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USP22 controls necroptosis by regulating receptor-interacting protein kinase 3 ubiquitination
(2020)
Dynamic control of ubiquitination by deubiquitinating enzymes is essential for almost all biological processes. Ubiquitin-specific peptidase 22 (USP22) is part of the SAGA complex and catalyzes the removal of mono-ubiquitination from histones H2A and H2B, thereby regulating gene transcription. However, novel roles for USP22 have emerged recently, such as tumor development and cell death. Apart from apoptosis, the relevance of USP22 in other programmed cell death pathways still remains unclear. Here, we describe a novel role for USP22 in controlling necroptotic cell death in human tumor cell lines. Loss of USP22 expression significantly delays TNFα/Smac mimetic/zVAD.fmk (TBZ)-induced necroptosis, without affecting TNFα-mediated NF-κB activation or extrinsic apoptosis. Ubiquitin remnant profiling identified receptor-interacting protein kinase 3 (RIPK3) lysines 42, 351, and 518 as novel, USP22-regulated ubiquitination sites during necroptosis. Importantly, mutation of RIPK3 K518 reduced necroptosis-associated RIPK3 ubiquitination and amplified necrosome formation and necroptotic cell death. In conclusion, we identify a novel role of USP22 in necroptosis and further elucidate the relevance of RIPK3 ubiquitination as crucial regulator of necroptotic cell death.
Background and purpose: Superficial siderosis of the central nervous system is a sporadic finding in magnetic resonance imaging, resulting from recurrent bleedings into the subarachnoid space. This study aimed to determine the frequency of spinal dural cerebrospinal fluid (CSF) leaks amongst patients with a symmetric infratentorial siderosis pattern. Methods: In all, 97,733 magnetic resonance images performed between 2007 and 2018 in our neurocenter were screened by a keyword search for “hemosiderosis” and “superficial siderosis.” Siderosis patterns on brain imaging were classified according to a previously published algorithm. Potential causative intracranial bleeding events were also assessed. Patients with a symmetric infratentorial siderosis pattern but without causative intracranial bleeding events in history were prospectively evaluated for spinal pathologies. Results: Forty-two patients with isolated supratentorial siderosis, 30 with symmetric infratentorial siderosis and 21 with limited (non-symmetric) infratentorial siderosis were identified. Amyloid angiopathy and subarachnoid hemorrhage were causes for isolated supratentorial siderosis. In all four patients with a symmetric infratentorial siderosis pattern but without a causative intracranial bleeding event in history, spinal dural abnormalities were detected. Dural leaks were searched for in patients with symmetric infratentorial siderosis and a history of intracranial bleeding event without known bleeding etiology, considering that spinal dural CSF leaks themselves may also cause intracranial hemorrhage, for example by inducing venous thrombosis due to low CSF pressure. Thereby, one additional spinal dural leak was detected. Conclusions: Persisting spinal dural CSF leaks can frequently be identified in patients with a symmetric infratentorial siderosis pattern. Diagnostic workup in these cases should include magnetic resonance imaging of the whole spine.
Autophagy is a highly conserved catabolic process cells use to maintain their homeostasis by degrading misfolded, damaged and excessive proteins, nonfunctional organelles, foreign pathogens and other cellular components. Hence, autophagy can be nonselective, where bulky portions of the cytoplasm are degraded upon stress, or a highly selective process, where preselected cellular components are degraded. To distinguish between different cellular components, autophagy employs selective autophagy receptors, which will link the cargo to the autophagy machinery, thereby sequestering it in the autophagosome for its subsequent degradation in the lysosome. Autophagy receptors undergo post-translational and structural modifications to fulfil their role in autophagy, or upon executing their role, for their own degradation. We highlight the four most prominent protein modifications – phosphorylation, ubiquitination, acetylation and oligomerisation – that are essential for autophagy receptor recruitment, function and turnover. Understanding the regulation of selective autophagy receptors will provide deeper insights into the pathway and open up potential therapeutic avenues.
Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma
(2020)
Aims: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas. Methods: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29). Results: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy. Conclusion: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.
