Pathways for macrophage uptake of cell-free circular RNAs.

Circular RNAs (circRNAs) are stable RNAs present in cell-free RNA, which may comprise cellular debris and pathogen genomes. Here, we investigate the phenomenon and mechanism of cellular uptake and intracellular fate of exogenous circRNAs. Human myeloid cells and B cells selectively internalize extracellular circRNAs. Macrophage uptake of circRNA is rapid, energy dependent, and saturable. CircRNA uptake can lead to translation of encoded sequences and antigen presentation. The route of internalization influences immune activation after circRNA uptake, with distinct gene expression programs depending on the route of RNA delivery. Genome-scale CRISPR screens and chemical inhibitor studies nominate macrophage scavenger receptor MSR1, Toll-like receptors, and mTOR signaling as key regulators of receptor-mediated phagocytosis of circRNAs, a dominant pathway to internalize circRNAs in parallel to macropinocytosis. These results suggest that cell-free circRNA serves as an "eat me" signal and danger-associated molecular pattern, indicating orderly pathways of recognition and disposal.

Inhibiting the Leidenfrost effect above 1,000 °C for sustained thermal cooling.

The Leidenfrost effect, namely the levitation of drops on hot solids1, is known to deteriorate heat transfer at high temperature2. The Leidenfrost point can be elevated by texturing materials to favour the solid-liquid contact2-10 and by arranging channels at the surface to decouple the wetting phenomena from the vapour dynamics3. However, maximizing both the Leidenfrost point and thermal cooling across a wide range of temperatures can be mutually exclusive3,7,8. Here we report a rational design of structured thermal armours that inhibit the Leidenfrost effect up to 1,150 °C, that is, 600 °C more than previously attained, yet preserving heat transfer. Our design consists of steel pillars serving as thermal bridges, an embedded insulating membrane that wicks and spreads the liquid and U-shaped channels for vapour evacuation. The coexistence of materials with contrasting thermal and geometrical properties cooperatively transforms normally uniform temperatures into non-uniform ones, generates lateral wicking at all temperatures and enhances thermal cooling. Structured thermal armours are limited only by their melting point, rather than by a failure in the design. The material can be made flexible, and thus attached to substrates otherwise challenging to structure. Our strategy holds the potential to enable the implementation of efficient water cooling at ultra-high solid temperatures, which is, to date, an uncharted property.

Surface Nanostructures Promote Droplet Splash on Hot Substrates.

Splash, one of the most visually apparent droplet dynamics, can manifest on any surface above a certain impact velocity, regardless of surface wettability. Previous studies demonstrate that elevating the substrate temperature can suppress droplet splash, which is unfavorable for many practical applications, such as spray cooling and combustion. Here, we report that the suppression effect of substrate temperature on splash is nullified by utilizing surfaces with nanostructures. By manipulating air evacuation time through surface nanostructures, we have identified a pathway for precise control over the splash threshold and the ability to tailor the dependence of the splash onset on surface temperature. We further propose a theoretical criterion to determine different splash regimes by considering the competition between air evacuation and the development of flow instabilities. Our findings underscore the crucial role of nanostructures in splash dynamics, offering valuable insights for the control of splash in various industrial scenarios.

Ophthalmic drug effects on the amyloidogenesis of a transforming growth factor ß-induced protein (TGFBIp) peptide fragment.

Drugs that can treat one disease may either be detrimental or beneficial toward another due to possible cross-interactions. Therefore, care in choosing a suitable drug for patients with multiple diseases is crucial in successful patient management. This study explores several currently available ophthalmic drugs used to treat common ocular diseases to understand how they can affect the amyloidogenesis of a transforming growth factor ß-induced protein (TGFBIp) peptide fragment found in abundance in the corneal protein aggregation deposits of lattice corneal dystrophy (LCD) patients. Results from this study provided supporting evidence that some drugs intended to treat other diseases can enhance or inhibit fibrillar aggregation of TGFBIp peptide, which may have potential implication of affecting the disease progression of LCD by either worsening or ameliorating it. Comparisons of the different properties of ophthalmic compounds explored in this study may also provide some guidance for future design of drugs geared toward the treatment of LCD.

Heterogenous Slippery Surfaces: Enabling Spontaneous and Rapid Transport of Viscous Liquids with Viscosities Exceeding 10 000 mPa s.

