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Hydride transfers play a crucial role in a multitude of biological redox reactions and are mediated by flavin, deazaflavin or nicotinamide adenine dinucleotide cofactors at standard redox potentials ranging from 0 to –340 mV. 2-Naphthoyl-CoA reductase, a key enzyme of oxygen-independent bacterial naphthalene degradation, uses a low-potential one-electron donor for the two-electron dearomatization of its substrate below the redox limit of known biological hydride transfer processes at E°’ = −493 mV. Here we demonstrate by X-ray structural analyses, QM/MM computational studies, and multiple spectroscopy/activity based titrations that highly cooperative electron transfer (n = 3) from a low-potential one-electron (FAD) to a two-electron (FMN) transferring flavin cofactor is the key to overcome the resonance stabilized aromatic system by hydride transfer in a highly hydrophobic pocket. The results evidence how the protein environment inversely functionalizes two flavins to switch from low-potential one-electron to hydride transfer at the thermodynamic limit of flavin redox chemistry.
Introduction: Previous studies have established graph theoretical analysis of functional network connectivity (FNC) as a potential tool to detect neurobiological underpinnings of psychiatric disorders. Despite the promising outcomes in studies that examined FNC aberrancies in bipolar disorder (BD) and major depressive disorder (MDD), there is still a lack of research comparing both mood disorders, especially in a nondepressed state. In this study, we used graph theoretical network analysis to compare brain network properties of euthymic BD, euthymic MDD and healthy controls (HC) to evaluate whether these groups showed distinct features in FNC.
Methods: We collected resting‐state functional magnetic resonance imaging (fMRI) data from 20 BD patients, 15 patients with recurrent MDD as well as 30 age‐ and gender‐matched HC. Graph theoretical analyses were then applied to investigate functional brain networks on a global and regional network level.
Results: Global network analysis revealed a significantly higher mean global clustering coefficient in BD compared to HC. We further detected frontal, temporal and subcortical nodes in emotion regulation areas such as the limbic system and associated regions exhibiting significant differences in network integration and segregation in BD compared to MDD patients and HC. Participants with MDD and HC only differed in frontal and insular network centrality.
Conclusion: In conclusion, our findings indicate that a significantly altered brain network topology in the limbic system might be a trait marker specific to BD. Brain network analysis in these regions may therefore be used to differentiate euthymic BD not only from HC but also from patients with MDD.
Objective. Evaluation of C-MAC PM® in combination with a standard Macintosh blade size 3 in direct and indirect laryngoscopy and D-Blade® in indirect laryngoscopy in a simulated difficult airway. Primary outcome was defined as the best view of the glottic structures. Secondary endpoints were subjective evaluation and assessment of the intubation process.
Methods. Prospective monocentric, observational study on 48 adult patients without predictors for difficult laryngoscopy/tracheal intubation undergoing orthopedic surgery. Every participant preoperatively received a cervical collar to simulate a difficult airway. Direct and indirect laryngoscopy w/o the BURP maneuver with a standard Macintosh blade and indirect laryngoscopy w/o the BURP maneuver using D-Blade® were performed to evaluate if blade geometry and the BURP maneuver improve the glottic view as measured by the Cormack-Lehane score.
Results. Using a C-MAC PM® laryngoscope, D-Blade® yielded improved glottic views compared with the Macintosh blade used with either the direct or indirect technique. Changing from direct laryngoscopy using a Macintosh blade to indirect videolaryngoscopy using C-MAC PM® with D-Blade® improved the Cormack-Lehane score from IIb, III, or IV to I or II in 31 cases.
Conclusion. The combination of C-MAC PM® and D-Blade® significantly enhances the view of the glottis compared to direct laryngoscopy with a Macintosh blade in patients with a simulated difficult airway.
Trial Registration Number. This trial is registered under number NCT03403946.
The present study aims to clarify the confused taxonomy of Z. schaufussi von Frauenfeld, 1862 and Zospeum suarezi Gittenberger, 1980. Revision of Iberian Zospeum micro snails is severely hindered by uncertainties regarding the identity of the oldest Iberian Zospeum species, Z. schaufussi von Frauenfeld, 1862. In this paper, we clarify its taxonomic status by designating a lectotype from the original syntype series and by describing its internal and external shell morphology. Using SEM-EDX, we attempt to identify the area of the type locality cave more precisely than "a cave in Spain". The shell described and illustrated by Gittenberger (1980) as Z. schaufussi appears not to be conspecific with the lectotype shell, and is considered a separate species, Z. gittenbergeri Jochum, Prieto & De Winter, sp. n.
Zospeum suarezi was described from various caves in NW Spain. Study of the type material reveals that these shells are not homogenous in shell morphology. The holotype shell of Z. suarezi is imaged here for the first time. The paratype shell, illustrated by Gittenberger (1980) from a distant, second cave, is described as Zospeum praetermissum Jochum, Prieto & De Winter, sp. n. The shell selected here as lectotype of Z. schaufussi, was also considered a paratype of Z. suarezi by Gittenberger (1980). Since this specimen is morphologically very similar to topotypic shells of Z. suarezi, the latter species is considered a junior synonym of Z. schaufussi (syn. n.). The internal shell morphology of all these taxa is described and illustrated using X-ray Micro Computer Tomography (Micro-CT).
Background: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear.
Methods: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy.
Results: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease.
In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3–4; HR 1.63, 95% CI 1.08–2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64–4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32–3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89–7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28–12.44, p < 0.001).
Conclusions: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.
Background: Esophageal cancer (EC) is one of the deadliest cancers worldwide. The contemporary strong increase of the adenocarcinomas in Western countries and the high mortality rates require the intensification of prospective multinational studies.
Methods: Therefore, this global health issue has been chosen for the bibliometric review of the global publication output. As source for meta and citation data, the Web of Science has been used and Density Equalizing Maps were applied for visualization.
Results: 17,387 articles on EC could be identified. The years with publication and citation maxima correspond to the appearance of the most prolific articles. China is the most publishing country, followed by Japan and the USA. Germany and the UK ranked 4th and 5th. The analysis of the ratios articles and socio-economic parameters emphasizes the leading position of the Scandinavian countries and Japan. Here, the high-income countries come out on top. The high incidence regions are mainly represented by Chinese and Japanese research. The association of the publication output and the overall research funding could be shown.
Conclusions: A strengthened international network increasingly consisting of the scientifically best positioned countries as well as more of the high incidence countries worldwide is mandatory for future research. The findings deliver scientists, clinicians and decision makers backgrounds for future decisions all over the world.