Long-term effects on cirrhosis and portal hypertension of direct antiviral agent (DAA)-based eradication of hepatitis C virus (HCV) are still under debate. We analysed dynamics of liver and spleen elastography to assess potential regression of cirrhosis and portal hypertension 3 years post-treatment. Fifty-four patients with HCV-associated cirrhosis and DAA-induced SVR were included. Liver and spleen stiffness were measured at baseline (BL), end of treatment (EOT), 24 weeks after EOT (FU24) and 1, 2 and 3 (FU144) years post-treatment by transient liver elastography (L-TE) and point shear wave elastography (pSWE) using acoustic radiation force impulse (ARFI) of the liver (L-ARFI) and spleen (S-ARFI). Biochemical, virological and clinical data were also obtained. Liver stiffness assessed by L-TE decreased between BL [median (range), 32.5(9.1–75) kPa] and EOT [21.3(6.7–73.5) kPa; p < .0001] and EOT and FU144 [16(4.1–75) kPa; p = .006]. L-ARFI values improved between EOT [2.5(1.2–4.1) m/s] and FU144 [1.7(0.9–4.1) m/s; p = .001], while spleen stiffness remained unchanged. Overall, L-TE improved in 38 of 54 (70.4%) patients at EOT and 29 of 38 (76.3%) declined further until FU144, whereas L-ARFI values decreased in 30/54 (55.6%) patients at EOT and continued to decrease in 28/30 (93.3%) patients at FU144. Low bilirubin and high albumin levels at BL were associated with improved L-ARFI values (p = .048) at EOT or regression of cirrhosis (<12.5 kPa) by L-TE at FU144 (p = .005), respectively. Liver stiffness, but not spleen stiffness, continued to decline in a considerable proportion of patients with advanced liver disease after HCV eradication.
Beneficial acute effects of resistance exercise on cognitive functions may be modified by exercise intensity or by habitual physical activity. Twenty-six participants (9 female and 17 male; 25.5 ± 3.4 years) completed four resistance exercise interventions in a randomized order on separate days (≥48 h washout). The intensities were set at 60%, 75%, and 90% of the one repetition maximum (1RM). Three interventions had matched workloads (equal resistance*nrepetitions). One intervention applied 75% of the 1RM and a 50% reduced workload (resistance*nrepetitions = 50%). Cognitive attention (Trail Making Test A—TMTA), task switching (Trail Making Test B—TMTB), and working memory (Digit Reading Spans Backward) were assessed before and immediately after exercise. Habitual activity was assessed as MET hours per week using the International Physical Activity Questionnaire. TMTB time to completion was significantly shorter after exercise with an intensity of 60% 1RM and 75% 1RM and 100% workload. Friedman test indicated a significant effect of exercise intensity in favor of 60% 1RM. TMTA performance was significantly shorter after exercise with an intensity of 60% 1RM, 90% 1RM, and 75% 1RM (50% workload). Habitual activity with vigorous intensity correlated positively with the baseline TMTB and Digit Span Forward performance but not with pre- to post-intervention changes. Task switching, based on working memory, mental flexibility, and inhibition, was beneficially influenced by acute exercise with moderate intensity whereas attention performance was increased after exercise with moderate and vigorous intensity. The effect of regular activity had no impact on acute exercise effects.
Purpose: 10-year retrospective study to assess burden of illness in individuals with tuberous sclerosis complex (TSC) identified from German healthcare data. Methods: Patients with TSC were identified by International Classification of Diseases code Q85.1. Patients with epilepsy were identified by epilepsy diagnosis or antiseizure medication (ASM) prescription after TSC diagnosis. Results: Using data from 2016 (final study year), 100 patients with TSC were identified (mean [range] age: 38 [1–86] years; male: 40%); prevalence: 7.9 per 100,000 (TSC), 2.2 per 100,000 (TSC with epilepsy). During the 10-year study period (2007–2016), 256 patients with TSC were identified and followed up for 1,784 patient- years (epilepsy: 36%, 616 patient-years). TSC manifestations/comorbidities (apart from epilepsy) were identi- fied more frequently in patients with epilepsy than without. Mean annual healthcare costs for patients with TSC were €6,139 per patient-year (PPY), mostly attributable to medication (35%) and inpatient care (29%). Patients with epilepsy incurred costs more than double those without. Mean (standard deviation [SD]) annual hospi- talisation rate (AHR) and length of stay (LOS) PPY: 0.5 (1.0) and 5.9 (18.6) days for TSC. AHR and LOS were greater in patients with epilepsy than without. Mean (SD) number of ASMs prescribed (TSC with epilepsy): 3.0 (2.3) over the entire observable time per patient. Mortality rates (vs. control): 5.08% (vs. 1.69%, p<0.001) for TSC, 7.53% (vs. 0.98%, p<0.001) for TSC with epilepsy, 3.68% (vs. 2.03%, p = 0.003) for TSC without epilepsy. Conclusion: Healthcare costs, resource utilisation, and mortality were greater in patients with TSC and epilepsy than those without epilepsy.
Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
Das Dermatofibrosarcoma protuberans (DFSP) ist ein seltenes fibroblastisches Weichteilsarkom. Bisher ist wenig über die optimale Therapie des primären und insbesondere des rezidivierten DFSP im Kindes- und Jugendalter bekannt. Zudem gibt es sehr wenig klinische Daten über das fibrosarkomatöse DFSP (FS-DFSP) bei pädiatrischen Patienten, welches eine intermediär maligne Variante des DFSP darstellt. Die vorliegende Studie untersuchte das Dermatofibrosarcoma protuberans im Kindes- und Jugendalter im Hinblick auf die Therapie und Prognose der primären Erkrankung und bei Rezidiven. Es wurden Daten von 40 Patienten mit DFSP, welche im Zeitraum von 1996 bis 2016 in der Cooperativen Weichteilsarkomstudiengruppe (CWS) prospektiv registriert wurden, retrospektiv analysiert. Zusätzlich wurde die Therapie und der Verlauf von 3 Patienten mit der Diagnose eines FS-DFSP beschrieben.
Alle Patienten erhielten vorrangig eine chirurgische Tumorresektion. Eine sekundäre Resektion erfolgte bei 18 Patienten nach unvollständiger oder grenzwertig vollständiger primärer Resektion. Insgesamt konnte bei 85% (n = 34/40) eine mikroskopisch vollständige chirurgische Resektion (R0) in der besten Resektion erreicht werden. Alle Patienten konnten eine komplette Remission nach der primären Erkrankung erreichen und das 5-Jahres Gesamtüberleben war 100% (± 0; CI, 95%). Die R0-Resektion (IRS I) stellte einen signifikanten Faktor für die Prävention eines Rezidivs dar. Ein lokales Rezidiv trat nach einem Median von 1,1 Jahren bei insgesamt 15% (n = 6/40) der Patienten auf und wurde durch erneute chirurgische Resektion behandelt. Darunter konnten alle Patienten eine komplette Remission erreichen. Zwei von 3 Patienten mit einem FS-DFSP überlebten nach einer R0-Resektion in kompletter Remission.
Zusammenfassend konnte gezeigt werden, dass das DFSP eine gute Prognose bei pädiatrischen Patienten hat. Der wichtigste prognostische Faktor für die Prävention von Rezidiven ist eine mikroskopisch vollständige chirurgische Resektion. Im Falle eines Rezidivs oder dem Vorliegen eines FS-DFSP sollte ebenfalls eine vollständige chirurgische Resektion angestrebt werden.
This research project investigated how motor activity, such as cycling, influences the acquisition of foreign language vocabulary under two distinct conditions of auditory-motor-synchronisation. In a mixed subject design, 48 participants had to learn 40 Polish-German vocabulary pairs by auditory presentation over headphones in two different conditions, in which they performed motor activity cycling on a bicycle ergometer: in experiment 1, vocabulary was presented in a fixed rhythm while in experiment 2, participants self-initiated the presentation of vocabulary through pedalling. After having listened to the word pairs, they had to perform online vocabulary tests, one directly after the learning session and a second one 24 hours later from home. Additionally, the individual pitch perception preference (i.e. fundamental vs. spectral pitch perception) of the participants was determined.
