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Introduction:
Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin’s lymphoma in a real-life clinical setting.
Methods:
Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results:
A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician’s visual analogue scale; mean improvement from baseline of 12.1 mm)
Herein, we report the one-pot synthesis of an electron-poor nanographene containing dicarboximide groups at the corners. We efficiently combined palladium-catalyzed Suzuki-Miyaura cross-coupling and dehydrohalogenation to synthesize an extended two-dimensional pi-scaffold of defined size in a single chemical operation starting from N-(2,6-diisopropylphenyl)-4,5-dibromo-1,8-naphthalimide and a tetrasubstituted pyrene boronic acid ester as readily accessible starting materials. The reaction of these precursors under the conditions commonly used for Suzuki-Miyaura cross-coupling afforded a C\(_{64}\) nanographene through the formation of ten C-C bonds in a one-pot process. Single-crystal X-ray analysis unequivocally confirmed the structure of this unique extended aromatic molecule with a planar geometry. The optical and electrochemical properties of this largest ever synthesized planar electron-poor nanographene skeleton were also analyzed.
Exciton coupling is of fundamental importance and determines functional properties of organic dyes in (opto-)electronic and photovoltaic devices. Here we show that strong exciton coupling is not limited to the situation of equal chromophores as often assumed. Quadruple dye stacks were obtained from two bis(merocyanine) dyes with same or different chromophores, respectively, which dimerize in less-polar solvents resulting in the respective homo- and heteroaggregates. The structures of the quadruple dye stacks were assigned by NMR techniques and unambiguously confirmed by single-crystal X-ray analysis. The heteroaggregate stack formed from the bis(merocyanine) bearing two different chromophores exhibits remarkably different ultraviolet/vis absorption bands compared with those of the homoaggregate of the bis(merocyanine) comprising two identical chromophores. Quantum chemical analysis based on an extension of Kasha’s exciton theory appropriately describes the absorption properties of both types of stacks revealing strong exciton coupling also between different chromophores within the heteroaggregate.
Understanding relationships between microstructure and electrical transport is an important goal for the materials science of organic semiconductors. Combining high-resolution surface potential mapping by scanning Kelvin probe microscopy (SKPM) with systematic field effect transport measurements, we show that step edges can trap electrons on the surfaces of single crystal organic semiconductors. n-type organic semiconductor crystals exhibiting positive step edge surface potentials display threshold voltages that increase and carrier mobilities that decrease with increasing step density, characteristic of trapping, whereas crystals that do not have positive step edge surface potentials do not have strongly step density dependent transport. A device model and microelectrostatics calculations suggest that trapping can be intrinsic to step edges for crystals of molecules with polar substituents. The results provide a unique example of a specific microstructure–charge trapping relationship and highlight the utility of surface potential imaging in combination with transport measurements as a productive strategy for uncovering microscopic structure–property relationships in organic semiconductors.
A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis
(2018)
Mechanisms that limit thrombosis are poorly defined. One of the few known endogenous platelet inhibitors is nitric oxide (NO). NO activates NO sensitive guanylyl cyclase (NO-GC) in platelets, resulting in an increase of cyclic guanosine monophosphate (cGMP). Here we show, using cGMP sensor mice to study spatiotemporal dynamics of platelet cGMP, that NO-induced cGMP production in pre-activated platelets is strongly shear-dependent. We delineate a new mode of platelet-inhibitory mechanotransduction via shear-activated NO-GC followed by cGMP synthesis, activation of cGMP-dependent protein kinase I (cGKI), and suppression of Ca2+ signaling. Correlative profiling of cGMP dynamics and thrombus formation in vivo indicates that high cGMP concentrations in shear-exposed platelets at the thrombus periphery limit thrombosis, primarily through facilitation of thrombus dissolution. We propose that an increase in shear stress during thrombus growth activates the NO-cGMP-cGKI pathway, which acts as an auto-regulatory brake to prevent vessel occlusion, while preserving wound closure under low shear.