Acute deterioration of liver cirrhosis (e.g., infections, acute‐on‐chronic liver failure [ACLF]) requires an increase in cardiac contractility. The insufficiency to respond to these situations could be deleterious. Left ventricular global longitudinal strain (LV‐GLS) has been shown to reflect left cardiac contractility in cirrhosis better than other parameters and might bear prognostic value. Therefore, this retrospective study investigated the role of LV‐GLS in the outcome after transjugular intrahepatic portosystemic shunt (TIPS) and the development of ACLF. We included 114 patients (48 female patients) from the Noninvasive Evaluation Program for TIPS and Their Follow‐Up Network (NEPTUN) cohort. This number provided sufficient quality and structured follow‐up with the possibility of calculating major scores (Child, Model for End‐Stage Liver Disease [MELD], Chronic Liver Failure Consortium acute decompensation [CLIF‐C AD] scores) and recording of the events (development of decompensation episode and ACLF). We analyzed the association of LV‐GLS with overall mortality and development of ACLF in patients with TIPS. LV‐GLS was independently associated with overall mortality (hazard ratio [HR], 1.123; 95% confidence interval [CI],1.010‐1.250) together with aspartate aminotransferase (HR, 1.009; 95% CI, 1.004‐1.014) and CLIF‐C AD score (HR, 1.080; 95% CI, 1.018‐1.137). Area under the receiver operating characteristic curve (AUROC) analysis for LV‐GLS for overall survival showed higher area under the curve (AUC) than MELD and CLIF‐C AD scores (AUC, 0.688 versus 0.646 and 0.573, respectively). The best AUROC‐determined LV‐GLS cutoff was −16.6% to identify patients with a significantly worse outcome after TIPS at 3 months, 6 months, and overall. LV‐GLS was independently associated with development of ACLF (HR, 1.613; 95% CI, 1.025‐2.540) together with a MELD score above 15 (HR, 2.222; 95% CI, 1.400‐3.528). Conclusion: LV‐GLS is useful for identifying patients at risk of developing ACLF and a worse outcome after TIPS. Although validation is required, this tool might help to stratify risk in patients receiving TIPS.
No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
The antitumor effect of curcumin in urothelial cancer cells is enhanced by light exposure in vitro
(2019)
The natural compound curcumin exerts antitumor properties in vitro, but its clinical application is limited due to low bioavailability. Light exposure in skin and skin cancer cells has been shown to improve curcumin bioavailability; thus, the object of this investigation was to determine whether light exposure might also enhance curcumin efficacy in bladder cancer cell lines. RT112, UMUC3, and TCCSUP cells were preincubated with low curcumin concentrations (0.1-0.4 μg/ml) and then exposed to 1.65 J/cm2 visible light for 5 min. Cell growth, cell proliferation, apoptosis, cell cycle progression, and cell cycle regulating proteins along with acetylation of histone H3 and H4 were investigated. Though curcumin alone did not alter cell proliferation or apoptosis, tumor cell growth and proliferation were strongly blocked when curcumin was combined with visible light. Curcumin-light caused the bladder cancer cells to become arrested in different cell phases: G0/G1 for RT112, G2/M for TCCSUP, and G2/M- and S-phase for UMUC3. Proteins of the Cdk-cyclin axis were diminished in RT112 after application of 0.1 and 0.4 μg/ml curcumin. Cell cycling proteins were upregulated in TCCSUP and UMUC3 in the presence of 0.1 μg/ml curcumin-light but were partially downregulated with 0.4 μg/ml curcumin. 0.4 μg/ml (but not 0.1 μg/ml) curcumin-light also evoked late apoptosis in TCCSUP and UMUC3 cells. H3 and H4 acetylation was found in UMUC3 cells treated with 0.4 μg/ml curcumin alone or with 0.1 μg/ml curcumin-light, pointing to an epigenetic mechanism. Light exposure enhanced the antitumor potential of curcumin on bladder cancer cells but by different molecular action modes in the different cell lines. Further studies are necessary to evaluate whether intravesical curcumin application, combined with visible light, might become an innovative tool in combating bladder cancer.
Background: Synovial fibroblasts (SF) play a major role in the pathogenesis of rheumatoid arthritis (RA) and develop an aggressive phenotype destroying cartilage and bone, thus termed RASF. JAK inhibitors have shown to be an efficient therapeutic option in RA treatment, but less is known about the effect of JAK inhibitors on activated RASF. The aim of the study was to examine the effects of JAK inhibitors on activated RASF.
Methods: Synovium of RA patients was obtained during knee replacement surgeries. Synoviocytes were isolated and pretreated with JAK inhibitors. Pro-inflammatory cytokines and matrix degrading proteinases were measured by ELISA in supernatant after stimulation with oncostatin M or IL-1β. The proliferation of RASF was measured by BrdU incorporation. Cell culture inserts were used to evaluate cell migration. For adhesion assays, RASF were seeded in culture plates. Then, plates were extensively shaken and adherent RASF quantified. Cell viability, cytotoxicity and apoptosis were measured using the ApoTox-Glo™ Triplex and the CellTox™ Green Cytotoxicity Assay.
Results: Tofacitinib and baricitinib decreased the IL-6 release of RASF stimulated with oncostatin M. JAK inhibition attenuated the IL-6 release of IL-1β activated and with soluble IL-6 receptor treated RASF. In contrast, only peficitinib and filgotinib decreased the IL-6 release of RASF activated with IL-1β. Peficitinib decreased also the MMP-3, CXCL8, and CXCL1 release at 5 μM. Moreover, peficitinib was the only JAK inhibitor suppressing proliferation of activated RASF at 1 μM. Peficitinib further decreased the migration of RASF without being cytotoxic or pro-apoptotic and without altering cell adhesion.
Conclusions: JAK inhibitors effectively suppress the inflammatory response induced by oncostatin M and by transsignaling of IL-6 in RASF. Only peficitinib modulated the IL-1β-induced response of RASF and their proliferation in vitro at concentrations close to reported Cmax values of well tolerated doses in vivo. In contrast to filgotinib, peficitinib also highly suppressed RASF migration showing the potential of peficitinib to target RASF.
Drebrin (DBN) regulates cytoskeletal functions during neuronal development, and is thought to contribute to structural and functional synaptic changes associated with aging and Alzheimer’s disease. Here we show that DBN coordinates stress signalling with cytoskeletal dynamics, via a mechanism involving kinase ataxia-telangiectasia mutated (ATM). An excess of reactive oxygen species (ROS) stimulates ATM-dependent phosphorylation of DBN at serine-647, which enhances protein stability and accounts for improved stress resilience in dendritic spines. We generated a humanized DBN Caenorhabditis elegans model and show that a phospho-DBN mutant disrupts the protective ATM effect on lifespan under sustained oxidative stress. Our data indicate a master regulatory function of ATM-DBN in integrating cytosolic stress-induced signalling with the dynamics of actin remodelling to provide protection from synapse dysfunction and ROS-triggered reduced lifespan. They further suggest that DBN protein abundance governs actin filament stability to contribute to the consequences of oxidative stress in physiological and pathological conditions.
Background: HER2 (ERBB2 or HER2/neu) is a tyrosine-kinase increasing cell proliferation. Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies. Consequently, HER2 targeting is established in breast and upper gastrointestinal tract cancer. There are conflicting data concerning the impact of HER2 overexpression on esophageal adenocarcinoma (EAC), as most studies do not differ between cancers of the esophagus/gastroesophageal junction and the stomach. The aim of this study was to analyze the expression/amplification of HER2 in EAC in correlation to clinicopathological data to verify its prognostic impact.
Methods: We analyzed 428 EAC patients that underwent transthoracic thoraco-abdominal esophagectomy between 1997 and 2014. We performed HER2 immunohistochemistry (IHC) according to the guidelines and fluorescence-in-situ-hybridization (FISH) for IHC score2+, using tissue micro arrays (TMA) with up to eight biopsies from the surface and infiltration area of a single tumor for evaluating HER2-heterogeneity and single-spot TMA. The HER2-status was correlated with clinicopathological data.
