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The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Standard values of the upper body posture in healthy adults with special regard to age, sex and BMI
(2023)
In order to classify and analyze the parameters of upper body posture in clinical or physiotherapeutic settings, a baseline in the form of standard values with special regard to age, sex and BMI is required. Thus, subjectively healthy men and women aged 21–60 years were measured in this project. The postural parameters of 800 symptom-free male (n = 397) and female (n = 407) volunteers aged 21–60 years (Ø♀: 39.7 ± 11.6, Ø ♂: 40.7 ± 11.5 y) were studied. The mean height of the men was 1.8 ± 0.07 m, with a mean body weight of 84.8 ± 13.1 kg and an average BMI of 26.0 ± 3.534 kg/m2. In contrast, the mean height of the women was 1.67 ± 0.06 m, with a mean body weight of 66.5 ± 12.7 kg and an average BMI of 23.9 ± 4.6 kg/m2. By means of video rasterstereography, a 3-dimensional scan of the upper back surface was measured when in a habitual standing position. The means or medians, confidence intervals, tolerance ranges, the minimum, 2.5, 25, 50, 75, 97.5 percentiles and the maximum, plus the kurtosis and skewness of the distribution, were calculated for all parameters. Additionally, ANOVA and a factor analyses (sex, BMI, age) were conducted. In both sexes across all age groups, balanced, symmetrical upper body statics were evident. Most strikingly, the females showed greater thoracic kyphosis and lumbar lordosis angles (kyphosis: Ø ♀ 56°, Ø♂ 51°; lordosis: Ø ♀ 49°, Ø♂ 32°) and lumbar bending angles (Ø ♀ 14°, Ø♂ 11°) than the males. The distance between the scapulae was more pronounced in men. These parameters also show an increase with age and BMI, respectively. Pelvic parameters were independent of age and sex. The upper body postures of women and men between the ages of 21 and 60 years were found to be almost symmetrical and axis-conforming with a positive correlation for BMI or age. Consequently, the present body posture parameters allow for comparisons with other studies, as well as for the evaluation of clinical (interim) diagnostics and applications.
By the fabrication of periodically arranged nanomagnetic systems it is possible to engineer novel physical properties by realizing artificial lattice geometries that are not accessible via natural crystallization or chemical synthesis. This has been accomplished with great success in two dimensions in the fields of artificial spin ice and magnetic logic devices, to name just two. Although first proposals have been made to advance into three dimensions (3D), established nanofabrication pathways based on electron beam lithography have not been adapted to obtain free-form 3D nanostructures. Here we demonstrate the direct-write fabrication of freestanding ferromagnetic 3D nano-architectures. By employing micro-Hall sensing, we have determined the magnetic stray field generated by our free-form structures in an externally applied magnetic field and we have performed micromagnetic and macro-spin simulations to deduce the spatial magnetization profiles in the structures and analyze their switching behavior. Furthermore we show that the magnetic 3D elements can be combined with other 3D elements of different chemical composition and intrinsic material properties.
Objectives: Symmetrical dental occlusion blocking is used in dentistry as a quick diagnostic tool to test for potential influences of the craniomandibular system on body sway and weight distribution. This study presents the changes of body sway and pressure distribution in healthy subjects, free of a temporomandibular dysfunction (TMD). Immediate effects between occlusal blocking and rest position on body sway and body weight distribution in general, as well as for both genders and for four age decades will be evaluated.
Materials and methods: 725 (396f/329 m) subjects (neither subjective signs of TMD nor acute/chronic complaints in the musculoskeletal system) volunteered (21 to 60 years) while both genders were divided into four age groups according to decades. A pressure measuring platform was used. Body sway and weight distribution were recorded in two dental occlusion conditions (a) in rest position and (b) symmetrical blocking (bicuspid region) by cotton rolls.
