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The physicochemical properties of chemical compounds can be altered and optimized by cocrystallization with a suitable coformer. However, discovering suitable coformers is a difficult and expensive process. Link prediction is one of the several techniques developed to predict suitable new coformers computationally. Link prediction uses a network of known coformers extracted from, e.g., the Cambridge Structural Database (CSD) to predict new cocrystals. We have investigated link prediction methods and were able to improve the performance of these methods using a scoring function called “multi-steps resource allocation”. Further improvements were obtained by examining the local structure of the network to remove imperfections and by using an algorithm previously designed by us to bipartise the network, thus removing imperfections on a global scale. By repeatedly predicting and synthesizing new cocrystals and adding them to the network to predict more new cocrystals, we obtain more and better predictions, but saturation of the local network eventually leads to diminishing returns. We demonstrate this for praziquantel (PZQ), a drug used to treat schistosomiasis. We discovered 11 new cocrystals for this compound, one of which is a racemic conglomerate that could be used to improve the medical efficacy of PZQ, and present 6 new cocrystal structures.

Chiral compounds that crystallize as conglomerates from racemic mixtures are desirable from the perspective of chiral resolution since they are relatively easy to resolve using, for instance, preferential crystallization. Here, a screening methodology to find conglomerate cocrystals is demonstrated using racemic praziquantel (rac-PZQ). Cocrystallization of rac-PZQ was performed using liquid-assisted grinding (LAG) with 20 potential achiral coformers. LAG screening results show that N-phenyl urea (PU) and 1,3-dimethylthiourea (DMTU) are the only two achiral coformers that form new cocrystal compounds with rac-PZQ. Single-crystal structure determination of cocrystals grown from solution shows that the rac-PZQ:PU cocrystal is a racemic cocrystal with space group P21/c, while the rac-PZQ:DMTU cocrystal is a conglomerate cocrystal with space group P21. Under gentle conditions, rac-PZQ:DMTU forms a true conglomerate cocrystal from solution. However, when grown from solution under higher supersaturations, the obtained single crystals of rac-PZQ:DMTU appear to be disordered racemic twin cocrystals: these contain alternating domains of (almost) pure enantiomers of PZQ that are related by inversion symmetry. The disordered racemic twin cocrystals probably form due to refreshment of the enantiomer at the crystal surface being diffusion-limited from the bulk solution to the boundary layer. Discovery of a conglomerate cocrystal form of PZQ opens up exciting possibilities for the optical resolution of PZQ by preferential crystallization, allowing for easy preparation of pure enantiomer formulations of this important API.

Leucettinibs are substituted 2-aminoimidazolin-4-ones (inspired by the marine sponge natural product Leucettamine B) developed as pharmacological inhibitors of DYRK1A (dual-specificity, tyrosine phosphorylation-regulated kinase 1A), a therapeutic target for indications such as Down syndrome and Alzheimer’s disease. Leucettinib-21 was selected as a drug candidate following extensive structure/activity studies and multiparametric evaluations. We here report its physicochemical properties (X-ray powder diffraction, differential scanning calorimetry, stability, solubility, crystal structure) and drug-like profile. Leucettinib-21’s selectivity (analyzed by radiometric, fluorescence, interaction, thermal shift, residence time assays) reveals DYRK1A as the first target but also some “off-targets” which may contribute to the drug’s biological effects. Leucettinib-21 was cocrystallized with CLK1 and modeled in the DYRK1A structure. Leucettinib-21 inhibits DYRK1A in cells (demonstrated by direct catalytic activity and phosphorylation levels of Thr286-cyclin D1 or Thr212-Tau). Leucettinib-21 corrects memory disorders in the Down syndrome mouse model Ts65Dn and is now entering safety/tolerance phase 1 clinical trials.

Fe(CN)64–(abbreviated as FeCN) is a well-known anticaking agent for NaCl that has a nearly perfect geometrical fit to the (001) surface. In this work, the investigation of the action of FeCN on nucleation and creeping is extended to a wide range of alkali halides of both the NaCl and CsCl structures. It was found that FeCN is a powerful nucleation inhibitor and enhances the creeping of alkali halides when FeCN geometrically fits well in the octahedral surface site of hosts with the NaCl crystal structure. The tested alkali halides that do not fall in this group or that have the CsCl structure show some reduction in creeping upon the addition of FeCN, while NaF and LiCl did not show a difference. For this category of crystals, there is a poor fit of the FeCN ion in the crystal surface. This study shows that a strong adsorption strength of FeCN enhances creeping, whereas a weak interaction reduces the creeping of alkali halide crystals.

Pharmaceutical cocrystals are highly interesting due to their effect on physicochemical properties and their role in separation technologies, particularly for chiral molecules. Detection of new cocrystals is a challenge, and robust screening methods are required. As numerous techniques exist that differ in their crystallization mechanisms, their efficiencies depend on the coformers investigated. The most important parameters characterizing the methods are the (a) screenable coformer fraction, (b) coformer success rate, (c) ability to give several cocrystals per successful coformer, (d) identification of new stable phases, and (e) experimental convenience. Based on these parameters, we compare and quantify the performance of three methods: liquid-assisted grinding, solvent evaporation, and saturation temperature measurements of mixtures. These methods were used to screen 30 molecules, predicted by a network-based link prediction algorithm (described in Cryst. Growth Des. 2021,21(6), 3428–3437) as potential coformers for the target molecule praziquantel. The solvent evaporation method presented more drawbacks than advantages, liquid-assisted grinding emerged as the most successful and the quickest, while saturation temperature measurements provided equally good results in a slower route yielding additional solubility information relevant for future screenings, single-crystal growth, and cocrystal production processes. Seventeen cocrystals were found, with 14 showing stability and 12 structures resolved.

