 mGy, subclinical hypothyroidism has been detected in 3%–6% of the cases with significant correlation to thyroid absorbed doses above 2.5 Gy. In case of nuclear emergencies, iodine thyroid blocking (ITB) is the method of choice to keep thyroid absorbed doses low. Large doses of stable iodine affect two different steps of internalization of radioiodine (transport and organification); perchlorate affecting the transport only may be an alternative to iodine. Administered before radioiodine incorporation, the effect of 100 mg iodide or more is still about 90% after 1 days, 80% after 2 days, and 50% or less after 3 days. If administered (too) late after exposure to radioiodine, the theoretically expected protective effect of ITB is about 50% after 6 h, 25% after 12 h, and about 6% after 24 h. In case of repeated or continuous exposure, repeated administration of 50 mg of iodide daily is indicated. If radiation-induced hypothyroidism cannot be avoided, thyroid hormone replacement therapy with individualized dosing and regular monitoring in order to maintain thyroid-stimulating hormone levels within the normal range ensures normal life expectancy.

This paper presents the application of an adaptive exoskeleton for finger rehabilitation. The system consists of a force-controlled exoskeleton of the finger and wireless coupling to a mobile application for the rehabilitation of complex regional pain syndrome (CRPS) patients. The exoskeleton has sensors for motion detection and force control as well as a wireless communication module. The proposed mobile application allows to interactively control the exoskeleton, store collected patient-specific data, and motivate the patient for therapy by means of gamification. The exoskeleton was applied to three CRPS patients over a period of six weeks. We present the design of the exoskeleton, the mobile application with its game content, and the results of the performed preliminary patient study. The exoskeleton system showed good applicability; recorded data can be used for objective therapy evaluation.

The incidence of differentiated thyroid cancer (DTC) is steadily increasing globally. Epidemiologists usually explain this global upsurge as the result of new diagnostic modalities, screening and overdiagnosis as well as results of lifestyle changes including obesity and comorbidity. However, there is evidence that there is a real increase of DTC incidence worldwide in all age groups. Here, we review studies on pediatric DTC after nuclear accidents in Belarus after Chernobyl and Japan after Fukushima as compared to cohorts without radiation exposure of those two countries. According to the Chernobyl data, radiation-induced DTC may be characterized by a lag time of 4–5 years until detection, a higher incidence in boys, in children of youngest age, extrathyroidal extension and distant metastases. Radiation doses to the thyroid were considerably lower by appr. two orders of magnitude in children and adolescents exposed to Fukushima as compared to Chernobyl. In DTC patients detected after Fukushima by population-based screening, most of those characteristics were not reported, which can be taken as proof against the hypothesis, that radiation is the (main) cause of those tumors. However, roughly 80% of the Fukushima cases presented with tumor stages higher than microcarcinomas pT1a and 80% with lymph node metastases pN1. Mortality rates in pediatric DTC patients are generally very low, even at higher tumor stages. However, those cases considered to be clinically relevant should be followed-up carefully after treatment because of the risk of recurrencies which is expected to be not negligible. Considering that thyroid doses from the Fukushima accident were quite small, it makes sense to assess the role of other environmental and lifestyle-related factors in thyroid carcinogenesis. Well-designed studies with assessment of radiation doses from medical procedures and exposure to confounders/modifiers from the environment as e.g., nitrate are required to quantify their combined effect on thyroid cancer risk., International Journal of Environmental Research and Public Health, 18 (7), art. no. 3444; 2021

Extracellular vesicles (EVs) are reminiscent of their cell of origin and thus represent a valuable source of biomarkers. However, for EVs to be used as biomarkers in clinical practice, simple, comparable, and reproducible analytical methods must be applied. Although progress is being made in EV separation methods for human biofluids, the implementation of EV assays for clinical diagnosis and common guidelines are still lacking. We conducted a comprehensive analysis of established EV separation techniques from human serum and plasma, including ultracentrifugation and size exclusion chromatography (SEC), followed by concentration using (a) ultracentrifugation, (b) ultrafiltration, or (c) precipitation, and immunoaffinity isolation. We analyzed the size, number, protein, and miRNA content of the obtained EVs and assessed the functional delivery of EV cargo. Our results demonstrate that all methods led to an adequate yield of small EVs. While no significant difference in miRNA content was observed for the different separation methods, ultracentrifugation was best for subsequent flow cytometry analysis. Immunoaffinity isolation is not suitable for subsequent protein analyses. SEC + ultracentrifugation showed the best functional delivery of EV cargo. In summary, combining SEC with ultracentrifugation gives the highest yield of pure and functional EVs and allows reliable analysis of both protein and miRNA contents. We propose this combination as the preferred EV isolation method for biomarker studies from human serum or plasma.

The COVID-19 global pandemic has prompted accelerated vaccine development efforts. This perspective discusses the importance of SARS-CoV-2 vaccine candidates’ recruitment of cellular T-cell immunity and encourages industry to increasingly investigate and publish parameters related to cellular immunity in their research reports.

