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The coupling between multiple nanocavities in close vicinity leads to the hybridization of their modes. Stacked metal-insulator-metal (MIM) nanocavities constitute a highly versatile and very interesting model system to study and engineer such mode coupling, as they can be realized by lithography-free fabrication methods with fine control on the optical and geometrical parameters. The resonant modes of such MIM cavities are epsilon-near-zero (ENZ) resonances, which are appealing for nonlinear photophysics and a variety of applications. Here, we study the hybridization of ENZ resonances in MIMIM nanocavities, obtaining a very large mode splitting reaching 0.477 eV, Q-factors of the order of 40 in the visible spectral range, and fine control on the resonance wavelength and mode linewidth by tuning the thickness of the dielectric and metallic layers. A semiclassical approach that analyzes the MIMIM structure as a double quantum well system allows to derive the exact analytical dispersion relation of the ENZ resonances, achieving perfect agreement with numerical simulations and experiments. Interestingly, the asymmetry of the mode splitting in a symmetric MIMIM cavity is not reflected in the classical model of coupled oscillators, which can be directly related to quantum mechanical tunneling for the coupling of the two cavities. Interpreting the cavity resonances as resonant tunneling modes elucidates that they can be excited without momentum matching techniques. The broad tunability of high-quality ENZ resonances together with their strong coupling efficiency makes such MIMIM cavities an ideal platform for exploring light-matter interaction, for example, by the integration of quantum emitters in dielectric layers.

PurposePancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment.Experimental designWe used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC.ResultsWe found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression.ConclusionsHedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumor progression. We identified sterol O-acyltransferase 1 (SOAT1) as a key player in sustaining the mevalonate pathway by converting cholesterol to inert cholesterol esters, thereby preventing the negative feedback elicited by unesterified cholesterol. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo and reveals a mevalonate pathway dependency in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH). In contrast, pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss, indicating a potential therapeutic window for inhibiting SOAT1 in PDAC.

Cancer-associated fibroblasts (CAF) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we use single-cell RNA sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human and mouse PDAC tumors. We corroborate the presence of myofibroblastic CAFs and inflammatory CAFs and define their unique gene signatures in vivo. Moreover, we describe a new population of CAFs that express MHC class II and CD74, but do not express classic costimulatory molecules. We term this cell population antigen-presenting CAFs and find that they activate CD4+ T cells in an antigen-specific fashion in a model system, confirming their putative immune-modulatory capacity. Our cross-species analysis paves the way for investigating distinct functions of CAF subtypes in PDAC immunity and progression. SIGNIFICANCE: Appreciating the full spectrum of fibroblast heterogeneity in pancreatic ductal adenocarcinoma is crucial to developing therapies that specifically target tumor-promoting CAFs. This work identifies MHC class II-expressing CAFs with a capacity to present antigens to CD4+ T cells, and potentially to modulate the immune response in pancreatic tumors.See related commentary by Belle and DeNardo, p. 1001.This article is highlighted in the In This Issue feature, p. 983.

Novel optical sources require fast decay rates, making hyperbolic metamaterials (HMMs) an increasingly attractive option. HMMs are well‐known for their remarkable anisotropy, and leverage hyperbolic dispersion to enhance the decay rate of a fluorophore placed on top of them. This study tackles the complex task of embedding a fluorophore into an HMM, successfully overcoming challenges related to surface roughness, thickness imperfections, and layer washing effects. Specifically, CsPbBr3 perovskite nanocrystals (NCs)‐based HMM are fabricated, by alternating silver/nanocrystals (Ag/NCs) layers. Through a systematic investigation of the photophysical response following the deposition of each bilayer, compelling evidence of the achievement of hyperbolic dispersion is provided. Specifically, the impact of "high‐k" modes is isolated, which is distinctive to the HMM architecture. Therefore, the longstanding debate regarding the number of bilayers needed to achieve hyperbolic dispersion is conclusively resolved. The research demonstrates a nearly twofold increase in the decay rate and a threefold enhancement in photoluminescence intensity. These findings are further supported by theoretical Purcell factor calculations. This study marks a pioneering advancement in the field of bulk dye‐embedded HMMs, laying the groundwork for the development of advanced optical sources such as "resonant gain HMMs". [ABSTRACT FROM AUTHOR]

Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of α-smooth muscle actin (αSMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated αSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.

Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

Four-stranded G-quadruplex DNA secondary structures have recently been visualized in the nuclei of human cultured cells. Here, we show that BG4, a G-quadruplex-specific antibody, can be used to stain DNA G-quadruplex structures in patient-derived tissues using immunohistochemistry. We observe a significantly elevated number of G-quadruplex-positive nuclei in human cancers of the liver and stomach as compared to background non-neoplastic tissue. Our results suggest that G-quadruplex formation can be detected and measured in patient-derived material and that elevated G-quadruplex formation may be a characteristic of some cancers.

For this reason, at 2 months of life, he was admitted to the hospital where physical, neurologic and cardiologic examination, brain ultrasound, standard EEG, blood cell count, serum ferritin level and electrocardiogram (ECG) showed no abnormalities. As the consciousness was regained, the background EEG rapidly returned to normal.[4] We provide an interesting video EEG with polygraphy providing insights on the pathophysiology of BHA. We report the complete video electroencephalogram (vEEG) features of a breath-holding attack event, describing the pathophysiological sequence of events. [Extracted from the article]