Results: HER2-positivity was found in up to 14.9% in our cohort (IHC score 3+ or IHC score 2+ with gene amplification) and demonstrated a significantly better overall survival (OS) in correlation to HER2-negative tumors (median OS 70.1 vs. 24.6 months, p = 0.006). HER2-overexpression was more frequently seen in lower tumor stages (pT1/pT2, p = 0.038), in the absence of lymphatic metastases (pN0/pN+, p = 0.020), and was significantly associated with better histological grading (G1/G2) (p = 0.041).
Conclusion: We demonstrated a positive prognostic impact of HER2 overexpression in a large cohort of EAC, contrary to other solid malignancies including gastric cancer and breast cancer, but consistent to the results of a large study on EAC from 2012.
Background: The invasive temperate mosquito Aedes japonicus japonicus is a potential vector for various infectious diseases and therefore a target of vector control measures. Even though established in Germany, it is unclear whether the species has already reached its full distribution potential. The possible range of the species, its annual population dynamics, the success of vector control measures and future expansions due to climate change still remain poorly understood. While numerous studies on occurrence have been conducted, they used mainly presence data from relatively few locations. In contrast, we used experimental life history data to model the dynamics of a continuous stage-structured population to infer potential seasonal densities and ask whether stable populations are likely to establish over a period of more than one year. In addition, we used climate change models to infer future ranges. Finally, we evaluated the effectiveness of various stage-specific vector control measures.
Results: Aedes j. japonicus has already established stable populations in the southwest and west of Germany. Our models predict a spread of Ae. j. japonicus beyond the currently observed range, but likely not much further eastwards under current climatic conditions. Climate change models, however, will expand this range substantially and higher annual densities can be expected. Applying vector control measures to oviposition, survival of eggs, larvae or adults showed that application of adulticides for 30 days between late spring and early autumn, while ambient temperatures are above 9 °C, can reduce population density by 75%. Continuous application of larvicide showed similar results in population reduction. Most importantly, we showed that with the consequent application of a mixed strategy, it should be possible to significantly reduce or even extinguish existing populations with reasonable effort.
Conclusion: Our study provides valuable insights into the mechanisms concerning the establishment of stable populations in invasive species. In order to minimise the hazard to public health, we recommend vector control measures to be applied in ‘high risk areas’ which are predicted to allow establishment of stable populations to establish.
Rhodopsins are the most universal biological light-energy transducers and abundant phototrophic mechanisms that evolved on Earth and have a remarkable diversity and potential for biotechnological applications. Recently, the first sodium-pumping rhodopsin KR2 from Krokinobacter eikastus was discovered and characterized. However, the existing structures of KR2 are contradictory, and the mechanism of Na+ pumping is not yet understood. Here, we present a structure of the cationic (non H+) light-driven pump at physiological pH in its pentameric form. We also present 13 atomic structures and functional data on the KR2 and its mutants, including potassium pumps, which show that oligomerization of the microbial rhodopsin is obligatory for its biological function. The studies reveal the structure of KR2 at nonphysiological low pH where it acts as a proton pump. The structure provides new insights into the mechanisms of microbial rhodopsins and opens the way to a rational design of novel cation pumps for optogenetics.
Purpose: To investigate the efficacy and safety of Descemet membrane endothelial keratoplasty (DMEK) for corneal decompensation following primary Descemet stripping automated endothelial keratoplasty (DSAEK).
Methods: This was a retrospective case series of 15 patients that underwent DMEK surgery for corneal decompensation after failed DSAEK. Main outcome parameter was corrected distance visual acuity (CDVA) after DMEK and DSAEK. Secondary outcome measures included central corneal thickness (CCT), endothelial cell density (ECD), rebubbling rate, and primary graft failure after DMEK. Explanted DSAEK grafts were evaluated by light microscopy.
Results: The mean (±SD) time period between DSAEK and DMEK surgery was 15±8 months (range, 6–31 months). Preoperative CDVA was 1.72±0.62 (logMAR). After DMEK, CDVA improved significantly to 0.78±0.48 at 1 month and to 0.23±0.24 after 12 months (P=0.022). Visual acuity data after DMEK were significantly better compared to preoperative values. The average CCT after DMEK decreased significantly from 869±210 µm (preoperative) to 505±45 µm (1 month postoperative) (P<0.001) and remained stable over 12 months. The ECD decreased from 2,589±209/mm2 (preoperative) to 1,691±589/mm2 (12 months postoperative). Rebubbling DMEK was required in three patients (=20%).
Conclusion: DMEK represents a feasible and safe procedure in achieving better functional results compared to DSAEK. Visual acuity and optical quality can be effectively reestablished after unsuccessful primary DSAEK surgery even in patients with long-standing corneal decompensation. Further investigations are required to validate the preliminary clinical findings.
Mechanism of the electroneutral sodium/proton antiporter PaNhaP from transition-path shooting
(2019)
Na+/H+ antiporters exchange sodium ions and protons on opposite sides of lipid membranes. The electroneutral Na+/H+ antiporter NhaP from archaea Pyrococcus abyssi (PaNhaP) is a functional homolog of the human Na+/H+ exchanger NHE1, which is an important drug target. Here we resolve the Na+ and H+ transport cycle of PaNhaP by transition-path sampling. The resulting molecular dynamics trajectories of repeated ion transport events proceed without bias force, and overcome the enormous time-scale gap between seconds-scale ion exchange and microseconds simulations. The simulations reveal a hydrophobic gate to the extracellular side that opens and closes in response to the transporter domain motion. Weakening the gate by mutagenesis makes the transporter faster, suggesting that the gate balances competing demands of fidelity and efficiency. Transition-path sampling and a committor-based reaction coordinate optimization identify the essential motions and interactions that realize conformational alternation between the two access states in transporter function.
With an increased understanding of the tumor biology of squamous cell carcinoma of the head and neck (SCCHN), targeted therapies have found their way into the clinical treatment routines against this entity. Nevertheless, to date platinum-based cytostatic agents remain the first line choice and targeting the epidermal growth factor-receptor (EGFR) with combined cetuximab and radiation therapy remains the only targeted therapy approved in the curative setting. Investigation of immune checkpoint inhibitors (ICI), such as antibodies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, resulted in a change of paradigms in oncology and in the first approval of new drugs for treating SCCHN. Nivolumab and pembrolizumab, two anti-PD-1 antibodies, were the first agents shown to improve overall survival for patients with metastatic/recurrent tumors in recent years. Currently, several clinical trials investigate the role of ICI in different therapeutic settings. A robust set of biomarkers will be an inevitable tool for future individualized treatment approaches including radiation dose de-escalation and escalation strategies. This review aims to summarize achieved goals, the current status and future perspectives regarding targeted therapies and ICI in the management of SCCHN.