Hyaluronic acid (hyaluronan; HA) is an essential component of the extracellular matrix (ECM) of the skin. The HA-degrading enzyme hyaluronidase (HYAL) is critically involved in the HA-metabolism. Yet, only little information is available regarding the skin´s HA-HYAL interactions on the molecular and cellular levels.OBJECTIVE To analyze the dose- and time-dependent molecular and cellular effects of HYAL on structural cells and the HA-metabolism in the skin.MATERIALS AND METHODS Chip-based, genome-wide expression analyses (Affymetrix® GeneChip PrimeView™ Human Gene Expression Array), quantitative real-time PCR analyses, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (DAB), and in vitro wound healing assays were performed to assess dose-dependent and time-kinetic effects of HA and HYAL (bovine hyaluronidase, Hylase “Dessau”) on normal human dermal fibroblasts (NHDF), primary human keratinocytes in vitro and human skin samples ex vivo.RESULTS Genome-wide expression analyses revealed an upregulation of HA synthases (HAS) up to 1.8-fold change in HA- and HYAL-treated NHDF. HA and HYAL significantly accelerated wound closure in an in vitro model for cutaneous wound healing. HYAL induced HAS1 and HAS2 mRNA gene expression in NHDF. Interestingly, low concentrations of HYAL (0.015 U/ml) resulted in a significantly higher induction of HAS compared to moderate (0.15 and 1.5 U/ml) and high concentrations (15 U/ml) of HYAL. This observation corresponded to increased concentrations of HA measured by ELISA in conditioned supernatants of HYAL-treated NHDF with the highest concentrations observed for 0.015 U/ml of HYAL. Finally, immunohistochemical analysis of human skin samples incubated with HYAL for up to 48 h ex vivo demonstrated that low concentrations of HYAL (0.015 U/ml) led to a pronounced accumulation of HA, whereas high concentrations of HYAL (15 U/ml) reduced dermal HA-levels.CONCLUSION HYAL is a bioactive enzyme that exerts multiple effects on the HA-metabolism as well as on the structural cells of the skin. Our results indicate that HYAL promotes wound healing and exerts a dose-dependent induction of HA-synthesis in structural cells of the skin. Herein, interestingly the most significant induction of HAS and HA were observed for the lowest concentration of HYAL.

Objective: This single-center, observational case-control feasibility study sought to test key elements of a protocol for an eventual long-term international observational case-control study of a larger patient cohort, to evaluate the risk of breast cancer as a second primary malignancy in females with differentiated thyroid cancer (DTC) given radioiodine therapy (RAI) during childhood or adolescence.Patients: Females developing DTC after the Chernobyl accident in Belarus and ≤19 years old at the time of thyroid surgery were enrolled: patients given RAI (n = 111) and controls of similar age not given RAI (n = 90).Results: One case of breast cancer was newly diagnosed among the RAI patients, but none in controls. Patients given RAI significantly less frequently needed 2nd surgeries than did controls (23%, 26/111 vs. 39%, 35/90, P < 0.05); the main indication for such procedures usually is suspicion of local recurrence. RAI patients appeared to have had more frequent reproductive difficulties than did controls: 78% (87/111) of the former vs. 93% (84/90) of the latter had a history of pregnancy (P < 0.01), and the mean number of pregnancies was 1.5 ± 1.2 in RAI patients vs. 1.9±1.1 in controls (P < 0.05). Most notably, infertility was observed in 23% (26/111) of RAI patients vs. 4% (4/90) of controls (P < 0.01). In conclusion, a international observational case-control study on breast cancer after DTC in patients given RAI vs. not given RAI appears to be feasible. Additional research and everyday clinical attention should be devoted to reproductive function after RAI in young females.

INTRODUCTION: Transforming growth factor β (TGFβ) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFβ activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed. METHODS & MATERIALS: We evaluated positron emission tomography (PET) to image (89)Zr -fresolimumab, a humanized TGFβ neutralizing monoclonal antibody, as means to detect TGFβ activation in intracranial tumor models. TGFβ pathway activity was validated by immunodetection of phosphorylated SMAD2 and TGFβ target, tenascin. The contribution of TGFβ to radiation response was assessed by Kaplan Meier survival analysis of mice bearing intracranial murine tumor models, GL261 and SB28 glioblastoma and brain-adapted 4T1 breast cancer (4T1-BrA) treated with TGFβ neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy). RESULTS: (89)Zr-fresolimumab PET imaging detected engineered, physiological and radiation-induced TGFβ activation, which was confirmed by immunostaining of biological markers. GL261 glioblastoma tumors had more PET signal compared to similar sized SB28 glioblastoma tumors, whereas widespread PET signal of 4T1-BrA intracranial tumors is consistent with its highly dispersed histological distribution. Survival of mice bearing intracranial tumors treated with 1D11 neutralizing antibody alone was similar to that of mice treated with control antibody whereas 1D11 improved survival when given in combination with focal radiation. The extent of survival benefit of combination of radiation and 1D11 was associated with the degree of TGFβ activity detected by PET. CONCLUSIONS: This study demonstrates that (89)Zr -fresolimumab PET imaging detects radiation-induced TGFβ activation in tumors. Functional imaging indicated a range of TGFβ activity in intracranial tumors, but TGFβ blockade provided survival benefit only in the context of radiation treatment. These studies are further evidence that radiation-induced TGFβ activity opposes therapeutic response to radiation.