Superhydrophobic and slippery lubricant-infused surfaces have garnered significant attention for their potential to passively transport low-viscosity liquids like water (1 mPa s). Despite exciting progress, these designs have proven ineffective for transporting high-viscosity liquids such as polydimethylsiloxane (5500 mPa s) due to their inherent limitations imposed by the homogenous surface design, resulting in high viscous drags and compromised capillary forces. Here, a heterogenous water-infused divergent surface (WIDS) is proposed that achieves spontaneous, rapid, and long-distance transport of viscous liquids. WIDS reduces viscous drag by spatially isolating the viscous liquids and surface roughness through its heterogenous, slippery topological design, and generates capillary forces through its heterogenous wetting distributions. The essential role of surface heterogeneity in viscous liquid transport is theoretically and experimentally verified. Remarkably, such a heterogenous paradigm enables transporting liquids with viscosities exceeding 12 500 mPa s, which is two orders of magnitude higher than state-of-the-art techniques. Furthermore, this heterogenous design is generic for various viscous liquids and can be made flexible, making it promising for various systems that require viscous liquid management, such as micropatterning.

Thermo-fluid dynamics and synergistic enhancement of heat transfer by interaction between Taylor-Couette flow and heat convection.

This study experimentally and numerically investigated the thermo-fluid dynamics of Taylor-Couette flow with an axial temperature gradient from the chemical engineering perspective. A Taylor-Couette apparatus with a jacket vertically divided into two parts was used in the experiments. Based on the flow visualization and temperature measurement for glycerol aqueous solutions with various concentrations, the flow pattern was classified into six modes: heat convection dominant mode (Case I), heat convection-Taylor vortex flow alternate mode (Case II), Taylor vortex flow dominant mode (Case III), fluctuation maintaining Taylor cell structure mode (Case IV), segregation between Couette flow and Taylor vortex flow mode (Case V) and upward motion mode (Case VI). These flow modes weremapped in terms of the Reynolds and Grashof numbers. Cases II, IV, V and VI are regarded as transition flow patterns between Case I and Case III, depending on the concentration. In addition, numerical simulations showed that in Case II, heat transfer was enhanced when the Taylor-Couette flow was altered by heat convection. Moreover, the average Nusselt number with the alternate flow was higher than that with the stable Taylor vortex flow. Thus, the interaction between heat convection and Taylor-Couette flow is an effective tool to enhance heat transfer. This article is part of the theme issue 'Taylor-Couette and related flows on the centennial of Taylor's seminal Philosophical Transactions paper (Part 2)'.

Comparison of margins and survival between transoral robotic surgery (TORS) and non-robotic endoscopic surgery for oropharyngeal cancer.

OBJECTIVE: To evaluate the impact of transoral robotic surgery (TORS) and non-robotic transoral endoscopic surgery on margin positivity, rates of adjuvant therapy and survival in early stage oropharyngeal squamous cell carcinoma. STUDY DESIGN: Retrospective cohort review. SUBJECTS AND METHODS: The National Cancer Database was queried to form a cohort of patients with T1-T2 N0-N1 MO oropharyngeal squamous cell carcinoma who underwent TORS or Non-robotic endoscopic surgery from 2010 to 2015. Demographics, disease characteristics and rate of positive margin and adjuvant therapy were summarized. A binary logistic regression and a cox-proportional hazard model were performed to evaluate patient demographic, disease, and treatment factors that could predict margin positivity and survival respectively. RESULTS: 1026 patients received TORS treatment while 734 patients received non-robotic endoscopic primary surgery. Non-robotic surgery was more likely to have residual tumor (31.6 % of all cases) compared to TORS procedures (13.6 % of TORS cases); p < .0001. Non-robotic surgery more frequently had non-evaluable margins at 8.1 % compared to only 1.4 % of TORS cases (p < .0001). Non-robotic cases had a significantly higher proportion of patients receiving adjuvant radiotherapy and systemic therapy compared to TORS (66.4 % vs 51.3 % for radiotherapy; p < .0001 and 33.4 % vs 22.2 % for chemotherapy; p < .0001). There was no difference in mortality between the two modalities (non-robotic vs TORS, HR 1.357, 95 % CI 0.937-1.967). CONCLUSION: TORS and non-robotic surgery may have a similar impact on survival in early-stage OPSCC, but non-robotic surgery was found to have a higher likelihood of positive margins and a higher rate of adjuvant chemoradiation therapy.

