Cachexia: A systemic consequence of progressive, unresolved disease.

Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.

Organoid models of human and mouse ductal pancreatic cancer.

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.

Diversity and Biology of Cancer-Associated Fibroblasts.

Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.

Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma.

The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant, including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here, we present the first comprehensive single-cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiple in vitro models of benign and malignant mesothelial cells, and characterise these through comparison with in vivo transcriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at the single-cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. It has already enabled us to shed light on the transdifferentiation of mesothelial cells, allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro.

Correlating Symmetries of Low-Frequency Vibrations and Self-Trapped Excitons in Layered Perovskites for Light Emission with Different Colors.

The soft hybrid organic-inorganic structure of two-dimensional layered perovskites (2DLPs) enables broadband emission at room temperature from a single material, which makes 2DLPs promising sources for solid-state white lighting, yet with low efficiency. The underlying photophysics involves self-trapping of excitons favored by distortions of the inorganic lattice and coupling to phonons, where the mechanism is still under debate. 2DLPs with different organic moieties and emission ranging from self-trapped exciton (STE)-dominated white light to blue band-edge photoluminescence are investigated. Detailed insights into the directional symmetries of phonon modes are gained using angle-resolved polarized Raman spectroscopy and are correlated to the temperature-dependence of the STE emission. It is demonstrated that weak STE bands at low-temperature are linked to in-plane phonons, and efficient room-temperature STE emission to more complex coupling to several phonon modes with out-of-plane components. Thereby, a unique view is provided into the lattice deformations and recombination dynamics that are key to designing more efficient materials.

Fast Intrinsic Emission Quenching in Cs4PbBr6 Nanocrystals.

Cs4PbBr6 (0D) nanocrystals at room temperature have both been reported as nonemissive and green-emissive systems in conflicting reports, with no consensus regarding both the origin of the green emission and the emission quenching mechanism. Here, via ab initio molecular dynamics (AIMD) simulations and temperature-dependent photoluminescence (PL) spectroscopy, we show that the PL in these 0D metal halides is thermally quenched well below 300 K via strong electron-phonon coupling. To unravel the source of green emission reported for bulk 0D systems, we further study two previously suggested candidate green emitters: (i) a Br vacancy, which we demonstrate to present a strong thermal emission quenching at room temperature; (ii) an impurity, based on octahedral connectivity, that succeeds in suppressing nonradiative quenching via a reduced electron-phonon coupling in the corner-shared lead bromide octahedral network. These findings contribute to unveiling the mechanism behind the temperature-dependent PL in lead halide materials of different dimensionality.

A Semi-Classical View on Epsilon-Near-Zero Resonant Tunneling Modes in Metal/Insulator/Metal Nanocavities.

Metal/Insulator/Metal nanocavities (MIMs) are highly versatile systems for nanometric light confinement and waveguiding, and their optical properties are mostly interpreted in terms of surface plasmon polaritons. Although classic electromagnetic theory accurately describes their behavior, it often lacks physical insight, leaving some fundamental aspects of light interaction with these structures unexplored. In this work, we elaborate a quantum mechanical description of the MIM cavity as a double barrier quantum well. We identify the square of the imaginary part κ of the refractive index ñ of the metal as the optical potential and find that MIM cavity resonances are suppressed if the ratio n/κ exceeds a certain limit, which shows that low n and high κ values are desired for strong and sharp cavity resonances. Interestingly, the spectral regions of cavity mode suppression correspond to the interband transitions of the metals, where the optical processes are intrinsically non-Hermitian. The quantum treatment allows to describe the tunnel effect for photons and reveals that the MIM cavity resonances can be excited by resonant tunneling via illumination through the metal, without the need of momentum matching techniques such as prisms or grating couplers. By combining this analysis with spectroscopic ellipsometry on experimental MIM structures and by developing a simple harmonic oscillator model of the MIM for the calculation of its effective permittivity, we show that the cavity eigenmodes coincide with low-loss zeros of the effective permittivity. Therefore, the MIM resonances correspond to epsilon-near-zero (ENZ) eigenmodes that can be excited via resonant tunneling. Our approach provides a toolbox for the engineering of ENZ resonances throughout the entire visible range, which we demonstrate experimentally and theoretically. In particular, we apply our quantum mechanical approach to asymmetric MIM superabsorbers and use it for configuring broadly tunable refractive index sensors. Our work elucidates the role of MIM cavities as photonic analogues to tunnel diodes and opens new perspectives for metamaterials with designed ENZ response.

Dual binding of an antibody and a small molecule increases the stability of TERRA G-quadruplex.

