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51.
Professor Ernst Schwalbe 《Virchows Archiv : an international journal of pathology》1907,189(3):526-528
Ohne Zusammenfassung 相似文献
52.
53.
P R Lowe C E Sansom C H Schwalbe M F Stevens A S Clark 《Journal of medicinal chemistry》1992,35(18):3377-3382
The antitumor imidazotetrazinone, temozolomide (5), C6H6N6O2, forms crystals with unit cell dimensions a = 17.332 (3), b = 7.351 (2), c = 13.247 (1), beta = 109.56 (1) degree and space group P21/c. A doubly hydrogen-bonded dimer constitutes the asymmetric unit. One carboxamide group forms an additional intermolecular NH...O hydrogen bond; in both molecules the carboxamide group is coplanar with the heterocycle and its NH2 group interacts with the imidazole nitrogen atom N(7). Molecular orbital calculations show the carbonyl carbon C(4) to be the most electron deficient atom, with relatively weak N(3)-C(4) and C(4)-N(5) bonds confirming that temozolomide should ring-open at this position in solution. The energy barrier to carboxamide group rotation of approximately 20 kJ mol-1 should permit interconversion between rotamers. In temozolomide and the related drug mitozolomide (4), N(7) is more negatively charged than N(1), which favors the formation of hydrogen bonds to the former atom in spite of their poor geometry. The relevance of these structural features to the action of temozolomide as a major-groove-directed prodrug of the alkylating agent MTIC (3) is discussed. 相似文献
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55.
Pönisch W Rozanski M Goldschmidt H Hoffmann FA Boldt T Schwarzer A Ritter U Rohrberg R Schwalbe E Uhlig J Zehrfeld T Schirmer V Haas A Kreibich U Niederwieser D;East German Study Group of Haematology Oncology 《British journal of haematology》2008,143(2):191-200
Thalidomide is an effective agent for advanced refractory or relapsed multiple myeloma (MM), although dose-limiting toxicity (DLT) may limit its use. This Phase I study found that a combination of low-dose thalidomide with bendamustine and prednisolone (BPT) maintained or increased efficacy, whilst avoiding DLT in 28 patients with MM that was refractory or that had relapsed after conventional chemotherapy or high-dose therapy with stem-cell support. BPT comprised fixed doses of bendamustine (60 mg/m(2)) and prednisolone (100 mg), and escalating doses of thalidomide (50, 100, 200 mg). Treatment cycles were repeated every 28 d until the occurrence of maximum response, DLT, or disease progression. Twenty-four patients responded after at least two cycles (four complete remission, six very good partial remission, 14 partial remission). Median progression-free and overall survival for all patients was 11 and 19 months respectively. Only mild/moderate non-haematological side effects were observed and no patient developed dose-limiting haematotoxicity. Transient grade 3-4 neutropenia was reported in 12 patients, and grade 3-4 thrombocytopenia occurred in two patients. We conclude that BPT therapy was well tolerated in patients with relapsed or refractory MM, with a response rate higher than 80%. The maximum tolerated dose of thalidomide was not reached in this study. 相似文献
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N R Schwalbe W A Wells A P Geaneotes A Forcellina M G Lee L Dicola H R Ignatius C L Walker T Raafat N Patel 《The international journal of tuberculosis and lung disease》2008,12(10):1173-1181
BACKGROUND: The successful introduction of new drugs into low- and middle-income countries requires an understanding of the existing market size and market dynamics for the therapeutic area of interest. The drug markets in these countries are, however, less well understood than those in high-income countries. METHODS: The global market for tuberculosis (TB) drugs was estimated by studying in detail six high-burden countries and four high-income countries, followed by extrapolation. Data were derived from existing pharmaceutical audit databases and interviews with government officials, medical staff and suppliers. RESULTS: The use of qualitative inputs to inform the collection of quantitative information, notably to identify where the major flows of TB drugs are located, allowed a confident estimate of the global market for first-line TB drugs. Final ranges were US$261-316 million or US$310-418 million, depending on whether case notification rates or incidence were used for extrapolations. CONCLUSIONS: An estimation of the global TB drug market is made more reliable by a qualitative understanding of TB drug distribution pathways, which differ greatly among countries. The understanding of this structure in key high-burden countries provides the basis for a simpler update of the market estimate in the future. 相似文献
58.