Modulation of Insulin Amyloid Fibrillization in Imidazolium-Based Ionic Liquids with Hofmeister Series Anions.

Amyloid fibrils have immense potential to become the basis of modern biomaterials. The formation of amyloid fibrils in vitro strongly depends on the solvent properties. Ionic liquids (ILs), alternative solvents with tunable properties, have been shown to modulate amyloid fibrillization. In this work, we studied the impact of five ILs with 1-ethyl-3-methylimidazolium cation [EMIM+] and anions of Hofmeisterseries hydrogen sulfate [HSO4-], acetate [AC-], chloride [Cl-], nitrate [NO3-], and tetrafluoroborate [BF4-] on the kinetics of insulin fibrillization and morphology, and the structure of insulin fibrils when applying fluorescence spectroscopy, AFM and ATR-FTIR spectroscopy. We found that the studied ILs were able to speed up the fibrillization process in an anion- and IL-concentration-dependent manner. At an IL concentration of 100 mM, the efficiency of the anions at promoting insulin amyloid fibrillization followed the reverse Hofmeister series, indicating the direct binding of ions with the protein surface. At a concentration of 25 mM, fibrils with different morphologies were formed, yet with similar secondary structure content. Moreover, no correlation with the Hofmeister ranking was detected for kinetics parameters. IL with the kosmotropic strongly hydrated [HSO4-] anion induced the formation of large amyloid fibril clusters, while the other kosmotropic anion [AC-] along with [Cl-] led to the formation of fibrils with similar needle-like morphologies to those formed in the IL-free solvent. The presence of the ILs with the chaotropic anions [NO3-] and [BF4-] resulted in longer laterally associated fibrils. The effect of the selected ILs was driven by a sensitive balance and interplay between specific protein-ion and ion-water interactions and non-specific long-range electrostatic shielding.

Protein-protein interaction networks as miners of biological discovery.

Protein-protein interactions (PPIs) form the basis of a myriad of biological pathways and mechanism, such as the formation of protein complexes or the components of signaling cascades. Here, we reviewed experimental methods for identifying PPI pairs, including yeast two-hybrid (Y2H), mass spectrometry (MS), co-localization, and co-immunoprecipitation. Furthermore, a range of computational methods leveraging biochemical properties, evolution history, protein structures and more have enabled identification of additional PPIs. Given the wealth of known PPIs, we reviewed important network methods to construct and analyze networks of PPIs. These methods aid biological discovery through identifying hub genes and dynamic changes in the network, and have been thoroughly applied in various fields of biological research. Lastly, we discussed the challenges and future direction of research utilizing the power of PPI networks.

Nature-Inspired High Temperature Scale-Resistant Slippery Lubricant-Induced Porous Surfaces (HTS-SLIPS).

Scale formation is a longstanding and unresolved problem in a number of fields, including power production, petroleum exploration, thermal desalination, and construction. Herein, a high-temperature scale-resistant slippery lubricant-induced surface (HTS-SLIPS) is developed by one-step electrodeposition and lubricant infusion. The fractal cauliflower-like morphology with lubricant oil is conducive to forming an ultralow contact angle hysteresis of ≈1°. The 10-d real-world boiling trial indicates that by replacing the uncoated surface with HTS-SLIPS, the reduction in scale mass is greater than 200% because of the low surface free energy (4.3 mJ m-2 ) and outstanding smoothness (Ra  = 41 ± 8 nm) of HTS-SLIPS. Thanks to the scale retardation, the bubble departure frequency of HTS-SLIPS is eightfold higher than that of uncoated surfaces, signifying superior heat transfer efficiency. In these demonstrations, HTS-SLIPS coated spiral tube exhibits better flowability and lower pressure drop than the uncoated one. In addition, favorable compatibility between HTS-SLIPS and mechanical vibration is experimentally verified to strengthen the descaling of SLIPS synergistically. It is anticipated that the simple and scalable coating fabrication approach will be applicable in numerous industrial high-temperature processes where scale formation is encountered.

A Randomized, Double-Blind, Multicenter, Noninferiority Study Comparing Paliperidone Palmitate 6-Month Versus the 3-Month Long-Acting Injectable in Patients With Schizophrenia.

