Most van der Waals crystals present highly anisotropic optical responses due to their strong in-plane covalent bonding and weak out-of-plane interactions. However, the determination of the ...polarization-dependent dielectric constants of van der Waals crystals remains a nontrivial task, since the size and dimension of the samples are often below or close to the diffraction limit of the probe light. In this work, we apply an optical nano-imaging technique to determine the anisotropic dielectric constants in representative van der Waals crystals. Through the study of both ordinary and extraordinary waveguide modes in real space, we are able to quantitatively determine the full dielectric tensors of nanometer-thin molybdenum disulfide and hexagonal boron nitride microcrystals, the most-promising van der Waals semiconductor and dielectric. Unlike traditional reflection-based methods, our measurements are reliable below the length scale of the free-space wavelength and reveal a universal route for characterizing low-dimensional crystals with high anisotropies.
Infrared nano-spectroscopy based on scattering-type scanning near-field optical microscopy (s-SNOM) is commonly employed to probe the vibrational fingerprints of materials at the nanometer length ...scale. However, due to the elongated and axisymmetric tip shank, s-SNOM is less sensitive to the in-plane sample anisotropy in general. In this article, we report an easy-to-implement method to probe the in-plane dielectric responses of materials with the assistance of a metallic disk micro-antenna. As a proof-of-concept demonstration, we investigate here the in-plane phonon responses of two prototypical samples, i.e. in (100) sapphire and x-cut lithium niobate (LiNbO
). In particular, the sapphire in-plane vibrations between 350 cm
to 800 cm
that correspond to LO phonon modes along the crystal b- and c-axis are determined with a spatial resolution of < λ/10, without needing any fitting parameters. In LiNbO
, we identify the in-plane orientation of its optical axis via the phonon modes, demonstrating that our method can be applied without prior knowledge of the crystal orientation. Our method can be elegantly adapted to retrieve the in-plane anisotropic response of a broad range of materials, i.e. subwavelength microcrystals, van-der-Waals materials, or topological insulators.
Antibody–drug conjugates (ADCs) are important molecular entities in the treatment of cancer. These conjugates combine the target specificity of monoclonal antibodies with the potent anti-cancer ...activity of small-molecule therapeutics. The complex structure of ADCs poses unique challenges to characterize the drug’s pharmacokinetics (PKs) and pharmacodynamics (PDs) since it requires a quantitative understanding of the PK and PD properties of multiple different molecular species (e.g., ADC conjugate, total antibody and unconjugated cytotoxic drug). As a result, clinical pharmacology strategy of an ADC is rather unique and dependent on the linker/cytotoxic drug technology, heterogeneity of the ADC, PK and safety/efficacy profile of the specific ADC in clinical development. In this review, we summarize the clinical pharmacology strategies in supporting development and approval of ADCs using the approved ADCs as specific examples to illustrate the customized approach to clinical pharmacology assessments in their clinical development.
Antibody–drug conjugates (ADCs) combine the specificity of an antibody with the cytotoxicity of a chemical agent. They represent a rapidly evolving area of oncology drug development and hold ...significant promise. There are currently nine ADCs on the market, more than half of which gained US Food and Drug Administration approval more recently, since 2019. Despite their enormous promise, the therapeutic window for these ADCs remains relatively narrow, especially when compared with other oncology drugs, such as targeted therapies or checkpoint inhibitors. In this review, we provide a detailed overview of the five dosing regimen optimization strategies that have been leveraged to broaden the therapeutic window by mitigating the safety risks while maintaining efficacy. These include body weight cap dosing; treatment duration capping; dose schedule (e.g., dosing frequency and dose fractionation); response‐guided dosing recommendations; and randomized dose‐finding. We then discuss how the lessons learned from these studies can inform ADC development going forward. Informed application of these dosing strategies should allow researchers to maximize the safety and efficacy for next‐generation ADCs.
Packed with biological information, extracellular vesicles (EVs) offer exciting promise for biomarker discovery and applications in therapeutics and non-invasive diagnostics. Currently, our ...understanding of EV contents is confined by the limited cells from which vesicles have been characterized utilizing the same enrichment method. Using sixty cell lines from the National Cancer Institute (NCI-60), here we provide the largest proteomic profile of EVs in a single study, identifying 6,071 proteins with 213 common to all isolates. Proteins included established EV markers, and vesicular trafficking proteins such as Rab GTPases and tetraspanins. Differentially-expressed proteins offer potential for cancer diagnosis and prognosis. Network analysis of vesicle quantity and proteomes identified EV components associated with vesicle secretion, including CD81, CD63, syntenin-1, VAMP3, Rab GTPases, and integrins. Integration of vesicle proteomes with whole-cell molecular profiles revealed similarities, suggesting EVs provide a reliable reflection of their progenitor cell content, and are therefore excellent indicators of disease.
