The intracellular location of a protein is crucial to its normal functioning in a cell. Cancer cells utilize the normal processes of nuclear-cytoplasmic transport through the nuclear pore complex of ...a cell to effectively evade anti-neoplastic mechanisms. CRM1-mediated export is increased in various cancers. Proteins that are exported in cancer include tumor-suppressive proteins such as retinoblastoma, APC, p53, BRAC1, FOXO proteins, INI1/hSNF5, galectin-3, Bok, nucleophosmin, RASSF2, Merlin, p21CIP, p27KIP1, N-WASP/FAK, estradiol receptor and Tob, drug targets topoisomerase I and IIα and BCR-ABL, and the molecular chaperone protein Hsp90. Here, we review in detail the current processes and known structures involved in the export of a protein through the nuclear pore complex. We also discuss the export receptor molecule CRM1 and its binding to the leucine-rich nuclear export signal of the cargo protein and the formation of a nuclear export trimer with RanGTP. The therapeutic potential of various CRM1 inhibitors will be addressed, including leptomycin B, ratjadone, KOS-2464, and specific small molecule inhibitors of CRM1, N-azolylacrylate analogs, FOXO export inhibitors, valtrate, acetoxychavicol acetate, CBS9106, and SINE inhibitors. We will also discuss examples of how drug resistance may be reversed by targeting the exported proteins topoisomerase IIα, BCR-ABL, and galectin-3. As effective and less toxic CRM1 export inhibitors become available, they may be used as both single agents and in combination with current chemotherapeutic drugs. We believe that the future development of low-toxicity, small-molecule CRM1 inhibitors may provide a new approach to treating cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although the solid state is typically characterised by inherent periodicity, many interesting physical and chemical properties of solids arise from a variation in this, i.e. changes in the nature of ...the atom occupying a particular site in a crystal structure or variation in the position of an atom (or group of atoms) in different parts of a structure, or variation as a function of time. This lack of long-range order poses significant challenges, not just for the characterisation of the structure of disordered materials, but also simply for its description. The sensitivity of nuclear magnetic resonance (NMR) spectroscopy to the local, atomic-scale environment, without the requirement for long-range order, makes it a powerful tool for the study of disorder in the solid state. Information on the number and type(s) of coordinating atoms or through-space and through-bond connectivity between atomic species enables the construction of a detailed picture of the structure. After a brief description of the background theory of NMR spectroscopy, and the experimental methods employed, we will describe the effects of disorder on NMR spectra and the use of calculations to help interpret experimental measurements. We will then review a range of applications to different types of disordered materials, including oxides and ceramics, minerals, porous materials, biomaterials, energy materials, pharmaceuticals, polymers and glasses. We will discuss the most successful approaches for studying different materials, and illustrate the type of information available and the structural insight gained.
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Highly porous metal-organic frameworks (MOFs), which have undergone exciting developments over the past few decades, show promise for a wide range of applications. However, many studies indicate that ...they suffer from significant stability issues, especially with respect to their interactions with water, which severely limits their practical potential. Here we demonstrate how the presence of 'sacrificial' bonds in the coordination environment of its metal centres (referred to as hemilability) endows a dehydrated copper-based MOF with good hydrolytic stability. On exposure to water, in contrast to the indiscriminate breaking of coordination bonds that typically results in structure degradation, it is non-structural weak interactions between the MOF's copper paddlewheel clusters that are broken and the framework recovers its as-synthesized, hydrated structure. This MOF retained its structural integrity even after contact with water for one year, whereas HKUST-1, a compositionally similar material that lacks these sacrificial bonds, loses its crystallinity in less than a day under the same conditions.
The hydrothermal synthesis of a zeolite with properties suitable for use in the assembly–disassembly–organization–reassembly (ADOR) process was designed, and a zeolite called SAZ-1 was successfully ...prepared. This zeolite was then used as a parent in the ADOR process, and two new daughter zeolites, IPC-15 and IPC-16, were prepared. The X-ray powder diffraction patterns of the new zeolites match well with those predicted using computational methods. The three materials form an isoreticular series with decreasing pores size from 14-ring to 12-ring to 10-ring.
