It is thought that KRAS oncoproteins are constitutively active because their guanosine triphosphatase (GTPase) activity is disabled. Consequently, drugs targeting the inactive or guanosine 5′-diphosphate–bound conformation are not expected to be effective. We describe a mechanism that enables such drugs to inhibit KRASG12C signaling and cancer cell growth. Inhibition requires intact GTPase activity and occurs because drug-bound KRASG12C is insusceptible to nucleotide exchange factors and thus trapped in its inactive state. Indeed, mutants completely lacking GTPase activity and those promoting exchange reduced the potency of the drug. Suppressing nucleotide exchange activity downstream of various tyrosine kinases enhanced KRASG12C inhibition, whereas its potentiation had the opposite effect. These findings reveal that KRASG12C undergoes nucleotide cycling in cancer cells and provide a basis for developing effective therapies to treat KRASG12C-driven cancers.

Summary MEK inhibitors are clinically active in BRAFV600E melanomas, but only marginally so in KRAS-mutant tumors. Here we found that MEK inhibitors suppress ERK signaling more potently in BRAFV600E- than in KRAS-mutant tumors. To understand this, we performed an RNAi screen in a KRAS-mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAFV600E. MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting such complexes enhanced inhibition of CRAF-dependent ERK signaling. Newer MEK inhibitors not only target MEK catalytic activity, but also impair its reactivation by CRAF: either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent RAF-mediated phosphorylation in the complex.

Circularly polarized light (CPL) exhibits an enantioselective interaction with chiral molecules, providing a pathway toward all-optical chiral resolution. High index dielectric nanoparticles have been shown to enhance this relationship, but with a spatially varying sign (or enantiospecificity) that yields a near zero spatially averaged enhancement. Using full field electromagnetic simulations, we design metasurfaces consisting of high index dielectric disks that provide large-volume, uniform-sign enhancements in both the optical density of chirality, C (the figure of merit for sensing and spectroscopy), and Kuhn’s dissymmetry factor, g (the figure of merit for separation). By varying disk radius, we achieve local enhancements in C and g up to 138-fold and 15-fold, respectively, as well as volumetric enhancements of 30-fold and 4.2-fold. The uniform-sign enhancements in C occur near the first Kerker condition, where overlapping electric and magnetic modes maximize field strength and preserve the π/2 phase lag between the electric and magnetic fields of CPL; in contrast, uniform-sign enhancements in g occur with spectrally separated modes, where fields and phase remain optimal without reduced molecular absorption. Using first-order kinetics of the molecule thiocamphor, we show how this optically enantiopure metasurface could enable 20% enantiomeric excesses with a >2000-fold increase in yield for a photoionization reaction compared to CPL alone.

Plasmonics is a rapidly developing field at the boundary of physical optics and condensed matter physics. It studies phenomena induced by and associated with surface plasmons-elementary polar excitations bound to surfaces and interfaces of nanostructured good metals. This Roadmap is written collectively by prominent researchers in the field of plasmonics. It encompasses selected aspects of nanoplasmonics. Among them are fundamental aspects such as quantum plasmonics based on quantum-mechanical properties of both underlying materials and plasmons themselves (such as their quantum generator, spaser), plasmonics in novel materials, ultrafast (attosecond) nanoplasmonics, etc. Selected applications of nanoplasmonics are also reflected in this Roadmap, in particular, plasmonic waveguiding, practical applications of plasmonics enabled by novel materials, thermo-plasmonics, plasmonic-induced photochemistry and photo-catalysis. This Roadmap is a concise but authoritative overview of modern plasmonics. It will be of interest to a wide audience of both fundamental physicists and chemists and applied scientists and engineers.

The principles governing evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of BRAF amplification (BRAFamp) in patient-derived tumor xenografts (PDX) treated with a direct ERK inhibitor, alone or in combination with other pathway inhibitors. Single cell sequencing and multiplex-fluorescence in situ hybridization mapped the emergence of extra-chromosomal amplification in parallel evolutionary tracts, arising in the same tumor shortly after treatment. The evolutionary selection of BRAFamp is determined by the fitness threshold, the barrier subclonal populations need to overcome to regain fitness in the presence of therapy. This differed for ERK signaling inhibitors, suggesting that sequential monotherapy is ineffective and selects for a progressively higher BRAF copy number. Concurrent targeting of RAF, MEK and ERK, however, imposes a sufficiently high fitness threshold to prevent the propagation of subclones with high-level amplification. Administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11-lung cancer and melanoma PDX without apparent toxicity in mice. Thus, gene amplification can be acquired and expanded through parallel evolution, enabling tumors to adapt while maintaining their intratumoral heterogeneity. Treatments that impose the highest fitness threshold will likely prevent the evolution of resistance-causing alterations and merit testing in patients.