BACKGROUND: This double-blind (DB), randomized, parallel-group study was designed to evaluate efficacy and safety of paliperidone palmitate 6-month (PP6M) formulation relative to paliperidone palmitate 3-month (PP3M) formulation in patients with schizophrenia. METHODS: Following screening, patients entered an open-label (OL) maintenance phase and received 1 injection cycle of paliperidone palmitate 1-month (PP1M; 100 or 150 mg eq.) or PP3M (350 or 525 mg eq.). Clinically stable patients were randomized (2:1) to receive PP6M (700 or 1000 mg eq., gluteal injections) or PP3M (350 or 525 mg eq.) in a 12-month DB phase; 2 doses of PP6M (corresponding to doses of PP1M and PP3M) were chosen. RESULTS: Overall, 1036 patients were screened, 838 entered the OL phase, and 702 (mean age: 40.8 years) were randomized (PP6M: 478; PP3M: 224); 618 (88.0%) patients completed the DB phase (PP6M: 416 [87.0%]; PP3M: 202 [90.2%]). Relapse rates were PP6M, 7.5% (n = 36) and PP3M, 4.9% (n = 11). The Kaplan-Meier estimate of the difference (95% CI) between treatment groups (PP6M - PP3M) in the percentages of patients who remained relapse free was -2.9% (-6.8%, 1.1%), thus meeting noninferiority criteria (95% CI lower bound is larger than the pre-specified noninferiority margin of -10%). Secondary efficacy endpoints corroborated the primary analysis. Incidences of treatment-emergent adverse events were similar between PP6M (62.1%) and PP3M (58.5%). No new safety concerns emerged. CONCLUSIONS: The efficacy of a twice-yearly dosing regimen of PP6M was noninferior to that of PP3M in preventing relapse in patients with schizophrenia adequately treated with PP1M or PP3M. TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT03345342.

The impact of socioeconomic and geographic factors on access to transoral robotic/endoscopic surgery for early stage oropharyngeal malignancy.

OBJECTIVE: To evaluate the role of social and geographic factors on the likelihood of receiving transoral robotic surgery (TORS) or non-robotic transoral endoscopic surgery treatment in early stage oropharyngeal squamous cell carcinoma (OPSCC). MATERIALS AND METHODS: The National Cancer Database was queried to form a cohort of patients with T1-T2 N0-N1 M0 OPSCC (AJCC v.7) who underwent treatment from 2010 to 2016. Demographics, tumor characteristics, treatment type, social, and geographic factors were all collected. Univariate analysis and multivariate logistic regression were then performed. RESULTS: Among 9267 identified patients, 1774 (19.1%) received transoral robotic surgery (TORS), 1191 (12.9%) received transoral endoscopic surgery, and 6302 (68%) received radiation therapy. We found that lower cancer stage, lower comorbidity burden and HPV- positive status predicted a statistically significant increased likelihood of receiving surgery. Patients who reside in suburban or small urban areas (>1 million population), were low-to- middle income, or rely on Medicaid were less likely to receive surgery. Patients that reside in Medicaid-expansion states were more likely to receive TORS (p > .0001). Patients that reside in states that expanded Medicaid January 2014 and after were more likely to receive non-robotic transoral endoscopic surgery (p > .0001). CONCLUSIONS: Poorer baseline health, lower socioeconomic status and residence in small urban areas may act as barriers to accessing minimally invasive transoral surgery while residence in a Medicaid-expansion state may improve access. Barriers to accessing robotic surgery may be greater than accessing non-robotic surgery.