Cyanobacteria are photoautotrophic microorganisms present in almost all ecologically niches on Earth. They exist as single-cell or filamentous forms and the latter often contain specialized cells for N2 fixation known as heterocysts. Heterocysts arise from photosynthetic active vegetative cells by multiple morphological and physiological rearrangements including the absence of O2 evolution and CO2 fixation. The key function of this cell type is carried out by the metalloprotein complex known as nitrogenase. Additionally, many other important processes in heterocysts also depend on metalloproteins. This leads to a high metal demand exceeding the one of other bacteria in content and concentration during heterocyst development and in mature heterocysts. This review provides an overview on the current knowledge of the transition metals and metalloproteins required by heterocysts in heterocyst-forming cyanobacteria. It discusses the molecular, physiological, and physicochemical properties of metalloproteins involved in N2 fixation, H2 metabolism, electron transport chains, oxidative stress management, storage, energy metabolism, and metabolic networks in the diazotrophic filament. This provides a detailed and comprehensive picture on the heterocyst demands for Fe, Cu, Mo, Ni, Mn, V, and Zn as cofactors for metalloproteins and highlights the importance of such metalloproteins for the biology of cyanobacterial heterocysts.
Different tissue engineering techniques are used to support rapid vascularisation. A novel technique is the use of platelet-rich fibrin (PRF), an autologous source of growth factors. This study was the first to investigate the influence of PRF matrices, isolated following different centrifugation protocols, on human dermal vascular endothelial cells (ECs) in mono-culture and co-culture with human primary fibroblasts (HFs) as an in vitro model for tissue regeneration. Focus was placed on vascular structure formation and growth factor release. HFs and ECs were cultivated with PRF prepared using a high (710 ×g) or low (44 ×g) relative centrifugation force (RCF) over 14 d. Immunofluorescence staining and immunohistochemistry were used to evaluate the microvascular formation. Cell culture supernatants were collected for evaluation of growth factor release. The results showed a PRF-mediated effect on the induction of angiogenesis in ECs. Microvessel-like structure formation was promoted when ECs were combined with low-RCF PRF as compared to high-RCF PRF or control group. The percentage of vascular lumen area was significantly higher in low-RCF PRF, especially at day 7, which coincided with statistically significantly higher growth factor [vascular endothelial factor (VEGF), transforming growth factor β1 (TGF-β1) and platelet derived growth factor (PDGF)] concentration measured in low-RCF PRF as compared to high-RCF PRF or control group. In conclusion, reducing the RCF according to the low-speed centrifugation concept (LSCC) resulted in increased growth factor release and angiogenic structure formation with EC mono-culture, suggesting that PRF may be a highly beneficial therapeutic tool for tissue engineering applications.
Background: Neonatal manifestation of life-threatening hyperammonemic encephalopathy in urea cycle disorders (UCD) is often misdiagnosed as neonatal sepsis, resulting in significantly delayed start of specific treatment and poor outcome. The major aim of this study was to identify specific initial symptoms or signs to clinically distinguish hyperammonemic encephalopathy in neonates from neonatal sepsis in order to identify affected individuals with UCD and to start metabolic therapy without delay. Furthermore, we evaluated the impact of diagnostic delay, peak plasma ammonium (NH4+) concentration, mode of emergency treatment and transfer to a tertiary referral center on the outcome.
Methods: Detailed information of 17 patients (born between 1994 and 2012) with confirmed diagnosis of UCD and neonatal hyperammonemic encephalopathy were collected from the original medical records.
Results: The initially suspected diagnosis was neonatal sepsis in all patients, but was not confirmed in any of them. Unlike neonatal sepsis and not previously reported blood pressure increased above the 95th percentile in 13 (81%) of UCD patients before emergency treatment was started. Respiratory alkalosis was found in 11 (65%) of UCD patients, and in 14 (81%) plasma NH4+concentrations further increased despite initiation of metabolic therapy.
Conclusion: Detection of high blood pressure could be a valuable parameter for distinguishing neonatal sepsis from neonatal manifestation of UCD. Since high blood pressure is not typical for neonatal sepsis, other reasons such as encephalopathy and especially hyperammonemic encephalopathy (caused by e.g. UCD) should be searched for immediately. However, our result that the majority of newborns with UCD initially present with high blood pressure has to be evaluated in larger patient cohorts.
Background: The number of Mesenchymal Stem/Stromal Cells (MSCs) in the human bone marrow (BM) is small compared to other cell types. BM aspirate concentration (BMAC) may be used to increase numbers of MSCs, but the composition of MSC subpopulations and growth factors after processing are unknown. The purpose of this study was to assess the enrichment of stem/progenitor cells and growth factors in BM aspirate by two different commercial concentration devices versus standard BM aspiration.
Methods: 120 mL of BM was aspirated from the iliac crest of 10 male donors. Each sample was processed simultaneously by either Emcyte GenesisCS® (Emcyte) or Harvest SmartPReP2 BMAC (Harvest) devices and compared to untreated BM aspirate. Samples were analyzed with multicolor flow cytometry for cellular viability and expression of stem/progenitor cells markers. Stem/progenitor cell content was verified by quantification of colony forming unit-fibroblasts (CFU-F). Platelet, red blood cell and total nucleated cell (TNC) content were determined using an automated hematology analyzer. Growth factors contents were analyzed with protein quantification assays. Statistical analyses were performed by ANOVA analysis of variance followed by Tukey’s multiple comparison test or Wilcoxon matched-pairs signed rank test with p < 0.05 for significance.
Results: Cell viability after processing was approximately 90% in all groups. Compared to control, both devices significantly enriched TNCs and platelets, as well as the CD45−CD73+ and CD45−CD73+CD90+ cell populations. Further, Harvest significantly concentrated CD45−CD10+, CD45−CD29+, CD45−CD90+, CD45−CD105+, CD45−CD119+ cells, and CD45dimCD90+CD271+ MSCs, whereas Emcyte significantly enriched CD45dimCD44+CD271+ MSCs. BM concentration also increased the numbers of CFU-F, platelet-derived growth factor, vascular endothelial growth factor, macrophage colony-stimulating factor, interleukin-1b, VCAM-1 and total protein. Neither system concentrated red blood cells, hematopoietic stem cells or bone morphogenetic proteins.
Conclusion: This data could contribute to the development of BMAC quality control assays as both BMAC systems concentrated platelets, growth factors and non-hematopoietic stem cell subpopulations with distinct phenotypes without loss of cell viability when compared to unprocessed BM.
Objective: To determine whether the performance of multiple sclerosis (MS) patients in the sound-induced flash illusion (SiFi), a multisensory perceptual illusion, would reflect their cognitive impairment.
Methods: We performed the SiFi task as well as an extensive neuropsychological testing in 95 subjects [39 patients with relapse-remitting MS (RRMS), 16 subjects with progressive multiple sclerosis (PMS) and 40 healthy control subjects (HC)].
Results: MS patients reported more frequently the multisensory SiFi than HC. In contrast, there were no group differences in the control conditions. Essentially, patients with progressive type of MS continued to perceive the illusion at stimulus onset asynchronies (SOA) that were more than three times longer than the SOA at which the illusion was already disrupted for healthy controls. Furthermore, MS patients' degree of cognitive impairment measured with a broad neuropsychological battery encompassing tests for memory, attention, executive functions, and fluency was predicted by their performance in the SiFi task for the longest SOA of 500 ms.
Conclusions: These findings support the notion that MS patients exhibit an altered multisensory perception in the SiFi task and that their susceptibility to the perceptual illusion is negatively correlated with their neuropsychological test performance. Since MS lesions affect white matter tracts and cortical regions which seem to be involved in the transfer and processing of both crossmodal and cognitive information, this might be one possible explanation for our findings. SiFi might be considered as a brief, non-expensive, language- and education-independent screening test for cognitive deficits in MS patients.