Results: Both, the frontal sway and the sagittal sway reduced by 0.67 mm (t(724) = − 3.9 (p < 0.001)) and by 0.33 mm (t(724) = − 3.4 (p < 0.001)). The relative pressure under the left forefoot increased by 0.33% (t(724) = 2.88 (p < 0.001)) and the relative pressure overall under the forefoot increased by 0.67% (t(724) = − 3.4 (p < 0.001)). Gender-specific, age-specific and BMI-specific reactions could not be identified.
Conclusions: Subjects, free of any TMD and with no complaints of the musculoskeletal system, show small changes of the body sway and weight distribution when biting symmetrically on a cotton roll. These changes are independent of age, gender or body mass index (BMI). Due to the relative large sample size, the presented results can also be seen as norm values when body sway is used as an additional assessment of a TMD.
Aims: Balloon pulmonary angioplasty (BPA) is an interventional treatment modality for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Therapy monitoring, based on non-invasive biomarkers, is a clinical challenge. This post-hoc study aimed to assess dynamics of high-sensitivity cardiac troponin T (hs-cTnT) as a marker for myocardial damage and its relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels as a marker for cardiac wall stress.
Methods and results: This study included 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between 3/2014 and 3/2017. Biomarker measurement was performed consecutively prior to each BPA and at 6-MFU.
In total, the 51 patients underwent an average of 5 BPA procedures. The 6-month survival rate was 96.1%. The baseline (BL) meanPAP (39.5±12.1mmHg) and PVR (515.8±219.2dyn×sec×cm-5) decreased significantly within the 6-MFU (meanPAP: 32.6±12.6mmHg, P<0.001; PVR: 396.9±182.6dyn×sec×cm-5, P<0.001). At BL, the median hs-cTnT level was 11 (IQR 6–16) ng/L and the median NT-proBNP level was 820 (IQR 153–1872) ng/L. The levels of both biomarkers decreased steadily after every BPA, showing the first significant difference after the first procedure. Within the 6-MFU, hs-cTnT levels (7 [IQR 5–12] ng/L; P<0.001) and NT-proBNP levels (159 [IQR 84–464] ng/l; P<0.001) continued to decrease. The hs-cTnT levels correlated with the PVR (rrs = 0.42; p = 0.005), the meanPAP (rrs = 0.32; p = 0.029) and the NT-proBNP (rrs = 0.51; p<0.001) levels at BL.
Conclusion: Non-invasive biomarker measurement provides valuable evidence for the decreasing impairment of myocardial function and structure during BPA therapy. Changes in hs-cTNT levels are suggestive for a reduction in ongoing myocardial damage.
The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC‐induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X‐linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B‐cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event‐free survival in patients treated with spindle poison‐containing chemotherapy. Accordingly, aggressive B‐cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ‐Myc lymphoma model. Together, we specify the USP9X–XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B‐cell lymphoma.
Background: Temporary occlusal changes and their influence on the upper body statics are still controversially discussed. Furthermore, concrete statements on whether age- or gender-specific differences in neurophysiological reactions exist are missing. Therefore, it is the aim of this study to evaluate the immediate effects of a symmetrical occlusion blocking on the upper body posture. These effects shall be investigated for both genders and for a larger age range.
Methods: In this study, 800 (407f/393 m) subjects volunteered aged from 21 to 60 years. Both genders were divided into four age groups according to decades. The three-dimensional upper body posture was measured by using the rasterstereography (ABW-Bodymapper). The habitual static posture was measured in two dental occlusion conditions (a) in rest position and (b) symmetrical blocking in the bicuspid region by cotton rolls.
Results: A significant reduction of the trunk length (0.72 mm; p < 0.001), an increase of the lumbar (0.30°; p < 0.001) and the thoracic bending angle (0.14°; p = 0.001), a reduction of the spinal forward decline (0.16°; p < 0.001) and a reduction of the scapular distance (0.36 mm; p = 0.001) was found. Gender-specific reactions can only be recorded in scapular distance, in that regard men reduce this distance while over all age groups women did not show a significant change.