Latent membrane protein 1 (LMP1) is an Epstein-Barr virus (EBV)-encoded oncoprotein that is packaged into small extracellular vesicles (EVs) called exosomes. Trafficking of LMP1 into multivesicular ...bodies (MVBs) alters the content and function of exosomes. LMP1-modified exosomes enhance the growth, migration, and invasion of malignant cells, demonstrating the capacity to manipulate the tumor microenvironment and enhance the progression of EBV-associated cancers. Despite the growing evidence surrounding the significance of LMP1-modified exosomes in cancer, very little is understood about the mechanisms that orchestrate LMP1 incorporation into these vesicles. Recently, LMP1 was shown to be copurified with CD63, a conserved tetraspanin protein enriched in late endosomal and lysosomal compartments. Here, we demonstrate the importance of CD63 presence for exosomal packaging of LMP1. Nanoparticle tracking analysis and gradient purification revealed an increase in extracellular vesicle secretion and exosomal proteins following LMP1 expression. Immunoisolation of CD63-positive exosomes exhibited accumulation of LMP1 in this vesicle population. Functionally, CRISPR/Cas9 knockout of CD63 resulted in a reduction of LMP1-induced particle secretion. Furthermore, LMP1 packaging was severely impaired in CD63 knockout cells, concomitant with a disruption in the perinuclear localization of LMP1. Importantly, LMP1 trafficking to lipid rafts and activation of NF-κB and PI3K/Akt pathways remained intact following CD63 knockout, while mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and noncanonical NF-κB activation were observed to be increased. These results suggest that CD63 is a critical player in LMP1 exosomal trafficking and LMP1-mediated enhancement of exosome production and may play further roles in limiting downstream LMP1 signaling.
EBV is a ubiquitous gamma herpesvirus linked to malignancies such as nasopharyngeal carcinoma, Burkitt's lymphoma, and Hodgkin's lymphoma. In the context of cancer, EBV hijacks the exosomal pathway to modulate cell-to-cell signaling by secreting viral components such as an oncoprotein, LMP1, into host cell membrane-bound EVs. Trafficking of LMP1 into exosomes is associated with increased oncogenicity of these secreted vesicles. However, we have only a limited understanding of the mechanisms surrounding exosomal cargo packaging, including viral proteins. Here, we describe a role of LMP1 in EV production that requires CD63 and provide an extensive demonstration of CD63-mediated exosomal LMP1 release that is distinct from lipid raft trafficking. Finally, we present further evidence of the role of CD63 in limiting LMP1-induced noncanonical NF-κB and ERK activation. Our findings have implications for future investigations of physiological and pathological mechanisms of exosome biogenesis, protein trafficking, and signal transduction, especially in viral-associated tumorigenesis.
Precise patterning of polymer‐based biomaterials for functional bio‐nanostructures has extensive applications including biosensing, tissue engineering, and regenerative medicine. Remarkable progress ...is made in both top‐down (based on lithographic methods) and bottom‐up (via self‐assembly) approaches with natural and synthetic biopolymers. However, most methods only yield 2D and pseudo‐3D structures with restricted geometries and functionalities. Here, it is reported that precise nanostructuring on genetically engineered spider silk by accurately directing ion and electron beam interactions with the protein's matrix at the nanoscale to create well‐defined 2D bionanopatterns and further assemble 3D bionanoarchitectures with shape and function on demand, termed “Protein Bricks.” The added control over protein sequence and molecular weight of recombinant spider silk via genetic engineering provides unprecedented lithographic resolution (approaching the molecular limit), sharpness, and biological functions compared to natural proteins. This approach provides a facile method for patterning and immobilizing functional molecules within nanoscopic, hierarchical protein structures, which sheds light on a wide range of biomedical applications such as structure‐enhanced fluorescence and biomimetic microenvironments for controlling cell fate.
A class of well‐defined, complex protein‐based 2D and 3D nanostructures with shape and function on demand is manufactured and assembled by precise patterning on genetically engineered spider silk. This multiplex of facile functionalization in addition to on‐demand nanoscale composite structures adds a new dimension to the versatility of this platform toward a wide range of biomedical applications.
