Ion-retention properties of graphene oxide/zinc oxide nanocomposite membranes at various pH and temperature conditions.

Laminar graphene oxide (GO) is a promising candidate material for next-generation highly water-permeable membranes. Despite extensive research, there is little information known concerning GO's ion-sieving properties at high acidic/basic pH and temperatures. In this study, the ion-blockage properties of the pristine GO and GO/zinc oxide (ZnO) nanocomposite membranes were tested using a non-pressure-driven filtration setup over a wide range of pH and temperatures. The ZnO nanoparticles within the composite membranes were synthesized via the room-temperature oxidation of zinc acetate and zinc acrylate precursors and were uniformly distributed across the composite membrane. It is observed that partially replacing the zinc acetate precursor with zinc acrylate improves the blockage performance of the composite membranes under extreme basic conditions by 42%. Moreover, photocatalytically-reduced composite membranes blocked copper sulfate ions 28% more than as-prepared composite membranes. Further, it was discovered that the composition of the membrane plays a vital role in its ion blockage performance at higher temperatures.

Long-read sequencing of oropharyngeal squamous cell carcinoma tumors reveal diverse patterns of high-risk Human Papillomavirus integration.

Introduction: In North America and in most European countries, Human Papillomavirus (HPV) is responsible for over 70% of oropharyngeal squamous cell carcinomas. The burden of OPSCC, in high-income countries, has been steadily increasing over the past 20 years. As a result, in the USA and in the UK, the burden of HPV-related oropharyngeal squamous cell carcinoma in men has now surpassed that of cervical cancer in women. However, the oncogenic impact of high-risk HPV integration in oropharyngeal squamous cell carcinomas hasn't been extensively studied. The present study aimed to explore the patterns of HPV integration in oropharyngeal squamous cell carcinomas and to assess the feasibility and reliability of long-read sequencing technology in detecting viral integration events in oropharyngeal head and neck cancers. Methods: A cohort of eight HPV-positive OPSCC pre-treatment patient tumors (four males and four females), were selected. All patients received a p16INK4A positive OPSCC diagnosis and were treated at the McGill University Health Centre, a quaternary center in Montreal. A minimum of 20mg of tumor tissue was used for DNA extraction. Extracted DNA was subjected to Nanopore long-read sequencing to detect and analyze for the presence of high-risk HPV sequences. PCR and Sanger sequencing experiments were performed to confirm Nanopore long-read sequencing readings. Results: Nanopore long-read sequencing showed that seven out of eight patient samples displayed either integrated or episomal high-risk HPV sequences. Out of these seven samples, four displayed verifiable integration events upon bioinformatic analysis. Integration confirmation experiments were designed for all four samples using PCR-based methods. Sanger sequencing was also performed. Four distinct HPV integration patterns were identified: concatemer chromosomal integration in a single chromosome, bi-chromosomal concatemer integration, single chromosome complete integration and bi-chromosomal complete integration. HPV concatemer integration also proved more common than full HPV integration events. Conclusion and relevance: Long-read sequencing technologies can be effectively used to assess HPV integration patterns in OPSCC tumors. Clinically, more research should be conducted on the prognostication value of high-risk HPV integration in OPSCC tumors using long-read sequencing technology.

PEGylation of a Peptide-Based Amphiphilic Delivery Agent and Influence on Protein Delivery to Cells.