Imidazole-based compounds are widely found in natural products, synthetic molecules, and biomolecules. Noncovalent interactions between the imidazole ring and other functional groups play an important role in determining the function of diverse molecules. However, there is a limited understanding of the underlying noncovalent interactions between imidazoles and aromatic systems. In this work, we report physical-organic chemistry studies on 2-(2,6-diarylphenyl)-1H-imidazoles and their protonated forms to investigate the noncovalent interactions between the central imidazole ring and two flanking aromatic rings possessing substituents at the para/meta position. Hammett analysis revealed that pKavalues and proton affinities correlate well with Hammett σ values of para-substituents at the flanking rings. Additional quantitative Kohn–Sham molecular orbital and energy decomposition analyses reveal that through-space π–π interactions and NH−π interactions contribute to the intramolecular stabilization of the imidazolium cation. The results are important because they clearly demonstrate that the imidazolium cation forms energetically favorable noncovalent interactions with aromatic rings via the through-space effect, a knowledge that can be used in rational drug and catalyst design.

Arene–arene interactions are fundamentally important in molecular recognition. To precisely probe arene–arene interactions in cyclophanes, we designed and synthesized (2,6-phenol)paracyclophanes and (2,6-aniline)paracyclophanes that possess two aromatic rings in close proximity. Fine-tuning the aromatic character of one aromatic ring by fluorine substituents enables investigations on the intramolecular interactions between the electron-rich phenol and aniline with tetra-H- and tetra-F-substituted benzene. pKameasurements revealed that the tetra-F-template increases the acidity of the phenol (ΔpKa= 0.55). X-ray crystallography and computational analyses demonstrated that all [3,3]metaparacyclophanes adopt cofacial parallel conformations, implying the presence of π–π stacking interactions. Advanced quantum chemical analyses furthermore revealed that both electrostatic interactions and orbital interactions provide the key contribution to the structure and stability of [3,3]metaparacyclophanes.

The stereoisomeric system of rac-2-phenylglycinamide (PGA) and rac-N-acetyl tryptophan (NAT) is significant in the application of chiral resolution because it has been shown that this system can be used for enantioseparation of PGA and/or NAT using a novel deracemization route of the conglomerate salt formed. However, it was also found that the conglomerate salt eventually converted into different crystal forms that limited the time available for the separation. Herein, we try to understand the phase conversion occurring in this system using DSC, PXRD, and SC-XRD. The related structures of the salt (two polymorphs of the more stable homochiral (dd- and ll-) salts and one polymorph of the less stable heterochiral (dl- and ld-) monohydrate salts) are demonstrated and discussed relating to their relative stabilities. The successful deracemization was demonstrated using the heterochiral (dl- or ld-) monohydrate salts. However, following Ostwald’s rule of stages, only limited time is available for the deracemization before the metastable compound converts into the more stable homochiral (dd- and ll-) pair. Moreover, the occurrence of the (dd- and ll-) phase always coincides with the formation of yet another phase of the racemic compound containing four components in a crystal. Ostwald’s rule of stages here thus involves three steps and phases and is highly significant during the deracemization of the homochiral species.

Cocrystallization has been promoted as an attractive early development tool as it can change the physicochemical properties of a target compound and possibly enable the purification of single enantiomers from racemic compounds. In general, the identification of adequate cocrystallization candidates (or coformers) is troublesome and hampers the exploration of the solid-state landscape. For this reason, several computational tools have been introduced over the last two decades. In this study, cocrystals of Praziquantel (PZQ), an anthelmintic drug used to treat schistosomiasis, are predicted with network-based link prediction and experimentally explored. Single crystals of 12 experimental cocrystal indications were grown and subjected to a structural analysis with single-crystal X-ray diffraction. This case study illustrates the power of the link-prediction approach and its ability to suggest a diverse set of new coformer candidates for a target compound when starting from only a limited number of known cocrystals.

Recent developments in the field of high efficiency perovskite solar cells are based on stabilization of the perovskite crystal structure of FAPbI3while preserving its excellent optoelectronic properties. Compositional engineering of, for example, MA or Br mixed into FAPbI3results in the desired effects, but detailed knowledge of local structural features, such as local (dis)order or cation interactions of formamidinium (FA) and methylammonium (MA), is still limited. This knowledge is, however, crucial for their further development. Here, we shed light on the microscopic distribution of MA and FA in mixed perovskites MA1–xFAxPbI3and MA0.15FA0.85PbI2.55Br0.45by combining high-resolution double-quantum 1H solid-state nuclear magnetic resonance (NMR) spectroscopy with state-of-the-art near-first-principles accuracy molecular dynamics (MD) simulations using machine-learning force-fields (MLFFs). We show that on a small local scale, partial MA and FA clustering takes place over the whole MA/FA compositional range. A reasonable driving force for the clustering might be an increase of the dynamical freedom of FA cations in FA-rich regions. While MA0.15FA0.85PbI2.55Br0.45displays similar MA and FA ordering as the MA1–xFAxPbI3systems, the average cation–cation interaction strength increased significantly in this double mixed material, indicating a restriction of the space accessible to the cations or their partial immobilization upon Br–incorporation. Our results shed light on the heterogeneities in cation composition of mixed halide perovskites, helping to exploit their full optoelectronic potential.