The results showed that fundamental listeners forgot significantly more vocabulary than spectral listeners during the fixed than during the self-initiated condition. There was no difference within the groups for the self-initiated condition. The analysis of the motor data revealed a significantly more accurate synchronisation for fundamental listeners during the fixed condition. Therefore, this study provides first evidence for the benefit of self-initiated auditory-motor synchronisation in the process of learning a foreign language in adults. It also reveals that pitch preference has an effect on auditory-motor synchronisation.
Die Multiple Sklerose (MS) gehört zu den häufigsten chronisch-entzündlichen Erkrankungen des zentralen Nervensystems in Deutschland und kann durch Sehstörungen, Paresen oder Sensibilitätsstörungen symptomatisch werden.
Konventionelle Magnetresonanztomographie (MRT)-Verfahren leisten in der Diagnostik der MS einen wichtigen Beitrag, da diese die Läsionslast der weißen Substanz gut darstellen können. Frühere Studien deuten an, dass kognitive und psychomotorische Symptome wie Fatigue sowie Konzentrations- und Gedächtnisstörungen bei der MS mit Schädigungen des zerebralen Kortex in Beziehung stehen könnten. Mit konventionellen MRT-Bildgebungsverfahren lässt sich zwar kortikale Atrophie, nicht jedoch die zugrundeliegenden mikrostrukturellen kortikalen Umbauprozesse erfassen. In der vorliegenden Studie wurden daher quantitative MRT(qMRT)-Verfahren verwendet, die eben diese diffusen kortikalen Gewebsveränderungen messen und quantifizieren können. Mithilfe der dabei genutzten Diffusions-Tensor-Bildgebung (DTI) als qMRT-Verfahren konnten Diffusionsanomalien analysiert und charakterisiert werden. Dabei wurden zwei Gewebsparameter im Gehirn bestimmt: die mittlere Diffusivität(MD) und die fraktionelle Anisotropie (FA). Da vorherige Studien uneinheitliche Ergebnisse hinsichtlich Änderungen von DTI-Parametern in der grauen Substanz bei der MS erbrachten, beschäftigten wir uns mit der Frage, ob kortikale MD- und FA-Veränderungen bei Patienten mit schubförmig-remittierender MS (RRMS) mithilfe optimierter DTI-Messtechniken zu detektieren sind, wie diese charakterisiert sind und wie sich diese im Kortex verteilen.
An der vorliegenden Studie nahmen 24 Patienten mit RRMS und 25 gesunde Kontrollprobanden teil. Der Schweregrad der Erkrankung wurde mithilfe des Expanded Disability Status Scale (EDSS) eingestuft.
Bei der MRT-Datenerfassung wurde eine optimierte DTI-Methode mit intrinsischer „Eddy-Current“-Kompensation verwendet. Die MD und die FA wurden für jeden Bildpunkt bestimmt. Kortikale Parameterwerte wurden ausgelesen und in Oberflächendatensätzen gespeichert. Es erfolgte ein oberflächenbasierter statistischer Gruppenvergleich. Kortikale Mittelwerte wurden für die MD und die FA bestimmt und zwischen den Gruppen verglichen.
Für Parameter mit nachgewiesenen globalen Gruppenunterschieden wurde die Korrelation mit dem klinischen Status (quantifiziert durch den EDSS) bestimmt.
Die Analyse kortikaler Mittelwerte zeigte eine Erhöhung der MD in der Patientengruppe. Die MD-Veränderungen waren räumlich ausgedehnt und es fanden sich Cluster mit erhöhten MD-Werten in der Patientengruppe, insbesondere in temporalen, okzipitalen und parietalen Regionen. Des Weiteren konnte eine signifikante positive Korrelation zwischen dem EDSS-Score und der kortikalen MD festgestellt werden. Außerdem ließen sich fokale FA-Erniedrigungen im Temporal- und Okzipitallappen nachweisen. Die MD quantifiziert das Ausmaß und die FA die Gerichtetheit der Diffusion.