Discussion: Slight gender- and age-independent reactions due to a symmetric occlusion blockade are shown: A gender independent reaction of the spinal related variables in the sagittal plane (thoracic and lumbar flexion angle, trunk length, spinal forward decline). In addition, a gender specific change of the shoulder blade distance could be observed, where men reduced the distance while female did not show a change. However, since these reactions are of a minimum amount, it can be concluded that neurophysiological compensation mechanisms work equally well regardless of age and sex, and the upper body posture of healthy people changes only very slightly due to a temporarily symmetrical altered bite position.
The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.
Background: In order to determine possible pathological deviations in body weight distribution and body sway, it is helpful to have reference values for comparison: gender and age are two main influencing factors. For this reason, it was the aim of the present study to present reference values for women between 51 and 60 years of age.
Methods: For this study, 101 subjectively healthy female Germans aged between 51 and 60 years (55.16 ± 2.89 years) volunteered and were required to stand in a habitual posture on a pressure measuring platform.
Results: The average BMI of this age group was 25.02 ± 4.55 kg/m². The left and right foot showed an almost evenly balanced load distribution with a median load of 52.33% on the left foot [tolerance interval (TR) 38.00%/68.03%; confidence interval (CI) 51.00%/53.33%] and 47.67% on the right foot [TR 31.97%/62.00%; CI 46.67%/49.00%]. The measured median load of the forefoot was 33.33% [TR 21.37%/54.60%; CI 30.67%/36.00%] and that of the rear foot was 66.67% [TR 45.50%/78.63%; CI 64.00%/69.33%]. The median body sway in the frontal plane was 11 mm [TR 5.70 mm/26.30 mm; CI 10.00 mm/11.67 mm] and that of the sagittal plane was 16 mm [TR 7.37 mm/34.32 mm; CI 14.67 mm/18.67 mm]. The median ellipse area was 1.17 cm² [TR 0.29 cm²/4.96 cm²; CI 0.98 cm²/1.35 cm²], the median ellipse width was 0.91 cm [TR 0.42 cm/1.9 cm; CI 0.84 cm/1.02 cm] and its height was 0.40 cm [TR 0.22 cm/0.89 cm; CI 0.38 cm/0.43 cm].
Conclusions: The left-to-right ratio is almost balanced. The load distribution of the forefoot to the rear foot is approximately 1:2. The median body sway values for the frontal and sagittal planes (11 and 16 mm, respectively) agree with other values. The values for the height, body weight and the BMI are comparable to the values of average German women at this age; therefore, the measured values show a presentable cross section of women in the 51–60 age group in Germany. The present data can be used as a basis for women aged 51–60 years and can support the detection of possible dysfunctions as well as injury prevention in the parameters of postural control.