Neovascular age-related macular degeneration (nAMD) is the most frequent cause of pigment epithelial detachment (PED). In the clinical routine the treatment of fibrovascular PED (fPED) and serous vascularized PED (svPED) with intravitreal vascular endothelial growth factor (VEGF) inhibitors has a restricted prognosis.There are limited data on the long-term outcome of PED under anti-VEGF therapy. Therefore, this study recorded the course of treated PEDs in nAMD eyes over a period of 5 years.All eyes with fPED or svPED that underwent anti-VEGF medication between 2006 and 2015 were retrospectively analyzed regarding the clinical course and the morphology seen on optical coherence tomography (OCT). The inclusion criteria were the detection of a PED on OCT, the angiographic verification of nAMD, a documented clinical history over 5 years and a good image quality.A total of 23 eyes from 22 patients met the inclusion criteria. After 5 years a significant deterioration of visual acuity (VA) was seen in all eyes (p = 0.007) and in the subgroup of cases with fPED (p = 0.045). In the eyes with svPED the decline of VA was not significant (p = 0.097). In the collective study group a statistically significant reduction of PED height (p = 0.006) and an increase of PED diameter was measured (p = 0.002). In the subgroup analysis the decrease of PED height and increase of PED diameter were significant for cases with svPED (p = 0.004, p = 0.013, respectively) but were not statistically significant for fPED eyes (height: p = 0.616; diameter: p = 0.097). In 17 (74%) eyes fibrosis or atrophy were seen on the final assessment of OCT images.After 5 years of anti-VEGF therapy for nAMD-associated PED the VA declined in half of the eyes and the OCT showed an unfavorable morphology in 3/4 of the cases. The average number of visits and injections was distinctly lower than in clinical trials and other real-life analyses. In summary, we observed an undertreatment with a worse functional and anatomical outcome in our clinical routine compared to other studies.HINTERGRUND: Die neovaskuläre altersabhängige Makuladegeneration (nAMD) ist die häufigste Ursache für das Auftreten einer Pigmentepithelabhebung (PED). Die Therapie der fibrovaskulären PED (fPED) und serös-vaskularisierten PED (svPED) mit intravitrealen VEGF(„vascular endothelial growth factor“)-Inhibitoren hat in der klinischen Praxis eine eingeschränkte Prognose.Die Datenlage zum PED-Langzeitverlauf ist überschaubar. Diese Arbeit erfasst den Verlauf therapierter PEDs bei nAMD über einen Zeitraum von 5 Jahren.Bei allen Augen, die im Zeitraum von 2006 bis 2015 aufgrund einer fPED oder svPED eine Behandlung mit Anti-VEGF-Präparaten erhielten, erfolgte eine retrospektive Analyse des klinischen Verlaufs und der Morphologie mittels optischer Kohärenztomographie (OCT). Es galten die folgenden Einschlusskriterien: OCT-Nachweis einer PED, angiographische Bestätigung einer nAMD, klinische Dokumentation über 5 Jahre sowie gute Bildqualität.Bei 23 Augen von 22 Patienten wurden die Einschlusskriterien erfüllt. Nach 5 Jahren zeigte sich im Gesamtkollektiv und in der Subgruppe der Augen mit fPED eine signifikante Verschlechterung des Visus (p = 0,007; p = 0,045). Bei den Augen mit svPED war die Visusabnahme nicht signifikant (p = 0,097). Im Gesamtkollektiv wurde eine statistisch signifikante Reduktion der PED-Höhe (p = 0,006) bei gleichzeitig signifikanter Zunahme des PED-Durchmessers (p = 0,002) gemessen, wobei innerhalb der Subgruppen die Abnahme der PED-Höhe und Zunahme des PED-Durchmessers nur für die Messwerte der svPED signifikant waren (p = 0,004; p = 0,013). Bei den Augen mit fPED war die Veränderung der OCT-Parameter nicht signifikant (p = 0,616; p = 0,097). Bei 17 (74 %) der Augen fand sich bei der finalen OCT-Beurteilung eine Fibrose oder Atrophie.Nach 5 Jahren Anti-VEGF-Behandlung bei nAMD-assoziierter PED zeigten sich in der Hälfte der Fälle eine Visusabnahme und in drei Viertel der Augen eine ungünstige OCT-Morphologie. Die mittlere Anzahl an Injektionen und Visiten war niedriger als in klinischen Studien und anderen Real-life-Erhebungen. Insgesamt beobachteten wir eine Unterbehandlung mit schlechterem funktionellem und anatomischem Outcome in unserer klinischen Praxis verglichen mit anderen Studien.

The incidence of differentiated thyroid carcinoma (DTC) has increased rapidly over the past several years. Thus far, the only conclusively established risk factor for developing DTC is exposure to ionizing radiation, especially when the exposure occurs in childhood. Since the number of childhood cancer survivors (CCS) is increasing due to improvements in treatment and supportive care, the number of patients who will develop DTC after surviving childhood cancer (secondary thyroid cancer) is also expected to rise. Currently, there are no recommendations for management of thyroid cancer specifically for patients who develop DTC as a consequence of cancer therapy during childhood. Since complications or late effects from prior cancer treatment may elevate the risk of toxicity from DTC therapy, the medical history of CCS should be considered carefully in choosing DTC treatment. In this paper, we emphasize how the occurrence and treatment of the initial childhood malignancy affects the medical and psychosocial factors that will play a role in the diagnosis and treatment of a secondary DTC. We present considerations for clinicians to use in the management of patients with secondary DTC, based on the available evidence combined with experience-based opinions of the authors.