Enlightening the photoactive site of channelrhodopsin-2 by DNP-enhanced solid-state NMR spectroscopy
Johanna Becker-Baldus Christian Bamann Krishna Saxena Henrik Gustmann Lynda J. Brown Richard C. D. Brown Christian Reiter Ernst Bamberg Josef Wachtveitl Harald Schwalbe Clemens Glaubitz 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(32):9896-9901
Channelrhodopsin-2 from Chlamydomonas reinhardtii is a light-gated ion channel. Over recent years, this ion channel has attracted considerable interest because of its unparalleled role in optogenetic applications. However, despite considerable efforts, an understanding of how molecular events during the photocycle, including the retinal trans-cis isomerization and the deprotonation/reprotonation of the Schiff base, are coupled to the channel-opening mechanism remains elusive. To elucidate this question, changes of conformation and configuration of several photocycle and conducting/nonconducting states need to be determined at atomic resolution. Here, we show that such data can be obtained by solid-state NMR enhanced by dynamic nuclear polarization applied to 15N-labeled channelrhodopsin-2 carrying 14,15-13C2 retinal reconstituted into lipid bilayers. In its dark state, a pure all-trans retinal conformation with a stretched C14-C15 bond and a significant out-of-plane twist of the H-C14-C15-H dihedral angle could be observed. Using a combination of illumination, freezing, and thermal relaxation procedures, a number of intermediate states was generated and analyzed by DNP-enhanced solid-state NMR. Three distinct intermediates could be analyzed with high structural resolution: the early K-like state, the slowly decaying late intermediate , and a third intermediate populated only under continuous illumination conditions. Our data provide novel insight into the photoactive site of channelrhodopsin-2 during the photocycle. They further show that DNP-enhanced solid-state NMR fills the gap for challenging membrane proteins between functional studies and X-ray–based structure analysis, which is required for resolving molecular mechanisms.Since their discovery (1), channelrhodopsins (ChRs) have generated enormous interest because of the rapid development of their applications in optogenetics (2–7). Commonly, ChR2 from Chlamydomonas reinhardtii (8) and its variants are used thanks to their favorable expression levels. They are the only proteins known today functioning as light-gated ion channels (Fig. 1A). Like other microbial retinal proteins, they undergo a periodic photocycle. In ChRs, this photocycle is coupled to channel opening and closing as revealed in electrophysiological recordings (8). A chimera of ChR1 and ChR2 has been crystallized to yield a structure at 2.3-Å resolution (9). However, little is known on how this coupling functions on a molecular level, and a large number of studies based on visible (10–13), IR (11, 14–19), resonance Raman spectroscopy (20, 21), and EPR spectroscopy (22, 23) has been performed to address this question.Open in a separate windowFig. 1.(A) Visualization of dimeric ChR2 reconstituted into the lipid bilayer as used in this study [cartoon based on the crystal structure of the ChR1/2 chimera (data from ref. 9)]. Blue light illumination activates ChR2. (B) Single turnover (black arrows) and continuous illumination photocycle (blue arrows) (14, 40). (C) Schematic view of the experimental setup for generating and measuring different photointermediates. (D) The DNP enhancement is generated by magnetization transfer from the biradical AMUPOL to ChR2.The photocycles of microbial rhodopsins are usually compared with bacteriorhodopsin, the first discovered and most studied light-driven proton pump (24). Without any illumination, microbial retinal proteins thermally equilibrate into a dark state (25). In the case of bacteriorhodopsin, for example, this state contains a mixture of two species termed bacteriorhodopsin568 (all-trans,15-anti retinal Schiff base) and bacteriorhodopsin548 (13-cis,15-syn conformation) (26, 27). On illumination, light adaption occurs from the dark state to the ground state, which contains only the all-trans,15-anti conformer as the photocycle starting point (28). A similar light–dark adaption has been found in halorhodopsin from Halobacterium salinarium (29). However, such a light/dark adaption in conjunction with a conformer mixture does not seem to be a general property of microbial membrane proteins. Other systems have been described where the ground state contains only an all-trans,15-anti retinal Schiff base chromophore [e.g., green proteorhodopsin (30), Anabaena sensory rhodopsin (31), Oxyrrhis marina proteorhodopsin (32), sensory rhodopsin I from H. salinarum (33) and Salinibacter ruber (34), and