Prescribing errors in post - COVID-19 patients: prevalence, severity, and risk factors in patients visiting a post - COVID-19 outpatient clinic.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has challenged healthcare globally. An acute increase in the number of hospitalized patients has necessitated a rigorous reorganization of hospital care, thereby creating circumstances that previously have been identified as facilitating prescribing errors (PEs), e.g. a demanding work environment, a high turnover of doctors, and prescribing beyond expertise. Hospitalized COVID-19 patients may be at risk of PEs, potentially resulting in patient harm. We determined the prevalence, severity, and risk factors for PEs in post-COVID-19 patients, hospitalized during the first wave of COVID-19 in the Netherlands, 3 months after discharge. METHODS: This prospective observational cohort study recruited patients who visited a post-COVID-19 outpatient clinic of an academic hospital in the Netherlands, 3 months after COVID-19 hospitalization, between June 1 and October 1 2020. All patients with appointments were eligible for inclusion. The prevalence and severity of PEs were assessed in a multidisciplinary consensus meeting. Odds ratios (ORs) were calculated by univariate and multivariate analysis to identify independent risk factors for PEs. RESULTS: Ninety-eight patients were included, of whom 92% had ≥1 PE and 8% experienced medication-related harm requiring an immediate change in medication therapy to prevent detoriation. Overall, 68% of all identified PEs were made during or after the COVID-19 related hospitalization. Multivariate analyses identified ICU admission (OR 6.08, 95% CI 2.16-17.09) and a medical history of COPD / asthma (OR 5.36, 95% CI 1.34-21.5) as independent risk factors for PEs. CONCLUSIONS: PEs occurred frequently during the SARS-CoV-2 pandemic. Patients admitted to an ICU during COVID-19 hospitalization or who had a medical history of COPD / asthma were at risk of PEs. These risk factors can be used to identify high-risk patients and to implement targeted interventions. Awareness of prescribing safely is crucial to prevent harm in this new patient population.

A Highly Controlled Organic-Inorganic Encapsulation Nanocomposite with Versatile Features toward Wearable Device Applications.

Ultraviolet-curable polyurethane acrylate (PUA) materials can be used in a number of important applications spanning from microfluidics, surface patterning to wearable technology. For the first time, the potential of encapsulation of modified zirconia (ZrO2 ) nanoparticles is reported in PUA-based hybrid films aimed to facilitate profoundly enhanced hardness and refractive index. By successfully manipulating the interfacial reaction conditions between ZrO2 nanoparticles and PUA film, the PUA-based nanocomposites exhibit an ultrahigh hardness of 9 and superior refractive index of 1.64 (589.3 nm). The outcomes obtained pave the way for seamless application of nanozirconia/PUA as a potent encapsulating material that provides structurally morphable, water resistant, and optically transparent light emitting diodes toward wearables devices in healthcare.

Quantitative Multiplex Substrate Profiling of Peptidases by Mass Spectrometry.

Proteolysis is an integral component of life and has been implicated in many disease processes. To improve our understanding of peptidase function, it is imperative to develop tools to uncover substrate specificity and cleavage efficiency. Here, we combine the quantitative power of tandem mass tags (TMTs) with an established peptide cleavage assay to yield quantitative Multiplex Substrate Profiling by Mass Spectrometry (qMSP-MS). This assay was validated with papain, a well-characterized cysteine peptidase, to generate cleavage efficiency values for hydrolysis of 275 unique peptide bonds in parallel. To demonstrate the breath of this assay, we show that qMSP-MS can uncover the substrate specificity of minimally characterized intramembrane rhomboid peptidases, as well as define hundreds of proteolytic activities in complex biological samples, including secretions from lung cancer cell lines. Importantly, our qMSP-MS library uses synthetic peptides whose termini are unmodified, allowing us to characterize not only endo- but also exo-peptidase activity. Each cleaved peptide sequence can be ranked by turnover rate, and the amino acid sequence of the best substrates can be used for designing fluorescent reporter substrates. Discovery of peptide substrates that are selectively cleaved by peptidases which are active at the site of disease highlights the potential for qMSP-MS to guide the development of peptidase-activating drugs for cancer and infectious disease.

Liquid Marbles in Liquid.

Traditional liquid marbles (LMs), liquid droplets encapsulated by hydrophobic particles at the liquid-gas interface, are restricted by their short lifetime and low heat transfer efficiency. Herein, a new paradigm for LMs immersed in various liquid mediums with massive enhanced heat transfer and spatial recognition is designed; without compromising the structural integrity, the lifetime of the liquid marbles in liquid (LMIL) is extended by ≈1000 times compared to classical LMs in air or naked droplets in organic reagents. The LMIL shows promising reverse structural re-configurability while under external stimuli and maintaining their functionality for a very long period of time (≈weeks). These superior behaviors are further exploited as a miniature reactor with prolonged lifetimes and excellent temperature control, combined with its feasible operation, new opportunities will open up in the advanced chemical and biomedical engineering fields. It is also shown that LMIL can be applied in methylene blue degradation and 3D in-vitro yeast cell cultures. These findings have important implications for real-world use of LMs, with a number of applications in cell culture technology, lab-in-a-drop, polymerization, encapsulation, formulation, and drug delivery.