The origin of the solvent dependence of fluorescence quantum yields in dipolar merocyanine dyes
(2019)
Fluorophores with high quantum yields are desired for a variety of applications. Optimization of promising chromophores requires an understanding of the non-radiative decay channels that compete with the emission of photons. We synthesized a new derivative of the famous laser dye 4-dicyanomethylen-2-methyl-6-p-dimethylaminostyryl-4H-pyran (DCM),i.e., merocyanine 4-(dicyanomethylene)-2-tert-butyl-6-[3-(3-butyl-benzothiazol-2-ylidene)1-propenyl]-4H-pyran (DCBT). We measured fluorescence lifetimes and quantum yields in a variety of solvents and found a trend opposite to the energy gap law.This motivated a theoretical investigation into the possible non-radiative decay channels. We propose that a barrier to a conical intersection exists that is very sensitive to the solvent polarity. The conical intersection is characterized by a twisted geometry which allows a subsequent photoisomerization. Transient absorption measurements confirmed the formation of a photoisomer in unpolar solvents, while the measurements of fluorescence quantum yields at low temperature demonstrated the existence of an activation energy barrier.
A new strategy is demonstrated for the synthesis of warped, negatively curved, all‐sp\(^2\)‐carbon π‐scaffolds. Multifold C−C coupling reactions are used to transform a polyaromatic borinic acid into a saddle‐shaped polyaromatic hydrocarbon (2 ) bearing two heptagonal rings. Notably, this Schwarzite substructure is synthesized in only two steps from an unfunctionalized alkene. A highly warped structure of 2 was revealed by X‐ray crystallographic studies and pronounced flexibility of this π‐scaffold was ascertained by experimental and computational studies. Compound 2 exhibits excellent solubility, visible range absorption and fluorescence, and readily undergoes two reversible one‐electron oxidations at mild potentials.
By introduction of four hydroxy (HO) groups into the two perylene bisimide (PBI) bay areas, new HO‐PBI ligands were obtained which upon deprotonation can complex ZnII ions and photosensitize semiconductive zinc oxide thin films. Such coordination is beneficial for dispersing PBI photosensitizer molecules evenly into metal oxide films to fabricate organic–inorganic hybrid interlayers for organic solar cells. Supported by the photoconductive effect of the ZnO:HO‐PBI hybrid interlayers, improved electron collection and transportation is achieved in fullerene and non‐fullerene polymer solar cell devices, leading to remarkable power conversion efficiencies of up to 15.95 % for a non‐fullerene based organic solar cell.
Objective
To identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms.
Methods
Screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays.
Results
Two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti–NF-155 IgG4 were directed against the NF-155–specific Fn3Fn4 domain. The description of a second phenotype of anti–NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year.
Conclusions
Our results indicate that anti–pan-NF-associated neuropathy differs from anti–NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti–NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response.
Protein-like enwrapped perylene bisimide chromophore as bright microcrystalline emitter material
(2019)
Strongly emissive solid‐state materials are mandatory components for many emerging optoelectronic technologies, but fluorescence is often quenched in the solid state owing to strong intermolecular interactions. The design of new organic pigments, which retain their optical properties despite their high tendency to crystallize, could overcome such limitations. Herein, we show a new material with monomer‐like absorption and emission profiles as well as fluorescence quantum yields over 90 % in its crystalline solid state. The material was synthesized by attaching two bulky tris(4‐tert‐butylphenyl)phenoxy substituents at the perylene bisimide bay positions. These substituents direct a packing arrangement with full enwrapping of the chromophore and unidirectional chromophore alignment within the crystal lattice to afford optical properties that resemble those of their natural pigment counterparts, in which chromophores are rigidly embedded in protein environments.