Cocrystallization of racemic-compound-forming chiral molecules can result in conglomerate cocrystals or diastereomerically related cocrystals, which enable the application of chiral separation techniques such as preferential crystallization and classic resolution. Here, a systematic method to identify the types and phase diagrams of cocrystals formed by chiral target compounds and candidate coformers in a particular solvent system is presented, which allows the design of suitable chiral resolution processes. The method is based on saturation temperature measurements of specific solution compositions containing both enantiomers of chiral molecules and a coformer. This method is applied to analyze three different systems. For racemic phenylalanine (Phe) in water/ethanol mixtures one of the enantiomers selectively cocrystallizes with the opposite enantiomer of valine (Val), forming the more stable diastereomerically related cocrystal. The racemic compound ibuprofen crystallizes with the nonchiral coformer 1,2-bis(4-pyridyl)ethane (BPN) as racemic compound cocrystals. More interestingly, when it is combined with trans-1-(2-pyridyl)-2-(4-pyridyl)ethylene (BPE), the racemic compound ibuprofen cocrystallizes as a conglomerate, which in principle enables the application of preferential crystallization of this racemic compound. The systematic method shows the benefit of using pseudo-binary phase diagrams. Such pseudo-binary phase diagrams depict the saturation temperature on a very specific route through the quaternary phase diagram, allowing the identification of various cocrystal types as well as the corresponding cocrystallization conditions. The systematic method can be used to identify a suitable solid phase for chiral separation, and the obtained phase diagram information enables the performance of a crystallization-mediated chiral resolution process design. Such a guideline for a chiral resolution process design has never been reported for conglomerate cocrystal systems such as IBU:BPE, presented in this study.

The use of an achiral metal–organic framework for structure determination of chiral compounds is demonstrated for camphene and pinene. The structure of enantiopure β-pinene can be resolved using the crystalline sponge method. However, α-pinene cannot be resolved using enantiopure material alone because no ordering of guest molecules takes place in that case. Interestingly, enantiomeric pairs order inside the channels of the host framework when impure (+)-camphene is offered to the host, which is also the case when a racemic mixture of α-pinene is used. A mixture of (+)-α-pinene and (−)-β-pinene also leads to ordered incorporation in the host, showing the influence of the presence of an inversion center in the host framework. We further show that powder X-ray diffraction provides a direct view on incorporation of ordered guest molecules. This technique, therefore, provides a way to determine the optimal and/or minimal soaking time. In contrast, color change of the crystal only demonstrates guest uptake, not ordering. Moreover, we show that color change can also be caused by guest-induced host degradation.

Energetically favorable cation−π interactions play important roles in numerous molecular recognition processes in chemistry and biology. Herein, we present synergistic experimental and computational physical–organic chemistry studies on 2,6-diarylanilines that contain flanking meta/para-substituted aromatic rings adjacent to the central anilinium ion. A combination of measurements of pKavalues, structural analyses of 2,6-diarylanilinium cations, and quantum chemical analyses based on the quantitative molecular orbital theory and a canonical energy decomposition analysis (EDA) scheme reveal that through-space cation−π interactions essentially contribute to observed trends in proton affinities and pKavalues of 2,6-diarylanilines.

The premise of most studies on the homogeneous electrocatalytic CO2reduction reaction (CO2RR) is a good understanding of the reaction mechanisms. Yet, analyzing the reaction intermediates formed at the working electrode is challenging and not always attainable. Here, we present a new, general approach to studying the reaction intermediates applied for CO2RR catalyzed by a series of cobalt complexes. The cobalt complexes were based on the TPA-ligands (TPA = tris(2-pyridylmethyl)amine) modified by amino groups in the secondary coordination sphere. By combining the electrochemical experiments, electrochemistry-coupled electrospray ionization mass spectrometry, with density functional theory (DFT) calculations, we identify and spectroscopically characterize the key reaction intermediates in the CO2RR and the competing hydrogen-evolution reaction (HER). Additionally, the experiments revealed the rarely reported in situchanges in the secondary coordination sphere of the cobalt complexes by the CO2-initiated transformation of the amino substituents to carbamates. This launched an even faster alternative HER pathway. The interplay of three catalytic cycles, as derived from the experiments and supported by the DFT calculations, explains the trends that cobalt complexes exhibit during the CO2RR and HER. Additionally, this study demonstrates the need for a molecular perspective in the electrocatalytic activation of small molecules efficiently obtained by the EC-ESI-MS technique.

A rare case of a polymorphic racemic compound has been discovered in the binary system of enantiomers of the praziquantel derivative 2-(cyclopropanecarbonyl)dodecahydro-4H-pyrazino[2,1-a]isoquinolin-4-one. Solid-state characterization of the three polymorphs has been performed, including the resolution of their crystal structures and the construction of a binary phase diagram between the enantiomers. Although the three polymorphs demonstrate high kinetic stability at room temperature, a thorough examination of the binary phase diagram through thermodynamic consideration reveals a complex situation in which the three racemic forms are found to be enantiotropically related. As a result of major structural differences between the polymorphs, no solid–solid polymorphic transition was observed, and the conversion from one form to the other systematically required melting and recrystallization. Such enantiotropic behavior is rarely observed and highlights the diversity of crystallization behaviors that can result from slight chemical modification.