The cell membrane is a restrictive biological barrier, especially for large, charged molecules, such as proteins. The use of cell-penetrating peptides (CPPs) can facilitate the delivery of proteins, protein complexes, and peptides across the membrane by a variety of mechanisms that are all limited by endosomal sequestration. To improve CPP-mediated delivery, we previously reported the rapid and effective cytosolic delivery of proteins in vitro and in vivo by their coadministration with the peptide S10, which combines a CPP and an endosomal leakage domain. Amphiphilic peptides with hydrophobic properties, such as S10, can interact with lipids to destabilize the cell membrane, thus promoting cargo internalization or escape from endosomal entrapment. However, acute membrane destabilization can result in a dose-limiting cytotoxicity. In this context, the partial or transient deactivation of S10 by modification with methoxy poly(ethylene glycol) (mPEG; i.e., PEGylation) may provide the means to alter membrane destabilization kinetics, thereby attenuating the impact of acute permeabilization on cell viability. This study investigates the influence of PEGylation parameters (molecular weight, architecture, and conjugation chemistry) on the delivery efficiency of a green fluorescent protein tagged with a nuclear localization signal (GFP-NLS) and cytotoxicity on cells in vitro. Results suggest that PEGylation mostly interferes with adsorption and secondary structure formation of S10 at the cell membrane, and this effect is exacerbated by the mPEG molecular weight. This effect can be compensated for by increasing the concentration of conjugates prepared with lower molecular weight mPEG (5 to ∼20 kDa) but not for conjugates prepared with higher molecular weight mPEG (40 kDa). For conjugates prepared with moderate-to-high molecular weight mPEG (10 to 20 kDa), partial compensation of inactivation could be achieved by the inclusion of a reducible disulfide bond, which provides a mechanism to liberate the S10 from the polymer. Grafting multiple copies of S10 to a high-molecular-weight multiarmed PEG (40 kDa) improved GFP-NLS delivery efficiency. However, these constructs were more cytotoxic than the native peptide. Considering that PEGylation could be harnessed for altering the pharmacokinetics and biodistribution profiles of peptide-based delivery agents in vivo, the trends observed herein provide new perspectives on how to manipulate the membrane permeabilization process, which is an important variable for achieving delivery.

Heart-Brain 346-7 Score: the development and validation of a simple mortality prediction score for carbon monoxide poisoning utilizing deep learning.

INTRODUCTION: Acute mortality from carbon monoxide poisoning is 1-3%. The long-term mortality risk of survivors of carbon monoxide poisoning is doubled compared to age-matched controls. Cardiac involvement also increases mortality risk. We built a clinical risk score to identify carbon monoxide-poisoned patients at risk for acute and long-term mortality. METHODS: We performed a retrospective analysis. We identified 811 adult carbon monoxide-poisoned patients in the derivation cohort, and 462 adult patients in the validation cohort. We utilized baseline demographics, laboratory values, hospital charge transactions, discharge disposition, and clinical charting information in the electronic medical record in Stepwise Akaike's Information Criteria with Firth logistic regression to determine optimal parameters to create a prediction model. RESULTS: In the derivation cohort, 5% had inpatient or 1-year mortality. Three variables following the final Firth logistic regression minimized Stepwise Akaike's Information Criteria: altered mental status, age, and cardiac complications. The following predict inpatient or 1-year mortality: age > 67, age > 37 with cardiac complications, age > 47 with altered mental status, or any age with cardiac complications and altered mental status. The sensitivity of the score was 82% (95% confidence interval: 65-92%), the specificity was 80% (95% confidence interval: 77-83%), negative predictive value was 99% (95% confidence interval: 98-100%), positive predictive value 17% (95% confidence interval: 12-23%), and the area under the receiver operating characteristic curve was 0.81 (95% confidence interval: 0.74-0.87). A score above the cut-off point of -2.9 was associated with an odds ratio of 18 (95% confidence interval: 8-40). In the validation cohort (462 patients), 4% had inpatient death or 1-year mortality. The score performed similarly in the validation cohort: sensitivity was 72% (95% confidence interval: 47-90%), specificity was 69% (95% confidence interval: 63-73%), negative predictive value was 98% (95% confidence interval: 96-99%), positive predictive value was 9% (95% confidence interval: 5-15%) and the area under the receiver operating characteristic curve was 0.70 (95% confidence interval: 60%-81%). CONCLUSIONS: We developed and validated a simple, clinical-based scoring system, the Heart-Brain 346-7 Score to predict inpatient and long-term mortality based on the following: age > 67, age > 37 with cardiac complications, age > 47 with altered mental status, or any age with cardiac complications and altered mental status. With further validation, this score will hopefully aid decision-making to identify carbon monoxide-poisoned patients with higher mortality risk.

Microwave-Induced Transient Heating Accelerates Protein PEGylation.