Complex regional pain syndrome (CRPS) develops after-limb injury, with persistent pain and deficits in movement frequently co-occurring. The striatum is critical for mediating multiple mechanisms that are often aberrant in CRPS, which includes sensory and pain processing, motor function, and goal-directed behaviors associated with movement. Yet, much remains unknown with regards to the morphological and functional properties of the striatum and its subregions in this disease. Thus, we investigated 20 patients (15 female, age 58 ± 9 years, right-handed) diagnosed with chronic (6+ months of pain duration) CRPS in the right hand and 20 matched, healthy controls with anatomical and resting-state, functional magnetic resonance imaging. In addition, a comprehensive clinical and behavioral evaluation was performed, where each participant's pain, motor function, and medical history were assessed. Complex regional pain syndrome patients harbored significant abnormalities in hand coordination, dexterity, and strength. These clinical pain- and movement-related findings in CRPS patients were concomitant with bilateral decreases in gray matter density in the putamen as well as functional connectivity increases and decreases among the putamen and pre-/postcentral gyri and cerebellum, respectively. Importantly, higher levels of clinical pain and motor impairment were associated with increased putamen-pre-/postcentral gyri functional connectivity strengths. Collectively, these findings suggest that putaminal alterations, specifically the functional interactions with sensorimotor structures, may underpin clinical pain and motor impairment in chronic CRPS patients.

Knowledge of protein structures is essential to understand proteins' functions, evolution, dynamics, stabilities, and interactions and for data-driven protein- or drug design. Yet, experimental structure determination rates are far exceeded by that of next-generation sequencing, resulting in less than 1/1000th of proteins having an experimentally known 3D structure. Computational structure prediction seeks to alleviate this problem, and the Critical Assessment of Protein Structure Prediction (CASP) has shown the value of consensus and meta-methods that utilize complementary algorithms. However, traditionally, such methods employ majority voting during template selection and model averaging during refinement, which can drive the model away from the native fold if it is underrepresented in the ensemble. Here, we present TopModel, a fully automated meta-method for protein structure prediction. In contrast to traditional consensus and meta-methods, TopModel uses top-down consensus and deep neural networks to select templates and identify and correct wrongly modeled regions. TopModel combines a broad range of state-of-the-art methods for threading, alignment, and model quality estimation and provides a versatile workflow and toolbox for template-based structure prediction. TopModel shows a superior template selection, alignment accuracy, and model quality for template-based structure prediction on the CASP10-12 datasets compared to 12 state-of-the-art stand-alone primary predictors. TopModel was validated by prospective predictions of the nisin resistance protein (NSR) protein from Streptococcus agalactiae and LipoP from Clostridium difficile, showing far better agreement with experimental data than any of its constituent primary predictors. These results, in general, demonstrate the utility of TopModel for protein structure prediction and, in particular, show how combining computational structure prediction with sparse or low-resolution experimental data can improve the final model.

Aims Chronic kidney disease (CKD) is an independent risk factor for the development of coronary artery disease (CAD). For both, CKD and CAD, the intercellular transfer of microRNAs (miRs) through extracellular vesicles (EVs) is an important factor of disease development. Whether the combination of CAD and CKD affects endothelial function through cellular crosstalk of EV-incorporated miRs is still unknown. Methods and results Out of 172 screened CAD patients, 31 patients with CAD + CKD were identified and matched with 31 CAD patients without CKD. Additionally, 13 controls without CAD and CKD were included. Large EVs from CAD + CKD patients contained significantly lower levels of the vasculo-protective miR-130a-3p and miR-126-3p compared to CAD patients and controls. Flow cytometric analysis of plasma-derived EVs revealed significantly higher numbers of endothelial cell-derived EVs in CAD and CAD + CKD patients compared to controls. EVs from CAD + CKD patients impaired target human coronary artery endothelial cell (HCAEC) proliferation upon incubation in vitro. Consistent with the clinical data, treatment with the uraemia toxin indoxyl sulfate (IS)-reduced miR-130a-3p levels in HCAEC-derived EVs. EVs from IS-treated donor HCAECs-reduced proliferation and re-endothelialization in EV-recipient cells and induced an anti-angiogenic gene expression profile. In a mouse-experiment, intravenous treatment with EVs from IS-treated endothelial cells significantly impaired endothelial regeneration. On the molecular level, we found that IS leads to an up-regulation of the heterogenous nuclear ribonucleoprotein U (hnRNPU), which retains miR-130a-3p in the cell leading to reduced vesicular miR-130a-3p export and impaired EV-recipient cell proliferation. Conclusion Our findings suggest that EV-miR-mediated vascular intercellular communication is altered in patients with CAD and CKD, promoting CKD-induced endothelial dysfunction.

Objective: To evaluate factors associated with health dissatisfaction of public elementary school teachers. Methods: Cross-sectional study conducted among teachers from a Midwest capital, in 2017. A self-administered questionnaire composed of a collection of validated instruments and additional questions was used. Poisson Regression was performed, considering significance p

Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case–control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10% false-positivity rate which potentially produced substantial “misdiagnosis.”

Chondrocytes, comparable to many cells from the connective tissue, dedifferentiate and end up in a similar fibroblastoid cell type, marked by the loss of the specific expression pattern. Here, chondrocytes isolated from osteoarthritic (OA) patients were investigated. The OA chondrocytes used in this work were not affected by the loss of specific gene expression upon cell culture. The mRNA levels of known cartilage markers, such as SOX5, SOX6, SOX9, aggrecan and proteoglycan 4, remained unchanged. Since chondrocytes from OA and healthy tissue show different DNA methylation patterns, the underlying mechanisms of cartilage marker maintenance were investigated with a focus on the epigenetic modification by DNA methylation. The treatment of dedifferentiated chondrocytes with the DNA methyltransferase inhibitor 5-aza-2´-deoxycytidine (5-aza-dC) displayed no considerable impact on the maintenance of marker gene expression observed in the dedifferentiated state, while the chondrogenic differentiation capacity was compromised. On the other hand, the pre-cultivation with 5-aza-dC improved the osteogenesis and adipogenesis of OA chondrocytes. Contradictory to these effects, the DNA methylation levels were not reduced after treatment for four weeks with 1 μM 5-aza-dC. In conclusion, 5-aza-dC affects the differentiation capacity of OA chondrocytes, while the global DNA methylation level remains stable. Furthermore, dedifferentiated chondrocytes isolated from late-stage OA patients represent a reliable cell source for in vitro studies and disease models without the need for additional alterations.