The rich landscape of enantiotropically related polymorphic forms and their solid-state phase transitions of dl-2-aminoheptanoic acid (dl-AHE) has been explored using a range of complementary characterization techniques, and is largely exemplary of the polymorphic behavior of linear aliphatic amino acids. As many as five new polymorphic forms were found, connected by four fully reversible solid-state phase transitions. Two low temperature forms were refined in a high Z′ crystal structure, which is a new phenomenon for linear aliphatic amino acids. All five structures consist of two-dimensional hydrogen-bonded bilayers interconnected by weak van der Waals interactions. The single-crystal-to-single-crystal phase transitions involve shifts of bilayers and/or conformational changes in the aliphatic chain. Compared to two similar phase transitions of the related amino acid dl-norleucine, the enthalpies of transition and NMR chemical shift differences are notably smaller in dl-aminoheptanoic acid. This is explained to be a result of both the nature of the conformational changes and the increased chain length, weakening the interactions between the bilayers.

Although it is well established that the acidity of phenol can be fine-tuned with substituents on its aromatic ring via through-bond effects, the role of through-space effects on the acidity of phenols is presently poorly understood. Here, we present integrated experimental and computational studies on substituted 2,6-diarylphenols that demonstrate the essential contribution from through-space OH−π interactions and O––π interactions in the observed trends in proton affinities and acidities of 2,6-diarylphenols.

The polymorphs of a phenylethynyl functionalized fluorenone derivative, and their controlled self-assembly for microstructures with different morphologies have been studied. These polymorphic microcrystals exhibit very distinctive NLO properties, which are highly correlated to their electronic and supramolecular structures.

Hybrid metal halide perovskites are characterized by excellent photoelectric properties with great tunability. By manipulation of their chemical composition, their crystal structure can be altered at the atomic level, leading to confined systems characterized by reduced dimensionality and distinct properties. Here, we provide an in-depth characterization of the structural and optoelectronic properties of 2D (NH4)3Sb2I9perovskite single crystals in a wide temperature range (4.2–300 K). Upon cooling, changes in the material’s thermal expansion led to a strong increase in the photoluminescence (PL) intensity. Our findings define the underlying photophysics of this system and the structure–property relationships, thereby paving the way for the optimization and rational design of optoelectronic applications.

In het nieuws is niet alles wat het lijkt. Steeds vaker weten belangengroepen de media voor hun karretje te spannen en de tegenpartij in een kwaad daglicht te stellen. Zoals Jeroen van den Oever, bestuurder van Vierstroom overkwam.

In continuation of our previous work on the applicability of the G(R∞) correction factor for the quantification of Raman spectra of coke during propane dehydrogenation experiments (Phys. Chem. Chem. Phys., 2005, 7, 211), research has been carried out on the potential of this correction factor for the quantification of supported metal oxides during reduction experiments. For this purpose, supported chromium oxide catalysts have been studied by combined in situRaman and UV-Vis spectroscopy during temperature programmed reduction experiments with hydrogen as reducing agent. The goal was to quantify on-line the amount of Cr6in a reactor based on the measured in situRaman spectra. During these experiments, a significant temperature effect was observed, which has been investigated in more detail with a thermal imaging technique. The results revealed a temperature ‘on the spot’ that can exceed 100 °C. It implies that Raman spectroscopy can have a considerable effect on the local reaction conditions and explains observed inconsistencies between the in situUV-Vis and Raman data. In order to minimize this heating effect, reduction of the laser power, mathematical matching of the spectroscopic data, a different cell design and a change in reaction conditions has been evaluated. It is demonstrated that increasing the reactor temperature is the most feasible method to solve the heating problem. Next, it allows the application of in situRaman spectroscopy in a reliable quantitative way without the need of an internal standard.

In continuation to the possibility of using a combined operandoRamanUV-Vis-NIR set-up for conducting qualitative Raman spectroscopy, the possibilities for quantitative Raman spectroscopic measurements of supported metal oxide catalysts under working conditions without the need of an internal standard have been explored. The dehydrogenation of propane over an industrial-like 13 wt CrAl2O3catalyst was used as a model system. During reaction, the catalytic solid was continuously monitored by both UV-Vis-NIR and Raman spectroscopy. As the dehydrogenation proceeds, the catalyst gradually darkens due to coke formation and consequently the UV-Vis-NIR diffuse reflectance and Raman scattered signal progressively decrease in intensity. The formation of coke was confirmed with TEOM, TGA and Raman. The measured Raman spectra can be used as a quantitative measure of the amount of carbonaceous deposits at the catalyst surface provided that a correction factor GR∞ is applied. This factor can be directly calculated from the corresponding UV-Vis-NIR diffuse reflectance spectra. The validity of the approach is compared with one, in which an internal boron nitride standard is added to the catalytic solid. It will be shown that the proposed methodology allows measurement of the amount of carbonaceous deposits on a catalyst material inside a reactor as a function of reaction time and catalyst bed height. As a consequence, an elegant technique for on-lineprocess control of e.g.an industrial propane dehydrogenation reactor emerges.