Engerlinge, die Larven der Scarabaeidae (Coleoptera), gehören weltweit zu den wichtigsten Bodenschädlingen und ihre Bedeutung scheint zuzunehmen. Wirksame, aber umweltschädigende und gesundheitsgefährdende Insektizide wurden verboten. In gewissen Regionen oder für bestimmte Indikationen waren nie welche bewilligt und im biologischen Anbau standen keine Bekämpfungsmittel zur Verfügung. Aus diesen Gründen wurde die Entwicklung von Mykoinsektiziden gegen Ende des letzten Jahrhunderts forciert. Heute stehen in der Schweiz zwei Produkte zur Verfügung: Ein Produkt basierend auf Beauveria brongniartii (Sacc.) Petch (Ascomycetes, Clavicipitaceae) zur Bekämpfung der Maikäfer (Melolontha melolontha L.)-Engerlinge und ein anderes basierend auf Metarhizium ansiopliae (Metschn.) Sorokin (Ascomycetes, Nectriaceae) zur Bekämpfung der Engerlinge des Juni- und des Gartenlaubkäfers [Amphimallon solostiale L., A. majale (Razoum.), Phyllopertha horticola L.]. Ersteres ist seit seiner Markteinführung 1991 zum Mittel der Wahl geworden, rund 2500 ha wurden bis heute damit behandelt (Keller, 2000a, 2004). Die Erfahrungen zeigen, dass besonderes Augenmerk auf die Qualität des Produktes und die Applikation sowie auf den Applikationszeitpunkt gelegt werden muss. Mit genetischen Markern stehen wirksame Hilfsmittel zum Studium der Ausbreitung, der Persistenz und der Nebenwirkungen zur Verfügung (Enkerli et al. 2001). Bei der Anwendung von M. anisopliae bestehen noch wenige Praxiserfahrungen. Das Produkt wurde bisher vorwiegend auf Golfplätzen eingesetzt. Über Langzeitwirkungen, die im Falle der Blastosporenanwendung von B. brongniartii gut dokumentiert sind (Keller, 2004), liegen erst wenige Daten vor. In den letzten Jahren wurden vermehrt Engerlingsschäden beobachtet, die durch zwei oder mehr Arten von Engerlingen verursacht werden. Wenn Maikäfer-Engerlinge beteiligt sind, stellt sich das Problem, dass zwei Pilzarten zur Bekämpfung eingesetzt werden müssen. Zur Zeit laufen Untersuchungen in solchen Schadgebieten, die Aufschluss geben werden über die wirksamste Art der Behandlung und über mögliche Interaktionen zwischen den Pilzen. In diesem Beitrag werden die neuesten Untersuchungsergebnisse vorgestellt.
In this paper we present first-order reversal curve (FORC) diagrams of ensembles of three-dimensional Co3Fe nanostructures as 2 × 2 arrays of nano-cubes and nano-trees. The structures are fabricated and investigated by an advanced platform of focused electron beam induced deposition combined with high-resolution detection of magnetic stray fields using a home-built micro-Hall magnetometer based on an AlGaAs/GaAs heterostructure. The experimental FORC diagrams are compared to macrospin simulations for both geometries at different angles of the externally applied magnetic field. The measured FORC diagrams are in good agreement with the simulated ones and reflect non-uniform magnetization reversal dominated by multi-vortex states within, and strong magnetic coupling between, the building blocks of our nanostructures. Thus, a FORC analysis of small arrays of 3D magnetic nanostructures provides more detailed insights into the mechanisms of magnetization reversal beyond standard major hysteresis loop measurements.
Sample-based longitudinal discrete choice experiments: preferences for electric vehicles over time
(2021)
Discrete choice experiments have emerged as the state-of-the-art method for measuring preferences, but they are mostly used in cross-sectional studies. In seeking to make them applicable for longitudinal studies, our study addresses two common challenges: working with different respondents and handling altering attributes. We propose a sample-based longitudinal discrete choice experiment in combination with a covariate-extended hierarchical Bayes logit estimator that allows one to test the statistical significance of changes. We showcase this method’s use in studies about preferences for electric vehicles over six years and empirically observe that preferences develop in an unpredictable, non-monotonous way. We also find that inspecting only the absolute differences in preferences between samples may result in misleading inferences. Moreover, surveying a new sample produced similar results as asking the same sample of respondents over time. Finally, we experimentally test how adding or removing an attribute affects preferences for the other attributes.