Anaerobic ammonium oxidation (anammox) is a major process in the biogeochemical nitrogen cycle in which nitrite and ammonium are converted to dinitrogen gas and water through the highly reactive intermediate hydrazine. So far, it is unknown how anammox organisms convert the toxic hydrazine into nitrogen and harvest the extremely low potential electrons (−750 mV) released in this process. We report the crystal structure and cryo electron microscopy structures of the responsible enzyme, hydrazine dehydrogenase, which is a 1.7 MDa multiprotein complex containing an extended electron transfer network of 192 heme groups spanning the entire complex. This unique molecular arrangement suggests a way in which the protein stores and releases the electrons obtained from hydrazine conversion, the final step in the globally important anammox process.
Fascial tissues form a ubiquitous network throughout the whole body, which is usually regarded as a passive contributor to biomechanical behavior. We aimed to answer the question, whether fascia may possess the capacity for cellular contraction which, in turn, could play an active role in musculoskeletal mechanics. Human and rat fascial specimens from different body sites were investigated for the presence of myofibroblasts using immunohistochemical staining for α-smooth muscle actin (n = 31 donors, n = 20 animals). In addition, mechanographic force registrations were performed on isolated rat fascial tissues (n = 8 to n = 18), which had been exposed to pharmacological stimulants. The density of myofibroblasts was increased in the human lumbar fascia in comparison to fasciae from the two other regions examined in this study: fascia lata and plantar fascia [H(2) = 14.0, p < 0.01]. Mechanographic force measurements revealed contractions in response to stimulation by fetal bovine serum, the thromboxane A2 analog U46619, TGF-β1, and mepyramine, while challenge by botulinum toxin type C3–used as a Rho kinase inhibitor– provoked relaxation (p < 0.05). In contrast, fascial tissues were insensitive to angiotensin II and caffeine (p < 0.05). A positive correlation between myofibroblast density and contractile response was found (rs = 0.83, p < 0.001). The hypothetical application of the registered forces to human lumbar tissues predicts a potential impact below the threshold for mechanical spinal stability but strong enough to possibly alter motoneuronal coordination in the lumbar region. It is concluded that tension of myofascial tissue is actively regulated by myofibroblasts with the potential to impact active musculoskeletal dynamics.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant and often lifelong effects on social, emotional, and cognitive functioning. Influential neurocognitive models of ADHD link behavioral symptoms to altered connections between and within functional brain networks. Here, we investigate whether network-based theories of ADHD can be generalized to understanding variations in ADHD-related behaviors within the normal (i.e., clinically unaffected) adult population. In a large and representative sample, self-rated presence of ADHD symptoms varied widely; only eight out of 291 participants scored in the clinical range. Subject-specific brain-network graphs were modeled from functional MRI resting-state data and revealed significant associations between (non-clinical) ADHD symptoms and region-specific profiles of between-module and within-module connectivity. Effects were located in brain regions associated with multiple neuronal systems including the default-mode network, the salience network, and the central executive system. Our results are consistent with network perspectives of ADHD and provide further evidence for the relevance of an appropriate information transfer between task-negative (default-mode) and task-positive brain regions. More generally, our findings support a dimensional conceptualization of ADHD and contribute to a growing understanding of cognition as an emerging property of functional brain networks.
Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
Background: To evaluate the current indications, resection strategies and short-term outcomes of surgery for benign goitre in a country with endemic goitre. Methods: Data of patients who underwent surgery for benign goitre were retrieved from the prospective StuDoQ/Thyroid registry and retrospectively analysed regarding the patient’s demographics, indications for surgery, surgical procedures, histology, and perioperative outcomes. Results: In a 15-month period, 12,888 patients from 83 departments underwent thyroid resections for benign conditions. Main indications for surgery were exclusion of malignancy (68%), compression symptoms (20.7%) and hyperthyroidism (9.7%). Preoperative fine needle aspiration cytology was performed in only 12.2% of patients with the indication "exclusion of malignancy". Thyroidectomy (49.8%) or hemithyroidectomy (36.9%) were performed in 86.7% of patients. Minimally invasive or alternative surgical techniques were applied in only 2.2%. Intraoperative neuromonitoring was used in 98.4% of procedures, in 97.5% of patients at least one parathyroid gland was visualized, and in 15.3% of patients parathyroid tissue was autografted, respectively. The rates of unilateral and bilateral transient recurrent nerve palsy were 3.6% and 0.07% of nerves at risk, the rate of transitory hypoparathyroidism was 15.3%. The rates of postoperative bleeding and wound infections requiring reoperation were 1.4% and 0.07%, respectively. Conclusions: The indication "exclusion of malignancy" is made too liberally, and there is a strong attitude to perform complete thyroid resections. Postoperative hypoparathyroidism is the major complication after surgery for benign thyroid disease, thus requiring more awareness.
The on-surface synthesis of bisheptahelicene by Ullmann coupling of 9-bromoheptahelicene on Au(111) and its temperature-induced dehydrogenation is studied using temperature-programmed reaction spectroscopy and time-of-flight secondary ion mass spectrometry. Specific dehydrogenation products of bisheptahelicene after loss of 6, 8 and 10 hydrogen atoms are identified, corresponding to molecules having undergone Diels–Alder transformations and intramolecular C–C coupling reactions. By combining with atomic hydrogen produced by dehydrogenation, the Ullmann coupling side-product bromine desorbs as HBr. H2 desorption emerges only after all Br has desorbed. Such characteristic behavior is explained by a kinetic model which explicitly considers the coverage of transient atomic H on the surface. Heating experiments performed with saturated layers of different Br-containing molecules reveal that the onset of HBr desorption depends strictly on the dehydrogenation step and therefore on the structure of the molecules.
Apigenin (4′,5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 μM and 60 μM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.
Latent tuberculosis infection (LTBI) is established in over 90% of persons infected with Mycobacterium tuberculosis (Mtb), from whom new active TB cases will arise. Understanding the spatio-temporal dynamics of host immune responses in LTBI granulomas is essential to designing effective post-exposure therapies that inhibit progression to TB. Information arising from cancer studies and other modalities – where local chronic inflammation leads to immunopathology – can help provide insights into the biological pathways at play in LTBI granulomas. Translational studies using patient material as well as LTBI+ donor-derived tissue samples are instrumental in understanding the various components of granuloma dynamics, immunological landscapes therein and how this could help to identify therapeutic targets. Deep sequencing technologies may aid to decipher the genetic changes in lung granuloma and blood samples from LTBI+ individuals associated with progression to active TB disease. This may lead to advancement of development of targeted Host-Directed Therapies (HDTs) and their evaluation as adjunct TB therapies for improving treatment outcomes for LTBI and pulmonary TB.
Introduction: Balanced fluid replacement solutions can possibly reduce the risks for electrolyte imbalances, for acid-base imbalances, and thus for renal failure. To assess the intraoperative change of base excess (BE) and chloride in serum after treatment with either a balanced gelatine/electrolyte solution or a non-balanced gelatine/electrolyte solution, a prospective, controlled, randomized, double-blind, dual centre phase III study was conducted in two tertiary care university hospitals in Germany.