Research to date on sprains, strains, and contusions has focused mainly on the analysis of sports-related injuries, occupational injuries, injuries resulting from automobile accidents, and severe injuries that result in inpatient hospital stays. Little is known about real-world acute sprains, strains, and contusions in an aging population. Patients may be treated with over-the-counter, oral, non-steroidal anti-inflammatory drugs (NSAIDs) for acute sprains, strains, and contusions or may require the use of prescription NSAIDs. For sprains, strains, and contusions treated with prescription NSAIDs, the choice of topical administration or oral administration likely depends on a number of factors such as age and comorbid conditions. The objective of the study was to identify factors associated with the use of a prescription topical NSAID or a prescription oral NSAID for the treatment of sprains, strains, and contusions among patients aged 65–89 years enrolled in the Medicare Advantage with Prescription Drug plan. The study sample was selected from the Humana Research Database (Louisville, KY, USA). Study subjects were identified as patients enrolled in Medicare Advantage with Prescription Drug plans, aged 65–89 years, having a medical claim with an International Classification of Diseases, Ninth Revision, Clinical Modification indicative of an acute sprain, strain, and contusion between 1 January, 2010 and 31 March, 2014 (identification period). The date of the first claim was considered the index date, and subjects were required to have 12 months of continuous enrollment before the index date and a minimum of 3 months continuous enrollment after the index date. Prescription NSAID use during the 3 months after the index sprain, strain, and contusion diagnosis was required for study inclusion and was identified based on a pharmacy claim for a topical or an oral NSAID. Patients with prescription NSAID use leading up to the sprains, strains, and contusions were excluded. Potential factors related to the use of a topical vs. oral NSAID were identified using stepwise logistic regression with backward elimination. After applying the inclusion and exclusion criteria, 42,283 patients were prescribed an oral or topical NSAID (39,294 oral; 2989 topical) within 3 months of the index sprain, strain, and contusion diagnosis. After applying stepwise logistic regression, and retaining variables with statistically significant parameter estimates (p < 0.05), use of topical NSAIDs was higher among female individuals [odds ratio and 95% confidence interval = 1.34 (1.24–1.45)], and appeared to increase with age [odds ratio = 1.04 (1.04–1.05)]. Topical NSAID use was lower in the Midwest region [odds ratio = 0.85 (0.77–0.94)] in comparison to the Southern region. Clinical factors associated with topical NSAID use included Elixhauser Comorbidity Index score [odds ratio = 1.06 (1.04–1.09)], medication burden [odds ratio = 1.06 (1.04–1.08), pill burden [odds ratio = 1.02 (1.01–1.03), specific comorbid conditions, including site-specific osteoarthritis of the upper arm [odds ratio = 2.34 (1.19–4.60)], ankle/foot [odds ratio = 1.46 (1.14–1.87)], or lower leg [odds ratio = 1.21 (1.07–1.36)], myofascial pain [odds ratio = 1.31 (1.21–1.42)], gastrointestinal/hepatic disorders [odds ratio = 1.15 (1.05–1.25)], systemic/central pain [odds ratio = 1.12 (1.01–1.23)], and cataracts [odds ratio = 1.10 (1.02–1.20)]. Conversely, a diagnosis of diabetes mellitus was related to use of an oral NSAID rather than a topical NSAID [odds ratio = 0.86 (0.78–0.94)]. Diagnosis of the index sprain, strain, and contusion in an emergency department instead of a physician’s office was also associated with oral NSAID use [odds ratio = 0.42 (0.37–0.47)]. Topical NSAIDs were used less often than oral NSAIDs following a sprain, strain, or contusion. Age, medication burden, pill burden, evidence of gastrointestinal disorder, and evidence of certain pain-related conditions were significant factors associated with topical NSAID as opposed to oral NSAID use. In comparison to oral NSAIDs, topical NSAIDs were more likely to be prescribed in a physician’s office than an emergency department, possibly because a patient’s physician has a better understanding of the patient’s concomitant medications and comorbidities. Although topical NSAIDs were more likely to be used than oral NSAIDs in patients with gastrointestinal disorders, the use of oral NSAIDs among patients with gastrointestinal bleeding was substantial.

Aims We conducted a nationwide educational initiative to determine the prevalence and risk factors of diagnosed and undiagnosed painful and painless distal sensory polyneuropathy (DSPN). Methods Among 1850 participants, 781 had no history of diabetes (ND), 126 had type 1 diabetes (T1D), and 943 had type 2 diabetes (T2D). Painful DSPN was defined as polyneuropathy detected by bedside tests with pain and/or burning in the feet, while painless DSPN was defined as polyneuropathy with paresthesias, numbness, or absence of symptoms. Results DSPN was detected in 48.2% of ND, 44.3% of T1D, and 55.3% of T2D subjects. DSPN was painful, painless, or atypical in 62.1, 24.8, and 13.1% of the participants. Painful DSPN was more severe than painless DSPN. Painful and painless DSPN were previously undiagnosed in 61.5 and 81.1% of the participants, respectively. In T2D subjects, painful and painless DSPN were associated with a higher and lower BMI, respectively. Among ND participants 39.2% had HbA1c levels indicating prediabetes/diabetes. Conclusions Around half of participants in an educational initiative had DSPN, 62% of whom had the painful entity that correlated with BMI in T2D. Since many cases of neuropathy and diabetes remain undiagnosed, effective strategies to timely detect both conditions should be implemented.