20S Proteasome as a Drug Target in Trichomonas vaginalis.

Trichomoniasis is a sexually transmitted disease with hundreds of millions of annual cases worldwide. Approved treatment options are limited to two related nitro-heterocyclic compounds, yet resistance to these drugs is an increasing concern. New antimicrobials against the causative agent, Trichomonas vaginalis, are urgently needed. We show here that clinically approved anticancer drugs that inhibit the proteasome, a large protease complex with a critical role in degrading intracellular proteins in eukaryotes, have submicromolar activity against the parasite in vitro and on-target activity against the enriched T. vaginalis proteasome in cell-free assays. Proteomic analysis confirmed that the parasite has all seven α and seven ß subunits of the eukaryotic proteasome although they have only modest sequence identities, ranging from 28 to 52%, relative to the respective human proteasome subunits. A screen of proteasome inhibitors derived from a marine natural product, carmaphycin, revealed one derivative, carmaphycin-17, with greater activity against T. vaginalis than the reference drug metronidazole, the ability to overcome metronidazole resistance, and reduced human cytotoxicity compared to that of the anticancer proteasome inhibitors. The increased selectivity of carmaphycin-17 for T. vaginalis was related to its >5-fold greater potency against the ß1 and ß5 catalytic subunits of the T. vaginalis proteasome than against the human proteasome subunits. In a murine model of vaginal trichomonad infection, proteasome inhibitors eliminated or significantly reduced parasite burden upon topical treatment without any apparent adverse effects. Together, these findings validate the proteasome of T. vaginalis as a therapeutic target for development of a novel class of trichomonacidal agents.

Advances in Biological Liquid Crystals.

Biological liquid crystals, a rich set of soft materials with rod-like structures widely existing in nature, possess typical lyotropic liquid crystalline phase properties both in vitro (e.g., cellulose, peptides, and protein assemblies) and in vivo (e.g., cellular lipid membrane, packed DNA in bacteria, and aligned fibroblasts). Given the ability to undergo phase transition in response to various stimuli, numerous practices are exercised to spatially arrange biological liquid crystals. Here, a fundamental understanding of interactions between rod-shaped biological building blocks and their orientational ordering across multiple length scales is addressed. Discussions are made with regard to the dependence of physical properties of nonmotile objects on the first-order phase transition and the coexistence of multi-phases in passive liquid crystalline systems. This work also focuses on how the applied physical stimuli drives the reorganization of constituent passive particles for a new steady-state alignment. A number of recent progresses in the dynamics behaviors of active liquid crystals are presented, and particular attention is given to those self-propelled animate elements, like the formation of motile topological defects, active turbulence, correlation of orientational ordering, and cellular functions. Finally, future implications and potential applications of the biological liquid crystalline materials are discussed.

Conformation-induced separation of 3-chloropropene from 1-chloropropane through nanoporous monolayer graphenes.

Achieving ultrahigh selectivity for separating paraffin/olefin mixtures with physical and chemical similarity, especially for halohydrocarbons, is a long-standing challenge in high-purity polymer production. We explored three H-saturated nanoporous graphene (NG) membranes with appropriate pore geometries that can achieve the complete exclusion of 1-chloropropane (C3H7Cl) from C3H5Cl during molecular dynamics simulations. Inferred from thermodynamics calculations, C3H5Cl has a lower energy barrier of penetration than C3H7Cl and the NG membranes show preferential adsorption to C3H5Cl, which facilitate the penetration of C3H5Cl through the pores. The conformational energy analysis of the two molecules shows that C3H5Cl has a lower energy penalty to twist to the molecular conformation that nanopores preferred than C3H7Cl, which mainly determines the ultrahigh selectivity for C3H5Cl. We anticipate that the conformation-induced mechanism outlined here can provide a reference to separate paraffin/olefin mixtures with distinctly different conformational energy profiles.

BRD4 inhibitors block telomere elongation.

Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase. Long-term treatment with BRD4 inhibitors caused telomere shortening in both mouse and human cells, suggesting BRD4 plays a role in telomere maintenance in vivo. Telomerase enzymatic activity was not directly affected by BRD4 inhibition. BRD4 is in clinical trials for a number of cancers, but its effects on telomere maintenance have not been previously investigated.