sensory rhodopsin II from Natronobacterium pharaonis (35, 36) and H. salinarum (37)].In ChR2, the retinal is covalently bound to the lysine residue 257 conserved in all retinal proteins through a Schiff base linkage (38). The X-ray structure of the ChR chimera shows the retinal in an all-trans configuration (9), although other conformations cannot be excluded at the obtained resolution. Results of retinal extraction in conjunction with resonance Raman studies were interpreted as an isomer mixture containing 30% of a 13-cis retinal in dark- and light-adapted ChR2 (20). In addition, nanosecond IR spectroscopy on the E123T mutant of ChR2 indicated the presence of some 13-cis retinal in the dark state using a similar spectroscopic assignment as in the resonance Raman study (39). In contrast to bacteriorhodopsin, no light adaption was observed using resonance Raman techniques (20) or visual spectroscopy (12). The occurrence of a conformer mixture in the ground state without light adaption would make ChR2 unique among the microbial retinal proteins, but additional data are needed to confirm these observations more directly at improved atomic resolution.The current model of the ChR2 photocycle is shown in Fig. 1B (14, 40). According to this model, blue light excitation leads to a retinal all-trans to 13-cis isomerization, resulting in a red-shifted first intermediate (12) resembling a K-like state, which most likely contains a 13-cis,15-anti retinal Schiff base chromophore similar to Bacteriorhodopsin (27). To our knowledge, such red-shifted K-like intermediates occur in all microbial retinal proteins (38). Schiff base deprotonation leads to the M-like state (10, 11). This state is followed by the red-shifted intermediate , which has previously been correlated with the open state (10). However, later data confirmed that channel opening occurs before formation and might happen during a spectroscopically silent transition between and states (41). The last photocycle intermediate is the long-lived intermediate state (τ = 24 s), which is referred to as the desensitized state with a spectral characteristic similar to the ground state (11, 42). In addition, time-resolved FTIR spectroscopy indicated that could partially convert directly to the ground state (14).The situation becomes more complicated under continuous light illumination (40, 43). Under these conditions, a high transient current is observed first that is quickly reduced to a much lower steady-state current. After turning off the irradiation, the steady-state current decays biexponentially. This observation can only be explained by a branching of the photocycle. Two open states and two closed states are required to quantitatively describe the observed behavior under continuous light conditions. The two closed states are most likely the ground state and the desensitized state that accumulates under continuous illumination and is identical to the same intermediate from a single turnover (18). One of the open states is probably the open state observed in single-turnover experiments. However, little is known about the identity of the second open state, which only occurs under continuous light conditions. It might be an M-like state, another state, or another unknown state. Light excitation of probably creates this additional state. This state or group of states here is referred to as Px containing at least one open state (Fig. 1B). It is also likely that the open states and Px to some extent can convert directly to the ground state, which is indicated by dashed lines in Fig. 1B.All of the above-described states were detected by visible and FTIR spectroscopy, and assignments of spectroscopic signatures to conformational and configurational states of the retinal were based on analogous data previously studied. However, detailed information on bond lengths or torsion angles that would also link to quantum chemical calculation is still missing. To fill this gap between static crystallographic data on the one hand and kinetic and functional data based on optical spectroscopy and electrophysiology on the other hand, we applied solid-state magic angle spinning NMR on isotope-labeled ChR2 and retinal to obtain site-resolved structural data directly in a membrane environment under various experimental conditions. In this way, fine details of the chromophore conformation during the photocycle could be resolved, which will be important to understand the link between channel and photocycle activity in ChR2. A limitation using proteoliposomes is the amount of sample that can be studied, because the protein-to-lipid ratio cannot be increased too much without compromising protein integrity. In addition, trapping photointermediates works best using samples with