PEGylation is one of the most widely employed strategies to increase the circulatory half-life of proteins and to reduce immune responses. However, conventional PEGylation protocols often require excess reagents and extended reaction times because of their inefficiency. This study demonstrates that a microwave-induced transient heating phenomenon can be exploited to significantly accelerate protein PEGylation and even increase the degree of PEGylation achievable beyond what is possible at room temperature. This can be accomplished under conditions that do not compromise protein integrity. Several PEGylation chemistries and proteins are tested, and mechanistic insight is provided. Under certain conditions, extremely high levels of PEGylation were achieved in a matter of minutes. Moreover, considering the significantly reduced reaction times, the microwave-induced transient heating concept was adapted for continuous flow manufacturing of bioconjugates.

CCL5 is a potential bridge between type 1 and type 2 inflammation in asthma.

BACKGROUND: Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. OBJECTIVE: We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation. METHODS: CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1high murine severe asthma model. RESULTS: Sputum CCL5 expression strongly correlated with T1 chemokines (P < .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5high participants had greater fractional exhaled nitric oxide (P = .009), blood eosinophils (P < .001), and sputum eosinophils (P = .001) in addition to sputum neutrophils (P = .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1high/T2variable/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P = .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation. CONCLUSION: CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.

The NOTCH-RIPK4-IRF6-ELOVL4 Axis Suppresses Squamous Cell Carcinoma.

Receptor-interacting serine/threonine protein kinase 4 (RIPK4) and its kinase substrate the transcription factor interferon regulatory factor 6 (IRF6) play critical roles in the development and maintenance of the epidermis. In addition, ourselves and others have previously shown that RIPK4 is a NOTCH target gene that suppresses the development of cutaneous and head and neck squamous cell carcinomas (HNSCCs). In this study, we used autochthonous mouse models, where the expression of Pik3caH1047R oncogene predisposes the skin and oral cavity to tumor development, and show that not only loss of Ripk4, but also loss of its kinase substrate Irf6, triggers rapid SCC development. In vivo rescue experiments using Ripk4 or a kinase-dead Ripk4 mutant showed that the tumor suppressive function of Ripk4 is dependent on its kinase activity. To elucidate critical mediators of this tumor suppressive pathway, we performed transcriptional profiling of Ripk4-deficient epidermal cells followed by multiplexed in vivo CRISPR screening to identify genes with tumor suppressive capabilities. We show that Elovl4 is a critical Notch-Ripk4-Irf6 downstream target gene, and that Elovl4 loss itself triggers SCC development. Importantly, overexpression of Elovl4 suppressed tumor growth of Ripk4-deficient keratinocytes. Altogether, our work identifies a potent Notch1-Ripk4-Irf6-Elovl4 tumor suppressor axis.

Overcoming PEG─Protein Mutual Repulsion to Improve the Efficiency of PEGylation.

Bioconjugation reactions, such as protein PEGylation, generally require excess reagents because of their inefficiency. Intriguingly, few reports have investigated the fundamental causes of this inefficiency. This study demonstrates that the excluded volume effect (EVE)─caused by the mutual repulsion of methoxy poly(ethylene glycol) (mPEG) and proteins under typical PEGylation conditions─causes proteins and protein-reactive mPEG (5 kDa) to self-associate into separate "protein-rich" and "mPEG-rich" nano-domains (i.e., soluble self-assemblies). To overcome this obstacle to reaction, "unreactive" low-molecular-weight mPEG was added as a co-solvent to promote the association between the larger protein and the reactive mPEG molecules by harnessing the same EVE. The near complete PEGylation of lysozyme could be achieved with close to stoichiometric amounts of reactive mPEG, and beneficial effects were observed for other proteins. Considering the general nature of the EVE (e.g., salting-out and PEGying-out), this study provides important perspectives on enhancing bioconjugation reactions, which are relevant to many nanoscale systems.

Consecutive Alkylation, "Click", and "Clip" Reactions for the Traceless Methionine-Based Conjugation and Release of Methionine-Containing Peptides.