Somit bietet die MD möglicherweise Hinweise auf die Intaktheit mikrostruktureller Barrieren und die FA auf die Integrität von Faserverbindungen. Unsere Ergebnisse könnten demnach darauf hinweisen, dass im Kortex von MS-Patienten der Abbau mikrostruktureller Barrieren räumlich ausgedehnter stattfindet als eine Störung axonaler Strukturen. Die Korrelation der MD mit dem klinischen Status legt die Möglichkeit der Quantifizierung klinisch relevanter kortikaler Gewebsveränderungen und somit eine mögliche Relevanz dieser Techniken für klinische Studien nahe.
Background: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest. Methods: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM). Results: We found associations of higher TGIF protein expression with smaller tumor size (p= 0.015), well differentiated phenotype (p< 0.001) and estrogen receptor (ER)-positive BC (p< 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59–0.95], log-rank p=0.019) and overall survival (OS: HR 0.69 [95%CI 0.50–0.94], log-rank p= 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51–1.16]; p= 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51–0.91]; log-rank p= 0.009, interaction p= 0.130; OS: HR 0.60 [95%CI 0.41–0.88], log-rank p= 0.008, interaction p= 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50–0.88], log-rank p= 0.004, interaction p= 0.034; OS: HR 0.57 [95%CI 0.40–0.81], log-rank p= 0.002, interaction p= 0.015). Conclusions: Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer.
High-resolution fMRI in the sub-millimeter regime allows researchers to resolve brain activity across cortical layers and columns non-invasively. While these high-resolution data make it possible to address novel questions of directional information flow within and across brain circuits, the corresponding data analyses are challenged by MRI artifacts, including image blurring, image distortions, low SNR, and restricted coverage. These challenges often result in insufficient spatial accuracy of conventional analysis pipelines. Here we introduce a new software suite that is specifically designed for layer-specific functional MRI: LayNii. This toolbox is a collection of command-line executable programs written in C/C++ and is distributed opensource and as pre-compiled binaries for Linux, Windows, and macOS. LayNii is designed for layer-fMRI data that suffer from SNR and coverage constraints and thus cannot be straightforwardly analyzed in alternative software packages. Some of the most popular programs of LayNii contain ‘layerification’ and columnarization in the native voxel space of functional data as well as many other layer-fMRI specific analysis tasks: layer-specific smoothing, model-based vein mitigation of GE-BOLD data, quality assessment of artifact dominated sub-millimeter fMRI, as well as analyses of VASO data.
Aims: Cardio-oncology is a growing interdisciplinary field which aims to improve cardiological care for cancer patients in order to reduce morbidity and mortality. The impact of cardiac biomarkers, echocardiographic parameters, and cardiological assessment regarding risk stratification is still unclear. We aimed to identify potential parameters that allow an early risk stratification of cancer patients. Methods and results: In this cohort study, we evaluated 930 patients that were admitted to the cardio-oncology outpatient clinic of the University Hospital Heidelberg from January 2016 to January 2019. We performed echocardiography, including Global Longitudinal Strain (GLS) analysis and measured cardiac biomarkers including N-terminal pro brain-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T levels (hs-cTnT). Most patients were suffering from breast cancer (n = 450, 48.4%), upper gastrointestinal carcinoma (n = 99, 10.6%) or multiple myeloma (n = 51, 5.5%). At the initial visit, we observed 86.7% of patients having a preserved left ventricular ejection fraction (LVEF >50%). At the second follow up, still 78.9% of patients showed a preserved LVEF. Echocardiographic parameters or elevation of NT-proBNP did not significantly correlate with all-cause mortality (ACM) (logistic regression LVEF <50%: P = 0.46, NT-proBNP: P = 0.16) and failed to identify high-risk patients. In contrast, hs-cTnT above the median (≥7 ng/L) was an independent marker to determine ACM (multivariant logistic regression, OR: 2.21, P = 0.0038) among all included patients. In particular, hs-cTnT levels before start of a chemotherapy were predictive for ACM. Conclusions: Based on our non-selected cohort of cardio-oncological patients, hs-cTnT was able to identify patients with high mortality by using a low cutoff of 7 ng/L. We conclude that measurement of hs-cTnT is an important tool to stratify the risk for mortality of cancer patients before starting chemotherapy.
We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET-2) tended to be more common (P = 0·1078). Five-year progression-free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49–1·47] and overall survival (HR = 0·85; 95% CI = 0·49–1·51) did not differ between the groups after study treatment with PET-2-guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET-2-guided escalated BEACOPP.