low optical density, which reduces further the usable amount of protein, resulting in a poor NMR signal-to-noise ratio. Therefore, cross-effect dynamic nuclear polarization (DNP) enhanced magic angle spinning (MAS) NMR [review in the work by Maly et al. (44)] was indispensable in overcoming these sensitivity problems (Fig. 1C). This technique requires temperatures around 100 K that are also compatible with trapping of photointermediates as outlined below. DNP-enhanced MAS NMR is not yet a routine method but is applied increasingly to complex, mechanistic studies on retinal proteins (45–48) and other membrane proteins (49–51).Here, DNP-enhanced solid-state NMR spectroscopy has been applied to 15N-labeled ChR2 carrying 14,15-13C2 retinal reconstituted into lipid bilayers and incubated with the DNP polarizing agent AMUPOL (52) in a glycerol–water mixture. The labeling scheme adopted here is shown in Fig. 2A. The 13C14 chemical shift is sensitive to the configuration of the C13-C14 bond. Together with the neighboring 13C15 atom, the two 13C-labeled spins can be used for double quantum filtering of this spin pair against the natural abundance background and at the same time, offer the possibility to study the length and the dihedral angle of the C14-C15 bond. Furthermore, the chemical shift of the Schiff base nitrogen is also sensitive to the chromophore conformation, reports on the protonation state of the Schiff base, and reflects counterion interactions. Using this approach, we were able to provide a first analysis, to our knowledge, of the retinal–Schiff base chromophore in ChR2 in its ground state as well as three different photointermediate states at atomic resolution.Open in a separate windowFig. 2.(A) DNP-enhanced MAS NMR has been applied to U-15N-ChR2 containing 14,15-13C all-trans–retinal. (B) A 62-fold signal enhancement is achieved for 13C cross-polarization (CP; CP vs. CP + DNP). The 13C natural abundance background can be efficiently suppressed by a double quantum filter (DQF; DQF + DNP), resulting in a spectrum with only the resonances of C14 and C15. As a control, one additional CP spectrum was acquired at 850 MHz close to room temperature (CP at RT). The gray bar indicates where the 13C14 signal would be expected for a chromophore in the 13-cis,15-syn conformation. (C) 13C14-13C15 double-quantum (DQ) build-up curve. (D) HCCH dephasing curves for the C14-C15 spin system in ChR2 during two rotor periods reporting on the HCCH dihedral angle. 相似文献
59.
Geriatric patients represent an important population group in counselling and care of pharmacists. Despite this high need, there are only few investigations in this special patient population and derived aids for competent and practice-oriented pharmaceutical care. The Beers criteria developed in the US represent an instrument to detect potentially inappropriate medication in older adults. In order to propagate in Germany a translation and adaptation to the German drug market was performed. Systematic consensus building by an expert panel will be necessary for wide acceptability. Applying the Beers criteria presents an opportunity of pharmacist to optimise the pharmacotherapy of geriatric patients. 相似文献
60.
Ryan SL Schwalbe EC Cole M Lu Y Lusher ME Megahed H O'Toole K Nicholson SL Bognar L Garami M Hauser P Korshunov A Pfister SM Williamson D Taylor RE Ellison DW Bailey S Clifford SC 《Acta neuropathologica》2012,123(4):501-513
The MYC oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and comprehensive investigations of MYCC, MYCN and MYCL in an extensive medulloblastoma cohort (n?=?292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and individualisation of therapy. MYCC and MYCN expression elevations were multifactorial, associated with high-risk (gene amplification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene amplification patterns underlay overall MYC copy number elevations observed in tumour biopsies; we used these alternative measures together to define quantitative methodologies and thresholds for amplification detection in routinely collected tumour material. MYCC and MYCN amplification, but not gain, each had independent prognostic significance in non-infants (≥3.0-16.0?years), but MYCC conferred a greater hazard to survival than MYCN when considered across this treatment group. MYCN's weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups; MYCN predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or MYCC/MYCN amplification). This cumulative-risk model defines a patient group characterised by ≥2 independent risk-factors and an extremely poor prognosis (<15% survival), which can be identified straightforwardly using the reported MYC amplification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies. 相似文献