"Click" reactions have revolutionized research in many areas of science. However, a disadvantage of the high stability of the Click product is that identifying simple treatments for cleanly dissociating the latter under the same guiding principles, i.e., a "Clip" reaction, remains a challenge. This study demonstrates that electron-deficient alkynes, conveniently installed on methionine residues, can participate in well-known Click (nucleophilic thiol-allene addition) and subsequent Clip reactions (radical thiol-ene addition). To illustrate this concept, a variety of bioconjugates (peptide-peptide; peptide-fluorophore; peptide-polymer; and peptide-protein) were prepared. Interestingly, the Clip reaction of these bioconjugates releases the original peptides concurrent with regeneration of their unmodified methionine residue, in minutes. Moreover, the conjugates demonstrate substantial stability toward endogenous levels of reactive species in bacteria, illustrating the potential for this chemistry in the biosciences. The reaction conditions employed in the Click and Clip steps are compatible with the preservation of the integrity of biomolecules/fluorophores and involve readily accessible reagents and the natural functional groups on peptides/proteins.

New Perspectives for Developing Therapeutic Bioconjugates of Metabolite-Depleting Enzymes: Lessons Learned Combating Glutamate Excitotoxicity.

Glutamate, the main excitatory neurotransmitter in the central nervous system, plays an essential role in several cognitive activities such as memorizing and learning. Excessive glutamate release and disturbance of glutamate homeostasis participates in multiple neuronal pathologies including cerebral ischemia (inadequate blood supply), traumatic brain injury (e.g., from a fall or an accident), multiple sclerosis, epilepsy, migraine, fetal hypoxia, or Alzheimer's disease. Attenuating excitotoxicity by, for example, targeting glutamate receptors has proved to be beneficial in animal models but has largely failed in clinical trials because of toxic side effects. New therapeutic concepts have been explored to reduce the excitotoxic effect caused by the excessive glutamate release by using or stimulating glutamate-depleting enzymes in the bloodstream. These enzymes indirectly act upon the brain by depleting glutamate in the bloodstream, which is believed to siphon it out of the brain. Recent studies have shown that bioconjugate approaches applied to such enzymes exacerbate this therapeutic effect but raise additional questions for future research. This Perspective provides an overview of lessons learned by our group when exploring bioconjugate approaches for combatting glutamate excitotoxicity as an illustration of how research on therapeutic bioconjugates is evolving.

Dual role for CXCR3 and CCR5 in asthmatic type 1 inflammation.

BACKGROUND: Many patients with severe asthma (SA) fail to respond to type 2 inflammation-targeted therapies. We previously identified a cohort of subjects with SA expressing type 1 inflammation manifesting with IFN-γ expression and variable type 2 responses. OBJECTIVE: We investigated the role of the chemotactic receptors C-X-C chemokine receptor 3 (CXCR3) and C-C chemokine receptor 5 (CCR5) in establishing type 1 inflammation in SA. METHODS: Bronchoalveolar lavage microarray data from the Severe Asthma Research Program I/II were analyzed for pathway expression and paired with clinical parameters. Wild-type, Cxcr3-/-, and Ccr5-/- mice were exposed to a type 1-high SA model with analysis of whole lung gene expression and histology. Wild-type and Cxcr3-/- mice were treated with a US Food and Drug Administration-approved CCR5 inhibitor (maraviroc) with assessment of airway resistance, inflammatory cell recruitment by flow cytometry, whole lung gene expression, and histology. RESULTS: A cohort of subjects with increased IFN-γ expression showed higher asthma severity. IFN-γ expression was correlated with CXCR3 and CCR5 expression, but in Cxcr3-/- and Ccr5-/- mice type 1 inflammation was preserved in a murine SA model, most likely owing to compensation by the other pathway. Incorporation of maraviroc into the experimental model blunted airway hyperreactivity despite only mild effects on lung inflammation. CONCLUSIONS: IFNG expression in asthmatic airways was strongly correlated with expression of both the chemokine receptors CXCR3 and CCR5. Although these pathways provide redundancy for establishing type 1 lung inflammation, inhibition of the CCL5/CCR5 pathway with maraviroc provided unique benefits in reducing airway hyperreactivity. Targeting this pathway may be a novel approach for improving lung function in individuals with type 1-high asthma.

Nanostructured Metal Borides for Energy-Related Electrocatalysis: Recent Progress, Challenges, and Perspectives.