Recently reported molecular host complexes, modified metal dibenzoylmethanates (metal DBMs), are extended to polynuclear host receptors by connecting metal DBM units with bridging ligand 4,4‘-dipyridyl (bipy). Series of new solvent-free as well as inclusion materials were prepared and studied with XRD, NMR, and other methods. Template-directed synthesis gave inclusion compounds with three distinct types of host receptors:  dimeric [Zn2(bipy)(DBM)4], trimeric [Zn3(bipy)2(DBM)6], and polymeric [Zn(bipy)(DBM)2]n complexes. The dimeric complex was isolated as a solvent-free compound and as inclusion compounds with tert-butylbenzene and fluorobenzene (host per guest molar ratios of 1:1 and 1:²/3, respectively). The trimeric complex was prepared as an inclusion compound with DMSO (1:5 molar ratio). The polymeric complex was observed in inclusion compounds with fluorobenzene (host unit per guest molar ratio 1:2), tetrahydrofuran (1:2), 2-pentanone (1:2), bipy/DMSO (1:¹/2:¹/2), and bipy/tert-butylbenzene (1:1:2); a solvent-free material was obtained upon desolvation of tetrahydrofuran and 2-pentanone inclusions. The isolated host species have five-coordinated terminal zinc centers (two chelating DBMs and a singly coordinating bipy) and octahedrally coordinated intrinsic zinc centers (two chelating equatorial DBMs and two singly coordinating bipys). The bipy ligands bridge the zinc centers to give the di-, tri-, and polynuclear complexes. Nanosized voids between the DBM units coordinated to adjacent zinc centers form the basis for cages and channels in the inclusion materials. These voids have, in many cases, a typical size of between 1 and 2 nm and accommodate up to five molecules per single cavity or two rows of guest molecules in a single channel. When compared to previously reported metal DBMs, the multinuclear metal DBM receptors reported here exhibit stronger inclusion affinity and enhanced inclusion capacity.

A novel experimental set-up for characterizing supported metal oxide catalysts under working conditions has been developed. The set-up combines product analysis using on-line mass spectrometry MS with catalyst characterization by time-resolved operando UV-VIS and Raman spectroscopy. The potentials of this approach are illustrated by the propane dehydrogenation over a chromium oxide on alumina catalyst. It is demonstrated that these spectroscopic techniques give valuable complimentary information on the changing catalyst performance during successive propane dehydrogenation operating cycles.

A novel experimental set-up for characterizing supported metal oxide catalysts under working conditions has been developed. The set-up combines product analysis using on-line mass spectrometry (MS) with catalyst characterization by time-resolved operando UV-VIS and Raman spectroscopy. The potentials of this approach are illustrated by the propane dehydrogenation over a chromium oxide on alumina catalyst. It is demonstrated that these spectroscopic techniques give valuable complimentary information on the changing catalyst performance during successive propane dehydrogenation operating cycles.

: Results and experience with the treatmentof non-palpable breast cancer are reported and related to the future ofless invasive treatment of small breast cancers. The retrospectivestudy included 102 patients treated between 1980 and 1993 at theUniversity Hospital of Nijmegen. Most cancers were screen-detected.Tumor sizes on pathological examination proved 3 mm (SD 7.7 mm) largerthan on mammography (p = 0.0029). pT1 tumors wereencountered in 77 patients (75%); pT2 tumors in 17 patients (17%).Seventy-five patients were free of lymph node metastases, 26 patientsshowed stage pN1 (25%). Most patients had invasive ductal cancers.Only two patients died of breast cancer. A 10-year disease-freesurvival of 94% was calculated, after excluding four patients withknown systemic disease (M1) at diagnosis. T1a,T1b, and T1c had a 10-year survival of 100%,96%, and 96%, respectively. Early detection and multimodalitytreatment of breast cancer have significantly improved survival. Inpatients with small breast cancer tumors future developments intreatment must be aimed at the use of less invasive techniques,reducing morbidity while maintaining high levels of disease-freesurvival.

Results and experience with the treatmentof non-palpable breast cancer are reported and related to the future ofless invasive treatment of small breast cancers. The retrospectivestudy included 102 patients treated between 1980 and 1993 at theUniversity Hospital of Nijmegen. Most cancers were screen-detected.Tumor sizes on pathological examination proved 3 mm (SD 7.7 mm) largerthan on mammography (p = 0.0029). pT1 tumors wereencountered in 77 patients (75%); pT2 tumors in 17 patients (17%).Seventy-five patients were free of lymph node metastases, 26 patientsshowed stage pN1 (25%). Most patients had invasive ductal cancers.Only two patients died of breast cancer. A 10-year disease-freesurvival of 94% was calculated, after excluding four patients withknown systemic disease (M1) at diagnosis. T1a,T1b, and T1c had a 10-year survival of 100%,96%, and 96%, respectively. Early detection and multimodalitytreatment of breast cancer have significantly improved survival. Inpatients with small breast cancer tumors future developments intreatment must be aimed at the use of less invasive techniques,reducing morbidity while maintaining high levels of disease-freesurvival.

The photodecomposition of the S2O2‐8ion to the SO2‐4ion with concomitant oxidation of water to molecular oxygen over n‐type SrTiO3powders mixed with LaCrO3(mole fraction x= 0–1), using UV light (λ > 300 nm), is considerably faster than the photochemical (UV) decomposition of S2O2‐8in water or the thermal reaction with or without the powder under the same conditions. The rate of oxygen formation is dependent on the temperature (Eact= 61 kJ/mol), the persulfate concentration in first order and x. At 64°C and constant [S2O2‐8] a maximum rate is found at x= 0.25. The rate determining step, i.e. the transfer of an energy‐rich electron from the conduction band to the S2O2‐8ion, is expected to proceed faster in the case of p‐type semiconductors. In view of the reported p‐type conductivity of LaCrO3, which has previously been doped with the charge‐compensating Sr11ion, our results with the SrTiO3‐xLaCrO3powders are in agreement with these expectations. The sensitivity of these materials towards visible irradiation is much lower than their UV response (about 1–2%) which has also been found by determining i/Vand i/λ characteristics of SrTiO3‐xLaCrO3single crystals under illumination in a photoelectrochemical cell.