Alectinib, approved as 150 mg capsules for the treatment of adults with advanced ALK‐positive non‐small cell lung cancer, is being assessed in children with ALK‐positive solid and central nervous ...system tumors. An ad hoc pediatric‐friendly suspension of alectinib, prepared from capsule contents, is under investigation as an alternative formulation for children who cannot swallow capsules. This randomized, crossover, relative bioavailability, and food effect study evaluated alectinib administered as an oral suspension versus capsule formulation following conventional venipuncture and capillary microsampling. A total of 28 healthy adult subjects received a 600 mg single dose of alectinib in two groups: fasted (n = 14) and mixed fed (n = 14; seven receiving high‐fat meal and seven receiving low‐fat meal). Combined alectinib + M4 (active metabolite) exposure was higher for suspension versus capsule, with geometric mean ratio (GMR) of 2.6 for area under the concentration–time curve extrapolated to infinity (AUC0‐∞) and 3.0 for maximum observed concentration (Cmax) under fasted conditions, and 1.7 for both parameters for mixed fed. The suspension showed increased alectinib + M4 AUC0‐∞ following a high‐fat meal versus fasted conditions (GMR 1.7 90% confidence interval 1.4–2.2). Alectinib AUC0‐∞ and Cmax measured in venous and capillary samples were generally similar for the suspension and capsule. Single oral doses of 600 mg alectinib suspension and capsule were well tolerated, with no safety concerns. Based on these findings, the oral suspension of alectinib appears suitable for use in pediatric studies after appropriate dose adjustment relative to the capsule.
The competing and non‐equilibrium phase transitions, involving dynamic tunability of cooperative electronic and magnetic states in strongly correlated materials, show great promise in quantum sensing ...and information technology. To date, the stabilization of transient states is still in the preliminary stage, particularly with respect to molecular electronic solids. Here, a dynamic and cooperative phase in potassium‐7,7,8,8‐tetracyanoquinodimethane (K‐TCNQ) with the control of pulsed electromagnetic excitation is demonstrated. Simultaneous dynamic and coherent lattice perturbation with 8 ns pulsed laser (532 nm, 15 MW cm−2, 10 Hz) in such a molecular electronic crystal initiates a stable long‐lived (over 400 days) conducting paramagnetic state (≈42 Ωcm), showing the charge–spin bistability over a broad temperature range from 2 to 360 K. Comprehensive noise spectroscopy, in situ high‐pressure measurements, electron spin resonance (ESR), theoretical model, and scanning tunneling microscopy/spectroscopy (STM/STS) studies provide further evidence that such a transition is cooperative, requiring a dedicated charge–spin–lattice decoupling to activate and subsequently stabilize nonequilibrium phase. The cooperativity triggered by ultrahigh‐strain‐rate (above 106 s−1) pulsed excitation offers a collective control toward the generation and stabilization of strongly correlated electronic and magnetic orders in molecular electronic solids and offers unique electro‐magnetic phases with technological promises.
A major challenge in a supramolecular electronic crystal is switchable control of its hidden phase. The cooperative tuning of K‐TCNQ through a pulsed electromagnetic field into an emergent electronic disorder state, enabling access to a long‐lived (over 400 days) hidden conducting phase, is found. A switchable magneto‐electronic bistability is realized in a broad temperature range from 2 to 360 K.
In a group of healthy adults (N = 48), this study evaluated how fMRI Blood Oxygen Level-Dependent (BOLD) signal variability differed across letter n-back task load and quantified the extent to which ...BOLD signal variability was associated with in-scanner accuracy and reaction time as well as out-of-scanner measures of vigilance and working memory (WM). Within-individual BOLD signal variability in regions of interest (ROIs, identified as peak coordinates in an attention/vigilance and WM network using Neurosynth) was differentially modulated across vigilance and WM trials. Within-individual BOLD signal variability was significantly greater across the majority of the ROIs in the working memory trials (2- and 3-back trials) compared to 0-back trials. Notably, this increased variability across the network was accompanied by significantly less variability in the left cingulate gyrus and left inferior temporal lobe during the working memory trials. Significantly fewer differences in within-individual BOLD signal variability were identified for vigilance trials (0- and 1-back trials) compared to crosshair. We hypothesized that increased BOLD signal variability would be associated with n-back task performance and with out-of-scanner measures of vigilance (Digit Span Forward) and WM (Auditory Consonant Trigrams and Digit Span Backward). These results were non-significant after correcting for multiple comparisons. Furthermore, using multivariate analyses (partial least squares regression; PLS-R), within-individual BOLD signal variability in regions associated with a WM-vigilance network did not significantly predict out-of-scanner test performance after appropriate cross validation, yet provided a promising trend for WM trials; greater within-individual BOLD signal variability during WM n-back trials was associated with decreased performance on all included neuropsychological measures, which provides partial support for previous findings. This study demonstrates that patterns of variability differ based on task load in the scanner and illustrates an intriguing association between within-individual BOLD signal variability and out-of-scanner behavioral performance that may be better explored in future studies with a larger sample size.
•Within-individual BOLD signal variability differed based on n-back load.•Increased BOLD signal variability occurred during working memory (WM) trials.•Decreased BOLD signal variability occurred during vigilance trials.•BOLD signal variability was not linked to n-back accuracy or reaction time.•BOLD signal variability during WM trials trended with out-of-scanner performance.
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