Neurogenic dysphagia is one of the most frequent and prognostically relevant neurological deficits in a variety of disorders, such as stroke, parkinsonism and advanced neuromuscular diseases. Flexible endoscopic evaluation of swallowing (FEES) is now probably the most frequently used tool for objective dysphagia assessment in Germany. It allows evaluation of the efficacy and safety of swallowing, determination of appropriate feeding strategies and assessment of the efficacy of different swallowing manoeuvres. The literature furthermore indicates that FEES is a safe and well-tolerated procedure. In spite of the huge demand for qualified dysphagia diagnostics in neurology, a systematic FEES education has not yet been established. The structured training curriculum presented in this article aims to close this gap and intends to enforce a robust and qualified FEES service. As management of neurogenic dysphagia is not confined to neurologists, this educational programme is applicable to other clinicians and speech–language therapists with expertise in dysphagia as well. The systematic education in carrying out FEES across a variety of different professions proposed by this curriculum will help to spread this instrumental approach and to improve dysphagia management.
Objective: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.
Design: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.
Results: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.
Conclusion: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Background: The introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF.
Methods: Contemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used.
Results: In the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %.
Conclusions: Troponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
The current pandemic situation caused by the Betacoronavirus SARS-CoV-2 (SCoV2) highlights the need for coordinated research to combat COVID-19. A particularly important aspect is the development of medication. In addition to viral proteins, structured RNA elements represent a potent alternative as drug targets. The search for drugs that target RNA requires their high-resolution structural characterization. Using nuclear magnetic resonance (NMR) spectroscopy, a worldwide consortium of NMR researchers aims to characterize potential RNA drug targets of SCoV2. Here, we report the characterization of 15 conserved RNA elements located at the 5′ end, the ribosomal frameshift segment and the 3′-untranslated region (3′-UTR) of the SCoV2 genome, their large-scale production and NMR-based secondary structure determination. The NMR data are corroborated with secondary structure probing by DMS footprinting experiments. The close agreement of NMR secondary structure determination of isolated RNA elements with DMS footprinting and NMR performed on larger RNA regions shows that the secondary structure elements fold independently. The NMR data reported here provide the basis for NMR investigations of RNA function, RNA interactions with viral and host proteins and screening campaigns to identify potential RNA binders for pharmaceutical intervention.
Background: For prostate cancer treatment, treatment options with minimal side effects are desired. External beam radiation therapy (EBRT) is non-invasive, standard of care and delivered in either conventional fractionation over 8 weeks or with moderate hypo-fractionation over about 5 weeks. Recent advances in radiotherapy technology have made extreme hypo-fractionated stereotactic body radiation therapy (SBRT) of prostate cancer feasible, which has not yet been introduced as a standard treatment method in Germany. Initial results from other countries are promising, but long-term results are not yet available. The aim of this study is to investigate feasibility and effectiveness of SBRT for prostate cancer in Germany.
Methods/design: This German bi-center single group trial (HYPOSTAT) is designed to evaluate feasibility and effectiveness, as measured by toxicity and PSA-response, respectively, of an extreme hypo-fractionated SBRT regimen with five fractions of 7 Gy in treatment of localized low and intermediate risk prostate cancer. The target volume includes the prostate with or without the base of seminal vesicles depending on risk stratification and uncertainty margins that are kept at 3–5 mm. SBRT treatment is delivered with the robotic CyberKnife system, which was recently introduced in Germany. Acute and late toxicity after one year will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.0), Radiation Therapy Oncology Group (RTOG) and International Prostate Symptom Score (IPSS) Scores. The quality of life will be assessed before and after treatment with the EORTC QLQ C30 questionnaire. Hypothesizing that the proportion of patients with grade 2 side effects or higher is less or equal than 2.8%, thus markedly lower than the standard EBRT percentage (17.5%), the recruitment target is 85 patients.
Discussion: The HYPOSTAT trial aims at demonstrating short term feasibility of extreme hypo-fractioned SBRT for the treatment of prostate cancer and might be used as the pilot study for a multi-center multi-platform or for randomized-controlled trials comparing conventional radiotherapy with SBRT for localized prostate cancer in the future. The study concept of patient enrollment, follow up and evaluation by multiple public university clinics and actual patient treatment in dedicated private radiosurgery practices with high-tech radiation equipment is unique for clinical trials.
Study status: The study is ongoing and currently recruiting patients.