The photoassisted reduction or aqueous carbon dioxide was carried out in the presence of suspensions of powdered strontium titanate, surface treated with various transition metal oxide additives, using either high-pressure mercury lamps or sunlight as the energy source. The organic products observed included formic acid, formaldehyde, methanol, acetaldehyde and ethanol.

UV curable, hard, transparent inorganic/organic composites with covalent links between the inorganic and the organic networks were prepared by the sol-gel method. These hybrid coating materials were synthesized using a commercially available, acrylate end-capped polyester or polyurethane oligomeric resin (EBC80, EBC284), hexanedioldiacrylate (HDDA) as a reactive solvent, 3-(trimethoxysilyl)propoxymethacrylate (TMSPM) as a coupling agent between the organic and inorganic phase, and a metal alkoxide, tetraethylorthosilicate (TEOS). The materials were applied on primer or oxygen plasma pretreated polycarbonate sheets and UV cured, followed by a thermal treatment to give a transparent coating with a good adhesion and abrasion resistance. The high transmission and the thermogravimetric behavior indicate the presence of a nanoscale hybrid composite, as is confirmed by SAXS and TEM measurements. In a Taber Abrasion Test, uncoated polycarbonate sheets exhibit a 48% decrease in light transmittance at 600 nm after 300 wear cycles, whereas the EBC80 hybrid coating system containing 9 wt% SiO2(EBC80/25Si) shows only 28% decrease in light transmittance. A maximal improvement of the abrasion resistance is achieved when 23 wt% SiO2is incorporated (EBC80/60Si, EBC284/60Si) with only 20% decrease in light transmittance. The abrasion resistance of glass is not yet encountered. For optimal results, it is essential that the rate of condensation of the silanol groups is sufficiently high to form a dense three-dimensional network.

In a series of 44 bronchial biopsies from patients suspected of having endobronchial lung carcinoma, the validity of proliferating cell nuclear antigen (PCNA) and Ki67 antigen as proliferative indicators was evaluated in ethanol fixed, paraffin embedded tissue. The percentages of cells positive for these markers were compared to the in vivo bromodeoxyuridine (BrdU) labelling index. A good correlation was found between PCNA immunoreactivity and BrdU labelling index, while Ki67-antigen expression showed a significant relation with BrdU labelling index and with PCNA expression. All three parameters showed a trend towards similar values for the individual cases. Based on the fact that Ki67 antigen is expressed in all cycling cells, whereas replicon-associated PCNA and BrdU only reflect the S-phase fraction, the differences between Ki67-antigen scores on the one hand and BrdU and PCNA scores on the other were smaller than expected. In order to determine the degree of concordance between immunohistochemically and flow cytometrically detected proliferation variables, BrdU incorporation was measured using both methods in duplicate bronchial specimens. Discrepancies in labelling indices were observed predominantly in DNA diploid samples, with consistently lower values in the flow cytometrically analysed specimens. In tumour specimens with an aneuploid DNA content, flow cytometric determination of proliferative activity yielded results similar to those obtained by tissue section examination. We conclude that the scores for PCNA and Ki67 antigen, immunohistochemically detected in ethanol fixed, paraffin embedded tissue reflect functional proliferative activity.

The significance of mammography in the detection of contralateral primary breast cancer was evaluated in 55 patients with bilateral breast disease. Fifteen (65%) of 23 patients in the synchronous group and 16 (50%) of 32 patients in the metachronous group had clinically occult carcinoma in the opposite breast. Excluding the 2 malignancies discovered by prophylactic mastectomy, mammography alone was responsible for the detection of 29 (52.7%) nonpalpable, contralateral breast carcinomas. The whole series of 110 malignant breasts comprised 41 nonpalpable carcinomas, of which 12 were noninvasive [ductal carcinoma in situ (7) and lobular carcinoma in situ (5)] and the remaining 29 were invasive carcinomas, either ductal of various types (25) or lobular (4). With regard to the évaluable axillary nodes, 20 (54.1%) of 37 palpable breast cancers and only 3 (11.5%) of 26 nonpalpable breast carcinomas had positive lymph nodes. The multicentricity rate was particularly high in synchronous tumors (70.6%), and in invasive lobular (73.3%) and noninvasive (75%) carcinomas. The favorable 5- and 10-year survival of patients, both in synchronous and metachronous bilateral primary breast cancer, justify that they be treated with aggressive optimism.