In investigating the binding interactions between the human telomeric RNA (TERRA) G-quadruplex (GQ) and its ligands, it was found that the small molecule carboxypyridostatin (cPDS) and the GQ-selective antibody BG4 simultaneously bind the TERRA GQ. We previously showed that the overall binding affinity of BG4 for RNA GQs is not significantly affected in the presence of cPDS. However, single-molecule mechanical unfolding experiments revealed a population (48%) with substantially increased mechanical and thermodynamic stability. Force-jump kinetic investigations suggested competitive binding of cPDS and BG4 to the TERRA GQ. Following this, the two bound ligands slowly rearrange, thereby leading to the minor population with increased stability. Given the relevance of G-quadruplexes in the regulation of biological processes, we anticipate that the unprecedented conformational rearrangement observed in the TERRA-GQ-ligand complex may inspire new strategies for the selective stabilization of G-quadruplexes in cells.

Modelling the micro- and macro- environment of pancreatic cancer: from patients to pre-clinical models and back.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with very low survival rates. Over the past 50 years, improvements in PDAC survival have significantly lagged behind the progress made in other cancers. PDAC's dismal prognosis is due to typical late-stage diagnosis combined with lack of effective treatments and complex mechanisms of disease. We propose that improvements in survival are partly hindered by the current focus on largely modelling and targeting PDAC as one disease, despite it being heterogeneous. Implementing new disease-representative pre-clinical mouse models that capture this complexity could enable the development of transformative therapies. Specifically, these models should recapitulate human PDAC late-stage biology, heterogeneous genetics, extensive non-malignant stroma, and associated risk factors and comorbidities. In this Perspective, we focus on how pre-clinical mouse models could be improved to exemplify key features of PDAC micro- and macro- environments, which would drive clinically relevant patient stratification, tailored treatments and improved survival.

EGFR-activated myofibroblasts promote metastasis of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Cancer-associated fibroblasts (CAFs) are recognized potential therapeutic targets, but poor understanding of these heterogeneous cell populations has limited the development of effective treatment strategies. We previously identified transforming growth factor beta (TGF-ß) as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that epidermal growth factor receptor/Erb-B2 receptor (EGFR/ERBB2) signaling is induced by TGF-ß in myCAFs through an autocrine process mediated by amphiregulin. Inhibition of this EGFR/ERBB2-signaling network in PDAC organoid-derived cultures and mouse models differentially impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, EGFR-activated myCAFs promote PDAC metastasis in mice, unmasking functional significance in myCAF heterogeneity. Finally, analyses of other cancer datasets suggest that these processes might operate in other malignancies. These data provide functional relevance to myCAF heterogeneity and identify a candidate target for preventing tumor invasion in PDAC.

An intramolecular G-quadruplex structure is required for binding of telomeric repeat-containing RNA to the telomeric protein TRF2.

Telomeric repeat-containing RNA (TERRA) is important for telomere regulation, but the structural basis for how TERRA localizes to chromosome ends is unknown. Here we report on studies exploring whether the TERRA G-quadruplex structure is critical for binding to telomeres. We demonstrate that the telomeric protein TRF2 binds TERRA via interactions that necessitate the formation of a G-quadruplex structure rather than the TERRA sequence per se. We also show that TRF2 simultaneously binds TERRA and telomeric duplex or G-quadruplex DNA. These observations suggest that the TERRA G-quadruplex is a key feature of telomere organization.

Selective RNA versus DNA G-quadruplex targeting by in†situ click chemistry.

It all clicks into place: A potent telomere-targeting small molecule has been identified by using the copper-free 1,3-dipolar cycloaddition of a series of alkyne and azide building blocks catalyzed by a non-Watson-Crick DNA secondary structure (see picture). This method rapidly identifies, otherwise unanticipated, potent small-molecule probes to selectively target a given RNA or DNA.

Tracing back to one of the origins of immune evasion in pancreatic cancer.

In this issue of Cancer Cell, Huang et al. identify the origin and function of a subset of pancreatic cancer-associated fibroblasts. This work further highlights the power of lineage-tracing models for dissecting the tumor microenvironment in pancreatic cancer and provides new knowledge toward the development of novel therapeutic strategies.

Meningococcal Disease in Pediatric Age: A Focus on Epidemiology and Prevention.