Conspectus Chirality in Nature can be found across all length scales, from the subatomic to the galactic. At the molecular scale, the spatial dissymmetry in the atomic arrangements of pairs of mirror-image molecules, known as enantiomers, gives rise to fascinating and often critical differences in chemical and physical properties. With increasing hierarchical complexity, protein function, cell communication, and organism health rely on enantioselective interactions between molecules with selective handedness. For example, neurodegenerative and neuropsychiatric disorders including Alzheimer’s and Parkinson’s diseases have been linked to distortion of chiral-molecular structure. Moreover, d-amino acids have become increasingly recognized as potential biomarkers, necessitating comprehensive analytical methods for diagnosis that are capable of distinguishing l- from d-forms and quantifying trace concentrations of d-amino acids. Correspondingly, many pharmaceuticals and agrochemicals consist of chiral molecules that target particular enantioselective pathways. Yet, despite the importance of molecular chirality, it remains challenging to sense and to separate chiral compounds. Chiral-optical spectroscopies are designed to analyze the purity of chiral samples, but they are often insensitive to the trace enantiomeric excess that might be present in a patient sample, such as blood, urine, or sputum, or pharmaceutical product. Similarly, existing separation schemes to enable enantiopure solutions of chiral products are inefficient or costly. Consequently, most pharmaceuticals or agrochemicals are sold as racemic mixtures, with reduced efficacy and potential deleterious impacts. Recent advances in nanophotonics lay the foundation toward highly sensitive and efficient chiral detection and separation methods. In this Account, we highlight our group’s effort to leverage nanoscale chiral light–matter interactions to detect, characterize, and separate enantiomers, potentially down to the single molecule level. Notably, certain resonant nanostructures can significantly enhance circular dichroism for improved chiral sensing and spectroscopy as well as high-yield enantioselective photochemistry. We first describe how achiral metallic and dielectric nanostructures can be utilized to increase the local optical chirality density by engineering the coupling between electric and magnetic optical resonances. While plasmonic nanoparticles locally enhance the optical chirality density, high-index dielectric nanoparticles can enable large-volume and uniform-sign enhancements in the optical chirality density. By overlapping these electric and magnetic resonances, local chiral fields can be enhanced by several orders of magnitude. We show how these design rules can enable high-yield enantioselective photochemistry and project a 2000-fold improvement in the yield of a photoionization reaction. Next, we discuss how optical forces can enable selective manipulation and separation of enantiomers. We describe the design of low-power enantioselectiv...

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Aims: To characterise the clinical manifestations of late presenting Bochdalek diaphragmatic hernia (DH), the incidence of misdiagnosis, and prognosis; and to explore the sequence of events that leads to this clinical picture. Methods: Retrospective chart review. All children with Bochdalek DH were identified. Children 1 month of age and older at the time of diagnosis were included. Results: Twenty two children with Bochdalek DH met the inclusion criteria. Three clinical presentations could be defined. Fourteen children presented with acute onset of symptoms, predominantly vomiting and respiratory distress. Four had chronic non-specific gastrointestinal or respiratory symptoms, and in four the DH was found incidentally. Although five children were initially misdiagnosed, in 20 children (91%) the correct diagnosis was made on x ray examination. One child experienced a complicated course when the x ray picture was misinterpreted as pneumothorax. All children had favourable outcome. Two children had previously normal chest imaging, suggesting acquired herniation. A large pleural effusion without DH in a 9.5 year old girl with an abdominal infection prior to presenting with herniation suggests a pre-existing defect in the diaphragm. Conclusions: Late presenting Bochdalek DH can present with acute or chronic gastrointestinal, or less frequently, respiratory symptoms. It can also be found incidentally. Misdiagnosis can result in significant morbidity. Favourable outcome is expected when the correct diagnosis is made. The sequence of events is probably herniation of abdominal viscera through a pre-existing diaphragmatic defect. Although rare, DH should be considered in any child presenting with respiratory distress or with symptoms suggestive of gastrointestinal obstruction.