Objective To assess the changes resulting from the changes from UICC/AJCC TNM version 7 to version 8 and to subsequently determine whether TNM version 8 is an improvement compared to previous iterations of the TNM system and other staging systems for differentiated thyroid cancer (DTC) with regard to prognostic power. Design Database study of DTC patients treated in our centre between 1978 up to and including 1 July 2014. Results were compared to our previous comparison of prognostic systems using the same data set. Patients 2257 DTC patients. Measurements Staging in accordance with TNM 7 and TNM 8. Thyroid cancer-specific mortality; comparison was based on p-values of univariate Cox regression analyses as well as analysis of the proportion of variance explained (PVE). Results There is a redistribution from stage 3 to lower stages affecting 206 (9.1%) patients. DTC-related mortality according to Kaplan-Meier for younger and older patients in TNM 7 had a slightly lower prognostic power than that in accordance with TNM 8 (P = 8.0 10-16 and P = 1.5 10-21 , respectively). Overall staging is lower in 627/2257 (27.8%) patients. PVE (TNM 7: 0.29; TNM 8: 0.28) and the P-value of Cox regressions (TNM 7: P = 7.1*10-52 ; TNM 8: P = 3.9*10-49 ) for TNM version 8 are marginally lower than that for TNM version 7, but still better than for any other DTC staging system. Conclusion TNM 8 results in a marked downstaging of patients compared to TNM 7. Although some changes, like the change in age boundary, appear to be associated with an improvement in prognostic power, the overall effect of the changes does not improve the predictive power compared to TNM 7.

Contains fulltext : 196376.pdf (Publisher’s version ) (Closed access) BACKGROUND: Subclinical hypothyroidism is associated with dyslipidemia and atherosclerosis. Whether these effects are in part mediated via direct effects of thyrotropin (TSH) on peripheral thyroid hormone (TH) metabolism and/or concentrations of serum lipids is not clear. OBJECTIVE: This study examined whether TSH has direct effects on peripheral TH metabolism and serum lipids. METHODS: Eighty-two patients with differentiated thyroid cancer were retrospectively analyzed. All patients had undergone total thyroidectomy and (131)I remnant ablation. During follow-up, two successive injections of recombinant human TSH (rhTSH) were administered to patients on a stable dose of levothyroxine. In all patients, TSH, thyroxine (T4), free T4 (fT4), triiodothyronine (T3), reverse T3 (rT3), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), and triglyceride levels were measured immediately before the first and approximately 72 hours after the second injection of rhTSH. RESULTS: After rhTSH stimulation, T3 values decreased (from 1.91 to 1.81 nmol/L; p < 0.001). T4, fT4, and rT3 did not change. After rhTSH, median apolipoprotein B increased from 0.90 to 0.92 g/L (p = 0.03), lipoprotein(a) from 0.21 to 0.24 g/L (p < 0.001), and triglycerides from 1.98 to 2.50 mmol/L (p < 0.001). Serum high-density lipoprotein cholesterol decreased from 0.98 to 0.81 mmol/L (p < 0.001). Multiple regression analysis showed that the changes in lipids were most closely associated with the decrease in T3 levels. CONCLUSIONS: TSH has direct effects on peripheral TH metabolism by decreasing T3 levels in levothyroxine-treated thyroidectomized patients. This decrease in T3 levels is accompanied by unfavorable changes in serum lipids.

The objective of the work was to investigate the relationship between thyroglobulin doubling time (TgDT) as a marker of speed of response to 131I-therapy and the differentiated thyroid cancer (DTC) recurrence rate, DTC specific mortality rate, and relative survival rate in a DTC population followed over a long period of time after 131I-therapy. From our database, data of 1354 patients were reviewed. TgDT could be calculated in 174 patients, however, 376 patients did not have sufficient Tg values available for TgDT calculation and 804 patients reached biochemical remission before a sufficient number of Tg measurements for TgDT calculation was acquired. Main outcome measures were recurrence-free, DTC specific, and relative survival rates. In patients

SummaryAim: In a screening study on people of working age the prevalence of morphological thyroid disorders was 33.1 %. It is not known precisely whether this further increases after retirement. The present study aimed to establish whether the increase in the prevalence of morphological and functional thyroid disorders continues beyond working age in elderly citizens. Methods: 223 participants were recruited in an institute for geriatric rehabilitative medicine. All patients were screened by thyroid ultrasound, measurement of serum levels of thyroid hormones and thyroid related autoantibodies as well as measurement of urinary iodine excretion. Results: The median thyroid volume was 17 ml (range 4-41 ml) in men and 16 ml (range 0.4-73 ml) in women. 27/59 (46 %) of the men (median age [range]: 77 [58-87] years) and 85/139 (61 %) of the women (median age [range]: 77 [52-97] years), or a total of 112/198 (57 %) residents, showed morphological thyroid abnormalities. There was no clear increase with age. 85 % of the participants without a history of thyroid treatment were euthyroid. 12 % showed a subclinical hyperthyroidism whereas 1 % showed a biochemically manifest hyperthyroidism. 2 % were biochemically hypothyroid. Tg-antibodies was elevated in 10 (5 %) and TPO-antibodies in 18 (9 %) of the patients. Median iodine excretion was 129 pg/l. 41.5 % of the patients showed iodine excretion values below 100 pg/l whereas only 7 % of the patients showed a severe iodine deficiency with an excretion below 50 pg/l. Conclusion: Compared to a previously described population of working age, the prevalence of morphological thyroid disorders does not further increase above the age of 65; thyroid function abnormalities in this iodine sufficient screening population were relatively rare.