Material and methods: 40 patients of both sexes, aged 18 to 90 years, who were scheduled to undergo elective abdominal surgery with assumed intraoperative volume requirement of at least 15 mL/kg body weight gelatine solution were included. Administration of study drug was performed intravenously according to patients need. The trigger for volume replacement was a central venous pressure (CVP) minus positive end-expiratory pressure (PEEP) <10 mmHg (CVP <10 mmHg). The crystalloid:colloid ratio was 1:1 intra- and postoperatively. The targets for volume replacement were a CVP between 10 and 14 mmHg minus PEEP after treatment with vasoactive agent and mean arterial pressure (MAP) > 65 mmHg.
Results: The primary endpoints, intraoperative changes of base excess –2.59 ± 2.25 (median: –2.65) mmol/L (balanced group) and –4.79 ± 2.38 (median: –4.70) mmol/L (non-balanced group)) or serum chloride 2.4 ± 1.9 (median: 3.0) mmol/L and 5.2 ± 3.1 (median: 5.0) mmol/L were significantly different (p = 0.0117 and p = 0.0045, respectively). In both groups (each n = 20) the investigational product administration in terms of volume and infusion rate was comparable throughout the course of the study, i.e. before, during and after surgery.
Discussion: Balanced gelatine solution 4% combined with a balanced electrolyte solution demonstrated significant smaller impact on blood gas analytic parameters in the primary endpoints BE and serum chloride when compared to a non-balanced gelatine solution 4% combined with NaCl 0.9%. No marked treatment differences were observed with respect to haemodynamics, coagulation and renal function.
Trial registration: ClinicalTrials.gov (NCT01515397) and clinicaltrialsregister.eu, EudraCT number 2010-018524-58.
Haloferax volcanii is a well-established model species for haloarchaea. Small scale RNomics and bioinformatics predictions were used to identify small non-coding RNAs (sRNAs), and deletion mutants revealed that sRNAs have important regulatory functions. A recent dRNA-Seq study was used to characterize the primary transcriptome. Unexpectedly, it was revealed that, under optimal conditions, H. volcanii contains more non-coding sRNAs than protein-encoding mRNAs. However, the dRNA-Seq approach did not contain any length information. Therefore, a mixed RNA-Seq approach was used to determine transcript length and to identify additional transcripts, which are not present under optimal conditions. In total, 50 million paired end reads of 150 nt length were obtained. 1861 protein-coding RNAs (cdRNAs) were detected, which encoded 3092 proteins. This nearly doubled the coverage of cdRNAs, compared to the previous dRNA-Seq study. About 2/3 of the cdRNAs were monocistronic, and 1/3 covered more than one gene. In addition, 1635 non-coding sRNAs were identified. The highest fraction of non-coding RNAs were cis antisense RNAs (asRNAs). Analysis of the length distribution revealed that sRNAs have a median length of about 150 nt. Based on the RNA-Seq and dRNA-Seq results, genes were chosen to exemplify characteristics of the H. volcanii transcriptome by Northern blot analyses, e.g. 1) the transcript patterns of gene clusters can be straightforward, but also very complex, 2) many transcripts differ in expression level under the four analyzed conditions, 3) some genes are transcribed into RNA isoforms of different length, which can be differentially regulated, 4) transcripts with very long 5’-UTRs and with very long 3’-UTRs exist, and 5) about 30% of all cdRNAs have overlapping 3’-ends, which indicates, together with the asRNAs, that H. volcanii makes ample use of sense-antisense interactions. Taken together, this RNA-Seq study, together with a previous dRNA-Seq study, enabled an unprecedented view on the H. volcanii transcriptome.
Epigenetic control of the angiotensin-converting enzyme in endothelial cells during inflammation
(2019)
The angiotensin-converting enzyme (ACE) plays a central role in the renin-angiotensin system, which is involved in the regulation of blood pressure. Alterations in ACE expression or activity are associated with various pathological phenotypes, particularly cardiovascular diseases. In human endothelial cells, ACE was shown to be negatively regulated by tumor necrosis factor (TNF) α. To examine, whether or not, epigenetic factors were involved in ACE expression regulation, methylated DNA immunoprecipitation and RNA interference experiments directed against regulators of DNA methylation homeostasis i.e., DNA methyltransferases (DNMTs) and ten-eleven translocation methylcytosine dioxygenases (TETs), were performed. TNFα stimulation enhanced DNA methylation in two distinct regions within the ACE promoter via a mechanism linked to DNMT3a and DNMT3b, but not to DNMT1. At the same time, TET1 protein expression was downregulated. In addition, DNA methylation decreased the binding affinity of the transcription factor MYC associated factor X to the ACE promoter. In conclusion, DNA methylation determines the TNFα-dependent regulation of ACE gene transcription and thus protein expression in human endothelial cells.
Multidrug-resistant TB (MDR-TB) is a major threat to global health security. In 2017, only 50% of patients with MDR-TB who received WHO-recommended treatment were cured. Most MDR-TB patients who recover continue to suffer from functional disability due to long-term lung damage. Whilst new MDR-TB treatment regimens are becoming available, conventional drug therapies need to be complemented with host-directed therapies (HDTs) to reduce tissue damage and improve functional treatment outcomes. This viewpoint highlights recent data on biomarkers, immune cells, circulating effector molecules and genetics which could be utilised for developing personalised HDTs. Novel technologies currently used for cancer therapy which could facilitate in-depth understanding of host genetics and the microbiome in patients with MDR-TB are discussed. Against this background, personalised cell-based HDTs for adjunct MDR-TB treatment to improve clinical outcomes are proposed as a possibility for complementing standard therapy and other HDT agents. Insights into the molecular biology of the mechanisms of action of cellular HDTs may also aid to devise non-cell-based therapies targeting defined inflammatory pathway(s) in Mtb-driven immunopathology.
A body of research demonstrates convincingly a role for synchronization of auditory cortex to rhythmic structure in sounds including speech and music. Some studies hypothesize that an oscillator in auditory cortex could underlie important temporal processes such as segmentation and prediction. An important critique of these findings raises the plausible concern that what is measured is perhaps not an oscillator but is instead a sequence of evoked responses. The two distinct mechanisms could look very similar in the case of rhythmic input, but an oscillator might better provide the computational roles mentioned above (i.e., segmentation and prediction). We advance an approach to adjudicate between the two models: analyzing the phase lag between stimulus and neural signal across different stimulation rates. We ran numerical simulations of evoked and oscillatory computational models, showing that in the evoked case,phase lag is heavily rate-dependent, while the oscillatory model displays marked phase concentration across stimulation rates. Next, we compared these model predictions with magnetoencephalography data recorded while participants listened to music of varying note rates. Our results show that the phase concentration of the experimental data is more in line with the oscillatory model than with the evoked model. This finding supports an auditory cortical signal that (i) contains components of both bottom-up evoked responses and internal oscillatory synchronization whose strengths are weighted by their appropriateness for particular stimulus types and (ii) cannot be explained by evoked responses alone.
Background: While ICF-CY-based models of care are promising avenues for improving participation of children with chronic health conditions, feasible and valid instruments to assess participation as an outcome in routine are still needed. We aimed to validate a German parent-report version of the Child and Adolescent Scale of Participation (CASP) in children with chronic health conditions of different severity.