Meningococcal disease is caused by Neisseria meningitidis; 13 serogroups have been identified and differentiated from each other through their capsular polysaccharide. Serotypes A, B, C, W, X, and Y are responsible for nearly all infections worldwide. The most common clinical manifestations are meningitis and invasive meningococcal disease, both characterized by high mortality and long-term sequelae. The infection rate is higher in children younger than 1 year and in adolescents, who are frequently asymptomatic carriers. Vaccination is the most effective method of preventing infection and transmission. Currently, both monovalent meningococcal vaccines (against A, B, and C serotypes) and quadrivalent meningococcal vaccines (against serogroups ACYW) are available and recommended according to local epidemiology. The purpose of this article is to describe the meningococcal vaccines and to identify instruments that are useful for reducing transmission and implementing the vaccination coverage. This aim could be reached by switching from the monovalent to the quadrivalent vaccine in the first year of life, increasing vaccine promotion against ACYW serotypes among adolescents, and extending the free offer of the anti-meningococcal B vaccine to teens, co-administering it with others proposed in the same age group. Greater awareness of the severity of the disease and increased health education through web and social networks could represent the best strategies for promoting adhesion and active participation in the vaccination campaign. Finally, the development of a licensed universal meningococcal vaccine should be another important objective.

Phase Transitions in Low-Dimensional Layered Double Perovskites: The Role of the Organic Moieties.

Halide double perovskites are an interesting alternative to Pb-containing counterparts as active materials in optoelectronic devices. Low-dimensional double perovskites are fabricated by introducing large organic cations, resulting in organic/inorganic architectures with one or more inorganic octahedra layers separated by organic cations. Here, we synthesized layered double perovskites based on 3D Cs2AgBiBr6, consisting of double (2L) or single (1L) inorganic octahedra layers, using ammonium cations of different sizes and chemical structures. Temperature-dependent Raman spectroscopy revealed phase transition signatures in both inorganic lattice and organic moieties by detecting variations in their vibrational modes. Changes in the conformational arrangement of the organic cations to an ordered state coincided with a phase transition in the 1L systems with the shortest ammonium moieties. Significant changes of photoluminescence intensity observed around the transition temperature suggest that optical properties may be affected by the octahedral tilts emerging at the phase transition.

Engineering the Optical Emission and Robustness of Metal-Halide Layered Perovskites through Ligand Accommodation.

The unique combination of organic and inorganic layers in 2D layered perovskites offers promise for the design of a variety of materials for mechatronics, flexoelectrics, energy conversion, and lighting. However, the potential tailoring of their properties through the organic building blocks is not yet well understood. Here, different classes of organoammonium molecules are exploited to engineer the optical emission and robustness of a new set of Ruddlesden-Popper metal-halide layered perovskites. It is shown that the type of molecule regulates the number of hydrogen bonds that it forms with the edge-sharing [PbBr6 ]4- octahedra layers, leading to strong differences in the material emission and tunability of the color coordinates, from deep-blue to pure-white. Also, the emission intensity strongly depends on the length of the molecules, thereby providing an additional parameter to optimize their emission efficiency. The combined experimental and computational study provides a detailed understanding of the impact of lattice distortions, compositional defects, and the anisotropic crystal structure on the emission of such layered materials. It is foreseen that this rational design can be extended to other types of organic linkers, providing a yet unexplored path to tailor the optical and mechanical properties of these materials and to unlock new functionalities.

Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer.

PURPOSE: Pancreatic 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 DESIGN: We 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. RESULTS: We 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. CONCLUSIONS: Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.

Robustness to High Temperatures of Al2O3-Coated CsPbBr3 Nanocrystal Thin Films with High-Photoluminescence Quantum Yield for Light Emission.

Lead-halide perovskite nanocrystals are a promising material in optical devices due to their high photoluminescence (PL) quantum yield, excellent color purity, and low stimulated emission threshold. However, one problem is the stability of the nanocrystal films under different environmental conditions and under high temperatures. The latter is particularly relevant for device fabrication if further processes that require elevated temperatures are needed after the deposition of the nanocrystal film. In this work, we study the impact of a thin oxide layer of Al2O3 on the light emission properties of thin nanocrystal films. We find that nanocrystals passivated with quaternary ammonium bromide ligands maintain their advantageous optical properties in alumina-coated films and do not suffer from degradation at temperatures up to 100 °C. This is manifested by conservation of the PL peak position and line width, PL decay dynamics, and low threshold for amplified spontaneous emission. The PL remains stable for up to 100 h at a temperature of 80 °C, and the ASE intensity decreases by less than 30% under constant pumping at high fluence for 1 h. Our approach outlines that the combination of tailored surface chemistry with additional protective coating of the nanocrystal film is a feasible approach to obtain stable emission at elevated temperatures and under extended operational time scales.