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The synthesis of chiral metal–organic frameworks (MOFs) is highly relevant for asymmetric heterogenous catalysis, yet very challenging. Chiral MOFs with MOF‐74 topology were synthesised by using ...post‐synthetic modification with proline. Vibrational circular dichroism studies demonstrate that proline is the source of chirality. The solvents used in the synthesis play a key role in tuning the loading of proline and its interaction with the MOF‐74 framework. In N,N′‐dimethylformamide, proline coordinates monodentate to the Zn2+ ions within the MOF‐74 framework, whereas it is only weakly bound to the framework when using methanol as solvent. Introducing chirality within the MOF‐74 framework also leads to the formation of defects, with both the organic linker and metal ions missing from the framework. The formation of defects combined with the coordination of DMF and proline within the framework leads to a pore blocking effect. This is confirmed by adsorption studies and testing of the chiral MOFs in the asymmetric aldol reaction between acetone and para‐nitrobenzaldehyde.
Chiral MOF‐74 materials were synthesised by post‐synthetic modification by using proline as chiral inductor. Combined experimental and theoretical studies show that proline coordinates monodentate to the Zn2+ within the metal–organic framework (MOF). Along with introducing chiral features, defects are formed in the MOF‐74 topology.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Microporous materials, having pores and channels on the same size scale as small to medium molecules, have found many important applications in current technologies, including catalysis, gas ...separation and drug storage and delivery. Many of their properties and functions are related to their detailed local structure, such as the type and distribution of active sites within the pores, and the specific structures of these active sites. Solid-state NMR spectroscopy has a strong track record of providing the requisite detailed atomic-level insight into the structures of microporous materials, in addition to being able to probe dynamic processes occurring on timescales spanning many orders of magnitude (
i.e.
, from s to ps). In this Perspective, we provide a brief review of some of the basic experimental approaches used in solid-state NMR spectroscopy of microporous materials, and then discuss some more recent advances in this field, particularly those applied to the study of crystalline materials such as zeolites and metal-organic frameworks. These advances include improved software for aiding spectral interpretation, the development of the NMR-crystallography approach to structure determination, new routes for the synthesis of isotopically-labelled materials, methods for the characterisation of host-guest interactions, and methodologies suitable for observing NMR spectra of paramagnetic microporous materials. Finally, we discuss possible future directions, which we believe will have the greatest impact on the field over the coming years.
This Perspective describes how solid-state NMR spectroscopy can be used to investigate the structure, disorder, dynamics and reactivity of crystalline microporous framework materials.
Single-crystal to single-crystal polymorphic transformations in molecular solids are relatively rare, with changes in crystal structure more commonly leading to destruction of the parent crystal. ...However, the structural basis for such transitions is of considerable interest given the changes in material properties that can result. The antihistamine desloratadine displays a two-step, reversible single-crystal to single-crystal phase transition during heating/cooling cycles between three conformational polymorphs: the low temperature form I, a polytypic intermediate form II, and the high temperature form III. The two-step transition involves a sequential flipping of the piperidine rings of desloratadine molecules in the crystals, which induce reversible micrometer-scale contraction on heating and expansion on cooling of the largest face of a desloratadine single crystal. Distinct, slow-moving phase boundaries, originating on the (001) face of the crystal, were observed sweeping through the entire crystal in hot-stage microscopy, suggesting a single nucleation event. Computational spectroscopy, using periodic DFT-D phonon calculations, reproduces the experimental variable-temperatureTHz-Raman spectra and rules out the possibility of the phase transformations occurring via any classical soft mode. A combination of variable-temperature powder X-ray diffraction, solid-state NMR, and computational spectroscopy provides a detailed molecular description of the phase transitions, indicating a first-order diffusionless process between I → II and II → III, wherein both conformational changes and lattice distortions occur simultaneously in the crystal lattice. The study indicates that a nucleation and growth mechanism is compatible with concerted movements producing a conformational change in organic molecular crystals.