High molecular weight liquid-crystalline polyhydroxyethers, containing functional hydroxy groups, were synthesized from an aromatic diol and the diglycidylether of an aromatic diol. The polymers showed a liquid-crystalline melt when about 70% or more of the aromatic units in the chain were biphenyl units. Tensile modulus values varied from 3 GPa for as-cast films to 6 GPa for drawn films. These polymers are potentially suitable candidates to reinforce common thermoplastics by reactive blending. For this purpose polyhydroxyethers have been prepared, having a liquid-crystalline melt in the processing range of PET, viz. 260–290°C. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 66: 1971–1978, 1997

Poly(ethylene terephthalate) modified with a dianhydride (PET–anhydride) was melt-blended with a liquid crystalline copolyester (Vectra A) in the presence of a small amount of a liquid crystalline polyhydroxyether. The mechanical properties of a blend consisting of PET–anhydride/Vectra A/polyhydroxyether were drastically improved compared to blends without polyhydroxyether or without anhydride. Melt-spun fibers of PET–anhydride/Vectra A/polyhydroxyether in a 80/20/0.75 weight ratio displayed a much higher tensile modulus (17 GPa) and tensile strength (214 MPa) than did a 80/20 PET–anhydride/Vectra A blend (4 GPa and 60 MPa, respectively). A similar increase in modulus and strength was found for a 90/10/0.75 relative to a 90/10 blend. The tensile moduli of the blends can well be described by the Tsai–Halpin equation. A better fibril formation was observed, which was attributed to an improved viscosity ratio. Reactions between the various functional groups during melt processing were indicated by viscosity measurements. The polyhydroxyether may act as a reactive compatibilizer which improves the interfacial adhesion, chemically and/or physically. WAXD recordings of both blends showed a crystalline and highly oriented Vectra phase. The PET phase was unoriented and amorphous in a PET/Vectra blend and semicrystalline and weakly oriented in a PET/Vectra/polyhydroxyether blend. Postdrawing of the various blend fibers to λ = 4 increased the modulus by about 40% and the tensile strength by more than 100%, mainly through orientation of the PET phase. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 71: 1107–1123, 1999

In a more elaborate article, it was described that blends of poly(ethylene terephthalate) (PET), a liquid crystalline copolyester, and small amounts of a liquid crystalline polyhydroxyether showed an increase in tensile modulus and strength compared to the blends without polyhydroxyether. The results were obtained using a polyhydroxyether composed of 75 mol % biphenyl and 25 mol % phenyl units. In this article, the use of two other types of polyhydroxyether is described, one based on the α-methylstilbene unit and the other based on bisphenol A. Addition of either of these polyhydroxyethers to the PET/thermotropic liquid crystalline polymer (TLCP) blends increased the tensile modulus and strength of extruded fibers in a similar way as upon addition of the liquid crystalline polyhydroxyether. Improvement of the viscosity ratio and thereby improvement of the fibril formation, by reactions of the functional hydroxyl side groups in the polyhydroxyethers, appears to be the most important factor for the improvement of the mechanical properties. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 71: 1125–1131, 1999

The significance of mammography in the detection of contralateral primary breast cancer was evaluated in 55 patients with bilateral breast disease. Fifteen (65%) of 23 patients in the synchronous group and 16 (50%) of 32 patients in the metachronous group had clinically occult carcinoma in the opposite breast. Excluding the 2 malignancies discovered by prophylactic mastectomy, mammography alone was responsible for the detection of 29 (52.7%) nonpalpable, contralateral breast carcinomas. The whole series of 110 malignant breasts comprised 41 nonpalpable carcinomas, of which 12 were noninvasive [ductal carcinoma in situ (7) and lobular carcinoma in situ (5)] and the remaining 29 were invasive carcinomas, either ductal of various types (25) or lobular (4). With regard to the évaluable axillary nodes, 20 (54.1%) of 37 palpable breast cancers and only 3 (11.5%) of 26 nonpalpable breast carcinomas had positive lymph nodes. The multicentricity rate was particularly high in synchronous tumors (70.6%), and in invasive lobular (73.3%) and noninvasive (75%) carcinomas. The favorable 5- and 10-year survival of patients, both in synchronous and metachronous bilateral primary breast cancer, justify that they be treated with aggressive optimism. La valeur de la mammographie dans le dépistage du cancer mammaire primitif controlatéral a été étudié chez 55 malades qui ont présenté un cancer bilatéral du sein. Quinze des 23 malades (65%) dans le groupe synchrone et seize des 32 malades (50%) dans le groupe métachrone présentaient un cancer cliniquement occulte dans le sein opposé. Exclusion faite de 2 cas de tumeurs malignes découverts par une mammectomie prophylactique la mammographie à elle seule permit de dépister dans le sein opposé 29 (52.7%) cas de cancers impalpables. La série, au total 110 cas de tumeurs malignes, comprenait 41 cancers impalpables dont 12 étaient non invasifs (7 cancers in situ canaliculaires et 5 cancers in situ lobulaires) et 29 étaient invasifs (25 cancers canaliculaires de type variable et 4 cancers lobulaires). En ce qui concerne les ganglions axillaires ils étaient envahis dans 20 (54.1%) des 37 des cancers palpables et 3 (11.5%) des 26 cancers non palpables. Le taux de foyers multiples était particulièrement élevé dans les tumeurs synchrones (70.6%), dans les cancers lobulaires invasifs (73.3%) et dans les cancers non invasifs (75%). Le taux favorable de survie à 5 ans et à 10 ans des malades atteints de cancers du sein, aussi bien dans le groupe synchrone que dans le groupe métachrone justifie de les traiter avec aggressivité et optimisme. La significación de la mamografía en la detección del cáncer mamario primario contralateral fue valorada en 55 pacientes con enfermedad mamaria bilateral. Quince (65%) de 23 pacientes en el grupo con enfermedad síncrona y 16 (50%) de 32 pacientes en el grupo con enfermedad metácrona poseían carcinoma clínicamente oculto en el otro seno. Excluyendo las 2 neoplasias malignas descubiertas en mastectomfa profiláctica, la mamografía de por sí fue responsable de la detección de 29 (52.7%) carcinomas contralaterales no palpables. La totalidad de la serie de 110 neoplasias malignas comprendió 41 carcinomas no palpables, de los cuales 12 fueron no invasivos (7 carcinomas ductales in situ y 5 carcinomas lobulillares in situ) y los 29 restantes fueron carcinomas invasivos, unos ductales de diversos tipos (25) y otros lobulillares (4). En relación con los ganglios axilares valorables, 20 (54.1%) de 37 cánceres palpables y sólo 3 (11.5%) de 26 carcinomas no palpables tenían ganglios linfáticos palpables. La tasa de multicentricidad apareció particularmente alta en los tumores síncronos (70.6%) y en los carcinomas lobulillares invasivos (73.3%) y no invasivos (75%). La supervivencia favorable a 5 y 10 años de los pacientes, tanto en el cáncer primario bilateral síncrono como en el metácrono, justifica que sean tratadas con agresivo optimismo.