Complex regional pain syndrome (CRPS) is a poorly understood pain disorder of the limbs. Maladaptive cortical plasticity has been shown to play a major role in its pathophysiological presentation. Recently, there is increasing interest in the role of the basal ganglia (BG), since clinical findings and neuroimaging studies point to possible BG involvement in CRPS. CRPS symptoms are often characterized by movement disorders associated with BG dysfunction. Very frequently, dystonia and tremor are reported and, to a lesser extent, myoclonus. Neuroimaging studies present inconsistent findings concerning altered brain networks and mainly focus on cortical areas. Subcortical contribution to this disorder has so far been neglected. Clinical data presenting BG dysfunction-related movement disorders in CRPS patients raise the hypothesis of BG dysfunction in this syndrome. Moreover, several neuroimaging studies documented abnormalities in the BG and in the frontal, parietal and limbic cortical areas. These regions are functionally and anatomically connected in motor, pain and working memory networks. Put together, these findings call for further characterization of the dynamic cortical and subcortical interactions in CRPS. Significance This paper presents an overview of our current knowledge about BG pathology in CRPS. A better understanding of the involvement of the BG in the CRPS pathology holds the potential for developing and improving efficacious, mechanism-based treatment modalities.

Introduction Innate immunity represents the first step of activation of the immune system and dictates the quality of adaptive immune responses. Studies have reported links between systemic inflammatory or innate immune markers and prognosis in patients with lung cancer. To our knowledge, the prospective and concomitant study of these systemic markers has never been performed. Methods Advanced treatment-naive non–small cell lung cancer (NSCLC) patients eligible for first-line platinum-based chemotherapy were prospectively included from December 2012 to July 2015 (N = 148). Blood samples of patients were collected before the first cycle for fresh NK cell phenotyping. Peripheral blood mononuclear cells were cryopreserved for natural cytotoxicity receptor (NCR) genotyping as well as sera for NCR's ligand quantification. Data on leukocytes, neutrophils and monocyte counts and lactate dehydrogenase (LDH) levels were extracted from electronic medical records. Results Among all studied markers, monocytosis, neutrophilia, leucocytosis, high LDH and sBAG6 levels and reduced levels of NCR3 transcripts were associated with poor overall survival (OS) in univariate analysis. The levels of NCR3 transcripts was linked to age, number of metastatic sites, monocyte counts, LDH and sBAG6 levels. Neutrophilia was associated to high sBAG6 levels. NCR3 was the unique innate immune parameter that remained as an independent factor associated with both OS (P = 0.003) and progression-free survival (P = 0.009) in the multivariate analysis. Conclusion This study brought evidence that these biomarkers are entangled; parameters associated with an inflammatory process were related to reduced levels of NCR3 transcripts. Finally, the level of NCR3 transcripts was independently associated with outcomes in treatment-naive patients with advanced NSCLC.

Background Due to the current poaching crisis in Africa, increasing numbers of white rhinoceroses (Ceratotherium simum) require opioid immobilisation for medical interventions or management procedures. Alarmingly, the results of both blood gas analysis and pulse oximetry regularly indicate severe hypoxaemia. Yet, the recovery of the animals is uneventful. Thus, neither of the techniques seems to represent the real oxygenation level. We hypothesized that unusual haemoglobin characteristics of this species interfere with the techniques developed and calibrated for the use in human patients. Methods Haemoglobin was isolated from blood samples of four adult, white rhinoceroses. Oxygen dissociation curves at pH 7.2 and 7.4 (37°C) were determined based on the absorbance change of haemoglobin in the Soret-region (around 420 nm). Absorbance spectra of oxy- and deoxyhaemoglobin extending into the infrared region were measured. Results Oxygen dissociation curves of rhinoceros haemoglobin showed the typical high oxygen affinity (p50 of 2.75 ± 0.07 and 2.00 ± 0.04 kPa for pH 7.2 and 7.4, respectively) under near-physiological conditions with respect to pH, temperature and DPG. The infrared absorbance spectra of oxy- and deoxyhaemoglobin showed only marginal deviations from standard human spectra, possibly due to the presence of a few percent of methaemoglobin in vitro. Conclusions Our data enables the development of a rhinoceros-specific blood gas analysis algorithm, which allows for species-specific calculation of SaO2 levels in anaesthetized animals. The inconspicuous absorbance spectra do not contribute to the systematic underestimation of SpO2 by pulse-oximetry.