Herein we report a broad series of new trinuclear supramolecular Ru(bda) macrocycles bearing different substituents at the axial or equatorial ligands which enabled investigation of substituent effects on the catalytic activities in chemical and photocatalytic water oxidation. Our detailed investigations revealed that the activities of these functionalized macrocycles in water oxidation are significantly affected by the position at which the substituents were introduced. Interestingly, this effect could not be explained based on the redox properties of the catalysts since these are not markedly influenced by the functionalization of the ligands. Instead, detailed investigations by X-ray crystal structure analysis and theoretical simulations showed that conformational changes imparted by the substituents are responsible for the variation of catalytic activities of the Ru macrocycles. For the first time, macrocyclic structure of this class of water oxidation catalysts is unequivocally confirmed and experimental indication for a hydrogen-bonded water network present in the cavity of the macrocycles is provided by crystal structure analysis. We ascribe the high catalytic efficiency of our Ru(bda) macrocycles to cooperative proton abstractions facilitated by such a network of preorganized water molecules in their cavity, which is reminiscent of catalytic activities of enzymes at active sites.
Single crystals of three at bay area tetraphenoxy‐substituted perylene bisimide dyes are grown by vacuum sublimation. X‐ray analysis reveals the self‐assembly of these highly twisted perylene bisimides (PBIs) in the solid state via imide–imide hydrogen bonding into hydrogen‐bonded PBI chains. The crystallographic insights disclose that the conformation and sterical congestion imparted by the phenoxy substituents can be controlled by ortho‐substituents. Accordingly, whilst sterically less demanding methyl and isopropyl substituents afford double‐stranded PBI chains of complementary P and M atropo‐enantiomers, single hydrogen‐bonded chains of homochiral PBIs are observed for the sterically more demanding ortho‐phenyl substituents. Investigation of the absorption and fluorescence properties of microcrystals and thin films of these PBIs allow for an unambiguous interpretation of these exciton systems. Thus, the J‐aggregates of the double‐stranded crystals exhibit a much larger (negative) exciton coupling than the single‐stranded one, which in contrast has the higher solid‐state fluorescence quantum yield.
We report the direct imidization of naphthalene and perylene dicarboxylic anhydrides/esters with bulky ortho,ortho‐diaryl‐ and ortho,ortho‐dialkynylaniline derivatives. This imidization method uses n‐butyllithium as a strong base to increase the reactivity of bulky amine derivatives, proceeds under mild reaction conditions, requires only stoichiometric amounts of reactants and gives straightforward access to new sterically crowded rylene dicarboximides. Mechanistic investigations suggest an isoimide as intermediary product, which was converted to the corresponding imide upon addition of an aqueous base. Single‐crystal X‐ray diffraction analyses reveal dimeric packing motifs for monoimides, while two‐side shielded bisimides crystallize in isolated molecules without close π–π‐interactions. Spectroscopic investigations disclose the influence of the bulky substituents on the optical properties in the solid state.
Elementary building blocks for quantum repeaters based on fiber channels and memory stations are analyzed. Implementations are considered for three different physical platforms, for which suitable components are available: quantum dots, trapped atoms and ions, and color centers in diamond. The performances of basic quantum repeater links for these platforms are evaluated and compared, both for present‐day, state‐of‐the‐art experimental parameters as well as for parameters that can in principle be reached in the future. The ultimate goal is to experimentally explore regimes at intermediate distances—up to a few 100 km—in which the repeater‐assisted secret key transmission rates exceed the maximal rate achievable via direct transmission. Two different protocols are considered, one of which is better adapted to the higher source clock rate and lower memory coherence time of the quantum dot platform, while the other circumvents the need of writing photonic quantum states into the memories in a heralded, nondestructive fashion. The elementary building blocks and protocols can be connected in a modular form to construct a quantum repeater system that is potentially scalable to large distances.