Since the early 1970s several studies have reported distal splenic artery embolization, better known as partial spleen embolization (PSE), as an efficacious treatment of portal hypertensive variceal bleeding and hypersplenism in cirrhosis.(1, 2) However, the effect of PSE on portal pressure is secondary to the induction of splenic infarction. Depending on both the infarct volume and possible infection, PSE can induce serious complications including death.(2, 3) On the other hand, proximal splenic artery embolization (PSAE), which mimics surgical splenic artery ligation, prevents large infarction of the spleen, favoring collateral perfusion of its intact distal vasculature.(3) For this, PSAE has been extensively preferred over PSE for reducing portal hyperflow and treating refractory ascites (RA) after whole or partial liver transplantation (LT).(3, 4) We report here a case of PSAE used to treat RA in a patient with cirrhosis not eligible for transjugular intrahepatic portosystemic shunt (TIPS) and LT.
Inhibition of fatty acid synthesis (FAS) stimulates tumor cell death and reduces angiogenesis. When SH-SY5Y cells or primary neurons are exposed to hypoxia only, inhibition of FAS yields significantly enhanced cell injury. The pathophysiology of stroke, however, is not only restricted to hypoxia but also includes reoxygenation injury. Hence, an oxygen-glucose-deprivation (OGD) model with subsequent reoxygenation in both SH-SY5Y cells and primary neurons as well as a murine stroke model were used herein in order to study the role of FAS inhibition and its underlying mechanisms. SH-SY5Y cells and cortical neurons exposed to 10 h of OGD and 24 h of reoxygenation displayed prominent cell death when treated with the Acetyl-CoA carboxylase inhibitor TOFA or the fatty acid synthase inhibitor cerulenin. Such FAS inhibition reduced the reduction potential of these cells, as indicated by increased NADH2+/NAD+ ratios under both in vitro and in vivo stroke conditions. As observed in the OGD model, FAS inhibition also resulted in increased cell death in the stroke model. Stroke mice treated with cerulenin did not only display increased brain injury but also showed reduced neurological recovery during the observation period of 4 weeks. Interestingly, cerulenin treatment enhanced endothelial cell leakage, reduced transcellular electrical resistance (TER) of the endothelium and contributed to poststroke blood-brain barrier (BBB) breakdown. The latter was a consequence of the activated NF-κB pathway, stimulating MMP-9 and ABCB1 transporter activity on the luminal side of the endothelium. In conclusion, FAS inhibition aggravated poststroke brain injury as consequence of BBB breakdown and NF-κB-dependent inflammation.
Background: No simple staging system has emerged for basal cell carcinomas (BCCs), since they do not follow the TNM process, and practitioners failed to agree on simple clinical or pathological criteria as a basis for a classification. Operational classification of BCCs is required for decision-making, trials and guidelines. Unsupervised clustering of real cases of difficult-to-treat BCCs (DTT-BCCs; part 1) has demonstrated that experts could blindly agree on a five groups classification of DTT-BCCs based on five patterns of clinical situations. Objective: Using this five patterns to generate an operational and comprehensive classification of BCCs. Method: Testing practitioner's agreement, when using the five patterns classification to ensure that it is robust enough to be used in the practice. Generating the first version of a staging system of BCCs based on pattern recognition. Results: Sixty-two physicians, including 48 practitioners and the 14 experts who participated in the generation of the five different patterns of DTT-BCCs, agreed on 90% of cases when classifying 199 DTT-BCCs cases using the five patterns classification (part 1) attesting that this classification is understandable and usable in practice. In order to cover the whole field of BCCs, these five groups of DTT-BCCs were added a group representing the huge number of easy-to-treat BCCs, for which sub-classification has little interest, and a group of very rare metastatic cases, resulting in a four-stage and seven-substage staging system of BCCs. Conclusion: A practical classification adapted to the specificities of BCCs is proposed. It is the first tumour classification based on pattern recognition of clinical situations, which proves to be consistent and usable. This EADO staging system version 1 will be improved step by step and tested as a decision tool and a prognostic instrument.
Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.