Methods: Cross-sectional data were collected in 327 children (mean age 7.8 years, 55% boys) from two paediatric centres (n = 112) and one population-based sample (n = 215). Cronbach’s alpha, factor analyses, face validity assessments, correlation analyses, receiver operating characteristics (ROC) curves, and parent-reported health-related quality of life (HRQoL: KINDL) were used to examine internal consistency, test-retest reliability, and capacity to differentiate between disease severity groups. Disease severity was operationalized according to ICD-diagnosis groups and/or parent-reports on health problems, medical and educational support, and medication. A newly developed item "overall perceived participation" was added to the CASP and evaluated.
Results: We found good to excellent content validity, excellent internal consistency, and good-to-excellent test-retest reliability of the instrument. While children with mild disease had a significantly greater extent of participation (higher CASP scores) than children with severe disease, they did not differ from healthy children. Children with mild compared to severe disease much more differed in participation as measured by the CASP compared to the KINDL (area under the ROC curve: 0.92 vs. 0.75). In addition, the item "overall perceived participation" was highly correlated (r = 0.86) with the CASP total score, indicating the potential value of this specific single item. Finally, we provided preliminary reference values for the CASP obtained in a population-based sample of children without chronic health conditions.
Conclusions: The German version of the CASP and the new item are efficient, valid and reliable measures of social participation in childhood. The CASP-measured participation focuses more on attendance than on involvement into social circumstances of everyday life. To detect children with a high burden of disease on everyday life, the CASP may be more accurate than HRQoL instruments such as the KINDL. As outcome measurement, the CASP may facilitate the implementation of patient-centred paediatric health care.
Clinically relevant immune responses against Cytomegalovirus : implications for precision medicine
(2019)
Immune responses to human cytomegalovirus (CMV) can be used to assess immune fitness in an individual. Further to its clinical significance in posttransplantation settings, emerging clinical and translational studies provide examples of immune correlates of protection pertaining to anti-CMV immune responses in the context of cancer or infectious diseases, e.g., tuberculosis. In this viewpoint, we provide a brief overview about CMV-directed immune reactivity and immune fitness in a clinical context and incorporate some of our own findings obtained from peripheral blood or tumour-infiltrating lymphocytes (TIL) from patients with advanced cancer. Observations in patients with solid cancers whose lesions contain both CMV and tumour antigen-specific T-cell subsets are highlighted, due to a possible CMV-associated "bystander" effect in amplifying local inflammation and subsequent tumour rejection. The role of tumour-associated antibodies recognising diverse CMV-derived epitopes is also discussed in light of anti-cancer immune responses. We discuss here the use of anti-CMV immune responses as a theranostic tool—combining immunodiagnostics with a personalised therapeutic potential—to improve treatment outcomes in oncological indications.
Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.
Background: Oral anticoagulants can cause potentially serious adverse events. Therefore, before prescribing oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation (AF), stroke risk assessment is required to identify patients that are likely to benefit from treatment. Current guidelines recommend the CHA2DS2-VASc-score for stroke risk assessment. The CHA2DS2-VASc-score is based on observational studies from different treatment settings and countries. As ischemic stroke risk differs by setting and region, the aim of this study is to estimate ischemic stroke risk (stratified by the CHA2DS2-VASc-score) for a broadly representative population with AF from southern Germany and compare them to results from previous studies.
Methods: The study design is a retrospective cohort study on patients with atrial fibrillation based on secondary data. We calculated CHA2DS2-VASc-score based on patient’s diagnoses recorded in the year 2014 and assessed outcomes in 2015–2016. The primary outcome is hospitalization for ischemic stroke. The secondary outome is hospitalizations for any thromboembolic event, including ischemic stroke, transient ischemic attack, peripheral arterial embolism, pulmonary embolism, and mesenterial embolism. We estimated the incidence rates of the outcomes (and corresponding 95%-confidence intervals) stratified by CHA2DS2-VASc-score.
Results: The primary endpoint occurred in 961 of the 30,299 patients constituting the study population, resulting in a total incidence rate of 2.2 per 100 person-years. The secondary endpoint occurred in 1553 patients (3.6 per 100 person-years). Ischemic stroke rates stratified by the CHA2DS2-VASc-score tended to be lower than those reported previously. Thromboembolic event rates stratified tended to be similar to those reported previously.
Conclusions: Our results show that the performance of the CHA2DS2-VASc-score differs in the German population, as compared to internationally published data, with an overall trend towards lower risk of ischemic stroke in uncoagulated patients with AF. These results should not be practice changing, but they emphasize that stroke risk estimation in patients with atrial fibrillation should be further refined.
The mechanistic target of rapamycin (mTOR) is elevated in prostate cancer, making this protein attractive for tumor treatment. Unfortunately, resistance towards mTOR inhibitors develops and the tumor becomes reactivated. We determined whether epigenetic modulation by the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), may counteract non-responsiveness to the mTOR inhibitor, temsirolimus, in prostate cancer (PCa) cells. Prostate cancer cells, sensitive (parental) and resistant to temsirolimus, were exposed to VPA, and tumor cell growth behavior compared. Temsirolimus resistance enhanced the number of tumor cells in the G2/M-phase, correlating with elevated cell proliferation and clonal growth. The cell cycling proteins cdk1 and cyclin B, along with Akt-mTOR signaling increased, whereas p19, p21 and p27 decreased, compared to the parental cells. VPA significantly reduced cell growth and up-regulated the acetylated histones H3 and H4. Cdk1 and cyclin B decreased, as did phosphorylated mTOR and the mTOR sub-complex Raptor. The mTOR sub-member Rictor and phosphorylated Akt increased under VPA. Knockdown of cdk1, cyclin B, or Raptor led to significant cell growth reduction. HDAC inhibition through VPA counteracts temsirolimus resistance, probably by down-regulating cdk1, cyclin B and Raptor. Enhanced Rictor and Akt, however, may represent an undesired feedback loop, which should be considered when designing future therapeutic regimens.
Purpose: To evaluate if repeat Descemet membrane endothelial keratoplasty (DMEK) is appropriate to achieve functional improvements in patients with corneal decompensation from secondary graft failure after primary DMEK.
Methods: This is a retrospective monocentric cohort study including 13 eyes of 13 patients with repeat DMEK for corneal decompensation following primary DMEK. Eyes with primary DMEK only and comparable preoperative corrected distance visual acuity (CDVA) served as control. Main outcome parameter was CDVA. Secondary outcome measures were central corneal thickness (CCT), endothelial cell density, and rebubbling rate (RR).
Results: The average time interval (±SD) between primary and secondary DMEK was 12.5±6 months. Preoperative CDVA (logMAR) was 1.97±0.90 in the repeat DMEK group and 1.38±0.92 in the primary DMEK group. At 6 months, both groups showed significant improvement in visual acuity (repeat DMEK group, 0.49±0.35, P<0.01 and primary DMEK group, 0.40±0.36, P<0.01). CDVA did not differ significantly between both groups at all time points examined (1, 3, and 6 months postoperatively). Mean CCT values at 3 and 6 months postoperatively did not differ significantly between the two groups (P>0.05). The RR was
23% (n=3) in both groups.
Conclusion: Repeat DMEK is a useful therapeutic approach in the setting of corneal decompensation following primary DMEK. Functional results of repeat DMEK, visual acuity in particular, are comparable to patients with single DMEK only.