Extracellular vesicles released by tumor cells contribute to the reprogramming of the tumor microenvironment and interfere with hallmarks of cancer including metastasis. Notably, melanoma cell-derived EVs are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. However, molecular insights into how vesicles are selectively packaged with cargo defining their specific functions remain elusive. Methods: Here, we investigated the role of the chaperone Bcl2-associated anthogene 6 (BAG6, synonym Bat3) for the formation of pro- and anti-tumor EVs. EVs collected from wildtype cells and BAG6-deficient cells were characterized by mass spectrometry and RNAseq. Their tumorigenic potential was analyzed using the B-16V transplantation mouse melanoma model. Results: We demonstrate that EVs from B-16V cells inhibit lung metastasis associated with the mobilization of Ly6Clow patrolling monocytes. The formation of these anti-tumor-EVs was dependent on acetylation of p53 by the BAG6/CBP/p300-acetylase complex, followed by recruitment of components of the endosomal sorting complexes required for transport (ESCRT) via a P(S/T)AP double motif of BAG6. Genetic ablation of BAG6 and disruption of this pathway led to the release of a distinct EV subtype, which failed to suppress metastasis but recruited tumor-promoting neutrophils to the pre-metastatic niche. Conclusion: We conclude that the BAG6/CBP/p300-p53 axis is a key pathway directing EV cargo loading and thus a potential novel microenvironmental therapeutic target. CA extern

Thyroid nodules are detected in up to 50 to 60% of healthy subjects. Most nodules do not cause clinically significant symptoms, and as a result, the main challenge in their management is to rule out malignancy, with ultrasonography (US) and fine-needle aspiration (FNA) biopsy serving as diagnostic cornerstones. The key issues discussed in these guidelines are as follows: (1) US-based categorization of the malignancy risk and indications for US-guided FNA (henceforth, FNA), (2) cytologic classification of FNA samples, (3) the roles of immunocytochemistry and molecular testing applied to thyroid FNA, (4) therapeutic options, and (5) follow-up strategy. Thyroid nodule management during pregnancy and in children are also addressed. On the basis of US features, thyroid nodules may be categorized into 3 groups: low-, intermediate-and high-malignancy risk. FNA should be considered for nodules ≤10 mm diameter only when suspicious US signs are present, while nodules ≤5 mm should be monitored rather than biopsied. A classification scheme of 5 categories (nondiagnostic, benign, indeterminate, suspicious for malignancy, or malignant) is recommended for the cytologic report. Indeterminate lesions are further subdivided into 2 subclasses to more accurately stratify the risk of malignancy. At present, no single cytochemical or genetic marker can definitely rule out malignancy in indeterminate nodules. Nevertheless, these tools should be considered together with clinical data, US signs, elastographic pattern, or results of other imaging techniques to improve the management of these lesions. Most thyroid nodules do not require any treatment, and levothyroxine (LT4) suppressive therapy is not recommended. Percutaneous ethanol injection (PEI) should be the first-line treatment option for relapsing, benign cystic lesions, while US-guided thermal ablation treatments may be considered for solid or mixed symptomatic benign thyroid nodules. Surgery remains the treatment of choice for malignant or suspicious nodules. The present document updates previous guidelines released in 2006 and 2010 by the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE) and Associazione Medici Endocrinologi (AME).

// Hinrich P. Hansen 1 , Ahmad Trad 2 , Maria Dams 1 , Paola Zigrino 3 , Marcia Moss 4 , Maximilian Tator 1 , Gisela Schon 1 , Patricia C Grenzi 1 , Daniel Bachurski 1 , Bruno Aquino 5 , Horst Durkop 6 , Katrin S Reiners 1 , Michael von Bergwelt-Baildon 1 , Michael Hallek 1 , Joachim Grotzinger 2 , Andreas Engert 1 , Adriana F Paes Leme 5 , Elke Pogge von Strandmann 1 1 Department of Internal Medicine I, University of Cologne, Cologne, Germany 2 Department of Biochemistry, University Kiel, Kiel, Germany 3 Department of Dermatology, University of Cologne, Cologne, Germany 4 BioZyme Inc., Apex, North Carolina, USA 5 Brazilian Biosciences National Laboratory, LNBio, CNPEM, Campinas, Brazil 6 Pathodiagnostik Berlin, Berlin, Germany Correspondence to: Hinrich P. Hansen, e-mail: h.hansen@uni-koeln.de Keywords: Hodgkin lymphoma, extracellular vesicle, CD30, ADAM10, Brentuximab-Vedotin Received: January 11, 2016 Accepted: March 31, 2016 Published: April 20, 2016 ABSTRACT The goal of targeted immunotherapy in cancer is to damage both malignant and tumor-supporting cells of the microenvironment but spare unaffected tissue. The malignant cells in classical Hodgkin lymphoma (cHL) selectively express CD30. They release this receptor on extracellular vesicles (EVs) for the tumor-supporting communication with CD30 ligand (CD30L)-positive bystander cells. Here, we investigated how CD30-positive EVs influence the efficacy of the CD30 antibody drug conjugate (ADC) Brentuximab Vedotin (SGN-35). The malignant cells and the EVs expressed the active sheddase ADAM10. ADAM10 cleaved and released the CD30 ectodomain (sCD30), causing a gradual depletion of SGN-35 binding sites on EVs and creating a soluble competitor of the ADC therapy. In a 3D semi-solid tumor microenvironment model, the EVs were retained in the matrix whereas sCD30 penetrated readily into the surrounding culture medium. This resulted in a lowered ratio of EV-associated CD30 (CD30EV) to sCD30 in the surrounding medium in comparison to non-embedded cultures. A low percentage of CD30EV was also detected in the plasma of cHL patients, supporting the clinical relevance of the model. The adherence of CD30EV but not sCD30 to CD30 – /CD30L + mast cells and eosinophils allowed the indirect binding of SGN-35. Moreover, SGN-35 damaged CD30-negative cells, provided they were loaded with CD30 + EVs.