Various (AB)\(_{n}\) and (ABAC)\(_{n}\) segmented copolymers with hydrophilic and hydrophobic segments are processed via melt electrowriting (MEW). Two different (AB)\(_{n}\) segmented copolymers composed of bisurea segments and hydrophobic poly(dimethyl siloxane) (PDMS) or hydrophilic poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) (PPO-PEG-PPO) segments, while the amphiphilic (ABAC)\(_{n}\) segmented copolymers consist of bisurea segments in the combination of hydrophobic PDMS segments and hydrophilic PPO-PEG-PPO segments with different ratios, are explored. All copolymer compositions are processed using the same conditions, including nozzle temperature, applied voltage, and collector distance, while changes in applied pressure and collector speed altered the fiber diameter in the range of 7 and 60 µm. All copolymers showed excellent processability with MEW, well-controlled fiber stacking, and inter-layer bonding. Notably, the surfaces of all four copolymer fibers are very smooth when visualized using scanning electron microscopy. However, the fibers show different roughness demonstrated with atomic force microscopy. The non-cytotoxic copolymers increased L929 fibroblast attachment with increasing PDMS content while the different copolymer compositions result in a spectrum of physical properties.
Objective
The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer.
Materials and methods
A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations.
Results
Metastasis-directed radiotherapy results in high local control (often > 90% within a follow-up of 1–2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels.
Conclusion
ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations.
Hydrophilic (AB)\(_{n}\) Segmented Copolymers for Melt Extrusion‐Based Additive Manufacturing
(2021)
Several manufacturing technologies beneficially involve processing from the melt, including extrusion‐based printing, electrospinning, and electrohydrodynamic jetting. In this study, (AB)\(_{n}\) segmented copolymers are tailored for melt‐processing to form physically crosslinked hydrogels after swelling. The copolymers are composed of hydrophilic poly(ethylene glycol)‐based segments and hydrophobic bisurea segments, which form physical crosslinks via hydrogen bonds. The degree of polymerization was adjusted to match the melt viscosity to the different melt‐processing techniques. Using extrusion‐based printing, a width of approximately 260 µm is printed into 3D constructs, with excellent interlayer bonding at fiber junctions, due to hydrogen bonding between the layers. For melt electrospinning, much thinner fibers in the range of about 1–15 µm are obtained and produced in a typical nonwoven morphology. With melt electrowriting, fibers are deposited in a controlled way to well‐defined 3D constructs. In this case, multiple fiber layers fuse together enabling constructs with line width in the range of 70 to 160 µm. If exposed to water the printed constructs swell and form physically crosslinked hydrogels that slowly disintegrate, which is a feature for soluble inks within biofabrication strategies. In this context, cytotoxicity tests confirm the viability of cells and thus demonstrating biocompatibility of this class of copolymers.
A novel approach, in the context of bioprinting, is the targeted printing of a defined number of cells at desired positions in predefined locations, which thereby opens up new perspectives for life science engineering. One major challenge in this application is to realize the targeted printing of cells onto a gel substrate with high cell survival rates in advanced bioinks. For this purpose, different alginate-dialdehyde—polyethylene glycol (ADA-PEG) inks with different PEG modifications and chain lengths (1–8 kDa) were characterized to evaluate their application as bioinks for drop on demand (DoD) printing. The biochemical properties of the inks, printing process, NIH/3T3 fibroblast cell distribution within a droplet and shear forces during printing were analyzed. Finally, different hydrogels were evaluated as a printing substrate. By analysing different PEG chain lengths with covalently crosslinked and non-crosslinked ADA-PEG inks, it was shown that the influence of Schiff's bases on the viscosity of the corresponding materials is very low. Furthermore, it was shown that longer polymer chains resulted in less stable hydrogels, leading to fast degradation rates. Several bioinks highly exhibit biocompatibility, while the calculated nozzle shear stress increased from approx. 1.3 and 2.3 kPa. Moreover, we determined the number of cells for printed droplets depending on the initial cell concentration, which is crucially needed for targeted cell printing approaches.