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Methane Number (MN) is a fuel rating technique for gaseous fuels analogous to Octane Number. This study establishes and shares a repeatable and reproducible method for MN determination of a gaseous ...fuel using a modified Cooperative Fuel Research Engine (CFR). Adaptations required to convert a CFR engine for use in the MN test procedure are identified. The investigation includes allowable environmental parameters and operating variation limits. An essential aspect of the MN method involves identifying and quantifying Knock Intensity (KI) during engine operation. CFR engines, originally designed for gasoline testing, come equipped with their own knock measurement systems utilizing a capacitive detonation sensor. The original system is compared with a Fast Fourier Transform (FFT) approach that uses a piezoelectric pressure transducer. Quantification of methane number requires an accurate assessment of the reference fuel blend (CH4 + H2). A comparison is carried out between dynamic blending using mass flow meters and bracketing using certified gas bottles containing various CH4/H2 blends from a gas supplier.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We use a combination of one- and two-dimensional solid-state nuclear magnetic resonance (NMR) spectroscopy and density functional theory (DFT) calculations to obtain a full assignment of the
1
H and
...13
C signals for solid (+)-usnic acid, which contains two molecules in the asymmetric unit. By combining through-space
1
H-
1
H correlation data with computation it is possible to assign signals not just to the same molecules (relative assignment) but to assign the signals to specific crystallographic molecules (absolute assignment). Variable-temperature measurements reveal that there is some variation in many of the
13
C chemical shifts with temperature, likely arising from varying populations of different tautomeric forms of the molecule. The NMR spectrum of crystalline (+)-usnic acid is then compared with that of ground
Usnea dasopoga
lichen (the source material of the usnic acid). The abundance of usnic acid is so great in the lichen that this natural product can be observed directly in the NMR spectrum without further purification. This natural sample of usnic acid appears to have the same crystalline form as that in the pure commercial sample.
We characterise the solid form of the lichen metabolite, usnic acid, using NMR crystallography to achieve absolute assignment of all observed signals.
13
C NMR spectroscopy shows that usnic acid in wild
Usnea
lichen has the same crystalline form.
Epidemiology of liver metastases Horn, Samantha R; Stoltzfus, Kelsey C; Lehrer, Eric J ...
Cancer epidemiology,
August 2020, 2020-08-00, 20200801, Volume:
67
Journal Article
Peer reviewed
•5.14 % of primary cancer patients from 2010 to 2015 presented with synchronous liver metastases.•The most common primary sites with synchronous liver metastase were breast and colorectal ...cancers.•The primary site was more varied in older patients, with synchronous liver metastases from gastrointestinal, melanoma, bladder, and lung cancers.•Survival for patients with liver metastasis was significantly decreased as compared to patients without liver metastasis.
The objectives of this study were to (1) characterize the epidemiology of liver metastases at the time of primary cancer diagnosis (synchronous liver metastases), (2) characterize the incidence trends of synchronous liver metastases from 2010−2015 and (3) assess survival of patients with synchronous liver metastases.
The Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015 was queried to obtain cases of patients with liver metastases at the time of primary cancer diagnosis. The primary cancers with an incidence rate of liver metastasis >0.1 are presented in this analysis.
Among 2.4 million cancer patients, 5.14 % of cancer patients presented with synchronous liver metastases. The most common primary site was breast cancers for younger women (ages 20–50), and colorectal cancers for younger men. As patients get older, a more heterogenous population of the top cancers with liver metastases emerges including esophageal, stomach, small intestine, melanoma, and bladder cancer in addition to the large proportion of lung, pancreatic, and colorectal cancers. The 1-year survival of all patients with liver metastases was 15.1 %, compared to 24.0 % in those with non-hepatic metastases. Regression analysis showed that the presence of liver metastasis was associated with reduced survival, particularly in patients with cancers of the testis, prostate, breast, and anus, and in those with melanoma.
The most common primary sites for patients with liver metastases varied based on age at diagnosis. Survival for patients with liver metastasis was significantly decreased as compared to patients without liver metastasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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