• Three methods of excising nonpalpable breast lesions have been evaluated: (1) "blind" method, using mammographic coordinates; (2) preoperative localization with the Frank needle; and (3) Frank needle localization aided by a multiperforated compression plate. Successful removal at first attempt occurred in about 80% with any method. The size of the biopsy specimens did not differ significantly among the three groups and is most probably a function of the breast volume. The failure rate was seven (2.1%) of 332 biopsies. Since three of the six repeated biopsies yielded specimens with malignancy, the persistence of a radiographically suspicious lesion on follow-up mammogram of the operated-on breast is an urgent indication for reoperation.(Arch Surg 1987;122:802-806)

Cytokinetic parameters of various types of lung cancer were determined in bronchoscopy specimens after in vivo labelling with the thymidine analogue bromodeoxyuridine (BrdU). The S-phase fraction and BrdU labelling index were measured flow cytometrically, allowing calculation of the S-phase transit time and potential tumour doubling time. The methodology used was found to be feasible for obtaining cytokinetic data from 76% of the bronchial biopsy samples. Despite the difference in clinical behaviour and growth pattern between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), no significant differences were observed between the mean values of the cytokinetic parameters of SCLC and NSCLC. The estimated cell loss factor was higher in NSCLC than in SCLC. It appears that the growth of a tumour, as clinically observed, is to a considerable extent influenced by cell loss. In accord with this assumption is the fact that we have observed non-BrdU labelled S-phase cells, both in tumour biopsies and in apparently normal tissue. The presence of these so-called unlabelled S-phase cells in relation to cell loss is discussed.

Medewerkers van Viva! komen in 2011 voor een onmogelijke keuze te staan: een salarisverlaging van 25 procent accepteren of vertrekken. Protesten volgen. De toekomst is onzeker.Medewerkers van Viva! komen in 2011 voor een onmogelijke keuze te staan: een salarisverlaging van 25 procent accepteren of vertrekken. Protesten volgen. De toekomst is onzeker.

A case is described of acute defibrination following blunt head injury in a patient with a Spitz-Holter drain. The cause of the disseminated intravascular coagulation is thought to be due to brain thromboplastins entering the systemic circulation through the Spitz-Holter drain, thus bypassing the blood-brain barrier.

Wat Marcel Levi aanraakt, verandert in goud. Als de bijna 50-jarige voorzitter van de Raad van Bestuur van het AMC over een paar jaar de fusie met het VUmc voor elkaar heeft – ja, wat dan? Voorzitter van Ajax?

Zijn hele werkzame leven werkte Theo Langejan voor de rijksoverheid. Behept met een ietwat autoritaire bestuursstijl ontwikkelde hij zich tot een trouwe dienaar van ministers. Maar ambtelijke volgzaamheid is niet genoeg voor de voorzitter van de Nederlandse Zorgautoriteit (NZa).

De NPCF kan zich geen betere directeur wensen dan Wilna Wind. Ze is gepokt en gemazeld in de FNV, misschien wel de beste leerschool voor belangenbehartigers. Zwakke stee: op tv pakken haar retorische talenten niet zo goed uit als in de geschreven pers.

‘Dochter van Turkse gastarbeider trekt ziekenhuis uit slop’. Met zulk nieuws haal je de voorpagina´s. Maar eenmaal daar, is het moeilijk om uit de schijnwerpers te treden. En dat kan zich tegen je keren, zo ervoer Aysel Erbudak.

Het land klaagt steen en been over bezuinigingen. Ondertussen lijkt de minzame staatssecretaris van Volksgezondheid zonder al te veel weerstand 3,5 miljard op de langdurige zorg te besparen. Wat is het geheim van Van Rijn?

Heeft Loek Hermans er goed aan gedaan in alle talen te zwijgen over het Meavita-schandaal, totdat het definitieve onderzoeksrapport geopenbaard wordt?

In a group of 40 patients with non-palpable ductal carcinoma in situ (DCIS) of the breast, 41 breast specimens were available for studying residual tumour after biopsy. In one group of ten patients seen before 1977, simple histological examination revealed a 9 per cent incidence of residual tumour. However, after thorough examination residual foci of DCIS were found in 77 per cent of a subsequent group of 30 patients. This means that the majority of patients would have had to undergo reoperation if a breast-saving procedure had been performed. This fact must be taken into account when planning treatment of patients with non-palpable DCIS.