Trial registration: Registration number: NCT02635256 (clinicaltrials.gov). Registered 8 December 2015
Purpose: Stereotactic radiosurgery (SRS) is an established primary treatment for newly diagnosed brain metastases with high local control rates. However, data about local re-irradiation in case of local failure after SRS (re-SRS) are rare. We evaluated the feasibility, efficacy and patient selection characteristics in treating locally recurrent metastases with a second course of SRS.
Methods: We retrospectively evaluated patients with brain metastases treated with re-SRS for local tumor progression between 2011 and 2017. Patient and treatment characteristics as well as rates of tumor control, survival and toxicity were analyzed.
Results: Overall, 32 locally recurrent brain metastases in 31 patients were irradiated with re-SRS. Median age at re-SRS was 64.9 years. The primary histology was breast cancer and non-small-cellular lung cancer (NSCLC) in respectively 10 cases (31.3%), in 5 cases malignant melanoma (15.6%). In the first SRS-course 19 metastases (59.4%) and in the re-SRS-course 29 metastases (90.6%) were treated with CyberKnife® and the others with Gamma Knife. Median planning target volume (PTV) for re-SRS was 2.5 cm3 (range, 0.1–37.5 cm3) and median dose prescribed to the PTV was 19 Gy (range, 12–28 Gy) in 1–5 fractions to the median 69% isodose (range, 53–80%). The 1-year overall survival rate was 61.7% and the 1-year local control rate was 79.5%. The overall rate of radiological radio-necrosis was 16.1% and four patients (12.9%) experienced grade ≥ 3 toxicities.
Conclusions: A second course of SRS for locally recurrent brain metastases after prior local SRS appears to be feasible with acceptable toxicity and can be considered as salvage treatment option for selected patients with high performance status. Furthermore, this is the first study utilizing robotic radiosurgery for this indication, as an additional option for frameless fractionated treatment.
Background: Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which determines the length of their 3′ untranslated regions (3′UTRs). We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, connect APA with mRNA export. The mechanism underlying APA regulation by SRSF3 and SRSF7 remained unknown.
Results: Here we combine iCLIP and 3′-end sequencing and find that SRSF3 and SRSF7 bind upstream of proximal PASs (pPASs), but they exert opposite effects on 3′UTR length. SRSF7 enhances pPAS usage in a concentration-dependent but splicing-independent manner by recruiting the cleavage factor FIP1, generating short 3′UTRs. Protein domains unique to SRSF7, which are absent from SRSF3, contribute to FIP1 recruitment. In contrast, SRSF3 promotes distal PAS (dPAS) usage and hence long 3′UTRs directly by counteracting SRSF7, but also indirectly by maintaining high levels of cleavage factor Im (CFIm) via alternative splicing. Upon SRSF3 depletion, CFIm levels decrease and 3′UTRs are shortened. The indirect SRSF3 targets are particularly sensitive to low CFIm levels, because here CFIm serves a dual function; it enhances dPAS and inhibits pPAS usage by binding immediately downstream and assembling unproductive cleavage complexes, which together promotes long 3′UTRs.
Conclusions; We demonstrate that SRSF3 and SRSF7 are direct modulators of pPAS usage and show how small differences in the domain architecture of SR proteins can confer opposite effects on pPAS regulation.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
Oral swabs, sputum and blood samples from 18 patients with SARS-CoV-2 infection were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) testing. Whereas oral swabs or sputum from the lower respiratory tract were tested RT-PCR positive in all patients, RNAemia was neither detected in 3 patients without symptoms nor in 14 patients with flu-like symptoms, fever or pneumonia. The only patient with RNAemia suffered from acute respiratory distress syndrome (ARDS) and was artificially ventilated in an intensive care unit. Risk for SARS-CoV-2 transmission through blood components in asymptomatic SARS-CoV-2 infected individuals therefore seems negligible but further studies are needed.