The treatment of patients with advanced breast cancer has developed further in recent years. In addition to therapeutic progress in the established subgroups (hormone receptor and HER2 status), there are now therapies which are geared to individual molecular characteristics, such as PARP inhibitor therapy in BRCA-mutated patients. In addition to this, tests are being developed which are intended to establish additional markers within subgroups in order to predict the efficacy of a therapy. PI3K mutation testing in HER2-negative, hormone-receptor-positive tumours and PD-L1 testing of immune cells in triple-negative tumours are expected to become established in clinical practice in order to select patients for the respective therapies. With new therapeutic approaches, new adverse effects also appear. The management of these adverse effects, just as those of classical therapy (supportive therapy), is essential with the introduction of new treatments in order to preserve patientsʼ quality of life. Knowledge regarding measures to preserve and improve quality of life has significantly increased in recent years. Lifestyle factors should be taken into account, as should modern therapeutic methods. This review summarises the latest studies and publications and evaluates them in regard to the relevance for clinical practice.
Die Behandlung von Patientinnen mit fortgeschrittenem Mammakarzinom hat sich in den letzten Jahren weiterentwickelt. Zusätzlich zum Therapiefortschritt in den etablierten Subgruppen (Hormonrezeptor- und HER2-Status) gibt es nun Therapien, die sich an einzelnen molekularen Charakteristika orientieren, wie zum Beispiel die PARP-Inhibitortherapie bei BRCA-mutierten Patientinnen. Zusätzlich dazu sind Tests in der Entwicklung, die innerhalb von Subgruppen weitere Marker etablieren sollen, um die Wirksamkeit einer Therapie vorherzusagen. Die PI3K-Mutationstestung bei HER2-negativen, hormonrezeptorpositiven Tumoren, und die PD-L1-Testung von Immunzellen bei triple-negativen Tumoren werden voraussichtlich in der klinischen Praxis etabliert, um Patientinnen für die jeweiligen Therapien auszuwählen. Mit neuen Therapieansätzen treten auch neue Nebenwirkungen auf. Das Management dieser Nebenwirkungen ebenso wie die der klassischen Therapien (supportive Therapie) ist mit der Einführung neuer Behandlungen essenziell, um die Lebensqualität der Patientinnen zu erhalten. Das Wissen über Maßnahmen zur Erhaltung und Verbesserung der Lebensqualität hat in den letzten Jahren deutlich zugenommen. Lifestyle-Faktoren sollten dabei ebenso Berücksichtigung finden wie moderne Therapieverfahren. Diese Übersichtsarbeit fasst die neuesten Studien und Veröffentlichungen zusammen und bewertet sie in Bezug auf die Relevanz für die klinische Praxis.
For many years, small but significant advancements have been made time and again in the prevention and treatment of early breast cancer. The so-called panel gene analyses are becoming more and more important in prevention, since the risk due to the tested genes is better understood and as a result, concepts for integration in health care can be developed. In the adjuvant situation, the first study in the so-called post-neoadjuvant situation was able to demonstrate a clear improvement in the prognosis with an absent pathological complete remission following trastuzumab or pertuzumab + trastuzumab. Additional studies with this post-neoadjuvant therapeutic concept are still being conducted at present. The CDK4/6 inhibitors which had shown a significant improvement in progression-free survival in a metastatic situation are currently being tested in the adjuvant situation in large therapeutic studies. These and other new data for the treatment or prevention of primary breast cancer are presented in this review against the backdrop of current studies.
In der Prävention und Behandlung des frühen Mammakarzinoms sind über die Jahre immer wieder kleine, aber bedeutsame Fortschritte gemacht worden. In der Prävention gewinnen die sogenannten Panel-Gen-Analysen immer mehr an Bedeutung, da das durch die getesteten Gene bedingte Risiko immer besser verstanden wird und somit Konzepte für die Integration in die Krankenversorgung erarbeitet werden können. In der adjuvanten Situation konnte die erste Studie in der sogenannten postneoadjuvanten Situation bei fehlender pathologischer Komplettremission nach Trastuzumab oder Pertuzumab + Trastuzumab eine deutliche Verbesserung der Prognose zeigen. Weitere Studien mit diesem postneoadjuvanten Therapiekonzept werden zurzeit noch durchgeführt. Die CDK4/6-Inhibitoren, die in der metastasierten Situation eine deutliche Verbesserung des progressionsfreien Überlebens gezeigt hatten, werden zurzeit in der adjuvanten Situation in großen Therapiestudien getestet. Diese und weitere neue Daten zur Behandlung oder Prävention des primären Mammakarzinoms werden in dieser Übersichtsarbeit vor dem Hintergrund aktueller Studien vorgestellt.
The circumventricular organs (CVOs) in the central nervous system (CNS) lack a vascular blood-brain barrier (BBB), creating communication sites for sensory or secretory neurons, involved in body homeostasis. Wnt/β-catenin signaling is essential for BBB development and maintenance in endothelial cells (ECs) in most CNS vessels. Here we show that in mouse development, as well as in adult mouse and zebrafish, CVO ECs rendered Wnt-reporter negative, suggesting low level pathway activity. Characterization of the subfornical organ (SFO) vasculature revealed heterogenous claudin-5 (Cldn5) and Plvap/Meca32 expression indicative for tight and leaky vessels, respectively. Dominant, EC-specific β-catenin transcription in mice, converted phenotypically leaky into BBB-like vessels, by augmenting Cldn5+ vessels, stabilizing junctions and by reducing Plvap/Meca32+ and fenestrated vessels, resulting in decreased tracer permeability. Endothelial tightening augmented neuronal activity in the SFO of water restricted mice. Hence, regulating the SFO vessel barrier may influence neuronal function in the context of water homeostasis.
Introduction: The Retro-IDEAL (ILUVIEN Implant for chronic DiabEtic MAcuLar edema) study is a retrospective study designed to assess real-world outcomes achieved with the ILUVIEN® (0.19 mg fluocinolone acetonide (FAc)) in patients with chronic diabetic macular edema (DME) in clinical practices in Germany.
Methods: This study was conducted across 16 sites in Germany and involved 81 eyes (63 patients) with persistent or recurrent DME and a prior suboptimal response to a first-line intravitreal therapy (primarily anti-VEGF intravitreal therapies).
Results: Patients were followed-up for 30.8 ± 11.3 months (mean ± standard deviation) and had a mean age of 68.0 ± 10.4 years. Best-recorded visual acuity (BRVA) improved by +5.5 letters at month 9 (P ⩽ 0.005, n=56; from a baseline of 49 letters) and this was maintained through to month 30 (P ⩽ 0.05, n = 42). There was a concurrent improvement in central macular thickness with a reduction from 502 µm at baseline to 338 µm at year 1 (P ⩽ 0.0001, n = 43). This effect was sustained to year 3 (i.e. 318 µm; P ⩽ 0.0001, n = 29). Mean intraocular pressure (IOP) remained constant between baseline and year 3 with a peak change of 1.9 mm Hg occurring at year 1. Elevated IOP was observed in a similar percentage of patients prior to (22.2% of cases) and following (27.2%) treatment with the FAc implant. In the majority of cases, these elevations were managed effectively with IOP medications.
Conclusions: Despite substantial amounts of prior intravitreal treatments – primarily with anti–vascular endothelial growth factor (VEGF) drugs – this real-world study showed that sustained structural and functional improvements can last for up to 3 years with a single FAc implant.