The discovery of durable, active, and affordable electrocatalysts for energy-related catalytic applications plays a crucial role in the advancement of energy conversion and storage technologies to achieve a sustainable energy future. Transition metal borides (TMBs), with variable compositions and structures, present a number of interesting features including coordinated electronic structures, high conductivity, abundant natural reserves, and configurable physicochemical properties. Therefore, TMBs provide a wide range of opportunities for the development of multifunctional catalysts with high performance and long durability. This review first summarizes the typical structural and electronic features of TMBs. Subsequently, the various synthetic methods used thus far to prepare nanostructured TMBs are listed. Furthermore, advances in emerging TMB-catalyzed reactions (both theoretical and experimental) are highlighted, including the hydrogen evolution reaction, the oxygen evolution reaction, the oxygen reduction reaction, the carbon dioxide reduction reaction, the nitrogen reduction reaction, the methanol oxidation reaction, and the formic acid oxidation reaction. Finally, challenges facing the development of TMB electrocatalysts are discussed, with focus on synthesis and energy-related catalytic applications, and some potential strategies/perspectives are suggested as well, which will profit the design of more efficient TMB materials for application in future energy conversion and storage devices.

Noninvasive, label-free, and quantitative monitoring of lipase kinetics using terahertz emission technology.

Enzymes catalyze chemical transformations of great importance in many fields, and analysis of the rate of these transformations is equally important. The latter are typically monitored using surrogate substrates that produce quantifiable optical signals, owing to limitations associated with "label-free" techniques that could be used to monitor the transformation of original substrate molecules. In this study, terahertz (THz) emission technology is used as a noninvasive and label-free technique to monitor the kinetics of lipase-induced hydrolysis of several substrate molecules (including the complex substrate whole cow's milk) and horseradish peroxidase-catalyzed oxidation of o-phenylenediamine in the presence of H2 O2 . This technique was found to be quantitative, and kinetic parameters are compared to those obtained by proton NMR spectroscopy or UV/Vis spectroscopy. This study sets the stage for investigating THz emission technology as a tool for research and development involving enzymes, and for monitoring industrial processes in the food, cosmetic, detergent, pharmaceutical, and biodiesel sectors.

Immune responses and exacerbations in severe asthma.

Asthma as a clinical entity manifests with a broad spectrum of disease severity. Unlike milder asthma, severe disease is poorly controlled by inhaled corticosteroids, the current standard of care. Transcriptomic data, along with patient characteristics and response to biologics show that though Type 2 (T2) immune response remains an integral feature of asthma, additional molecular and immunologic factors may play important roles in pathogenesis. Mechanisms of T2 development, cellular sources of T2 cytokines and their relationship to additional immune pathways concurrently activated may distinguish several different subphenotypes, and perhaps endotypes of asthma, with differential response to non-specific and targeted anti-inflammatory therapies. Recent data have also associated non-T2 cytokines derived from T cells, particularly IFN-γ, and epithelial mediators with severe asthma. These topics and their relationships to acute asthma exacerbations are discussed in this review.

Sustained blood glutamate scavenging enhances protection in ischemic stroke.

Stroke is a major cause of morbidity, mortality, and disability. During ischemic stroke, a marked and prolonged rise of glutamate concentration in the brain causes neuronal cell death. This study explores the protective effect of a bioconjugate form of glutamate oxaloacetate transaminase (hrGOT), which catalyzes the depletion of blood glutamate in the bloodstream for ~6 days following a single administration. When treated with this bioconjugate, a significant reduction of the infarct volume and a better retention of sensorimotor function was observed for ischemic rats compared to those treated with saline. Moreover, the equivalent dose of native hrGOT yielded similar results to the saline treated group for some tests. Targeting the bioconjugate to the blood-brain-barrier did not improve its performance. The data suggest that the bioconjugates draw glutamate out of the brain by displacing homeostasis between the different glutamate pools of the body.

Comparative study on the inactivation of MS2 and M13 bacteriophages using energetic femtosecond lasers.

Femtosecond (fs) laser irradiation techniques are emerging tools for inactivating viruses that do not involve ionizing radiation. In this work, the inactivation of two bacteriophages representing protective capsids with different geometric constraints, that is, the near-spherical MS2 (with a diameter of 27 nm) and the filamentous M13 (with a length of 880 nm) is compared using energetic visible and near-infrared fs laser pulses with various energies, pulse durations, and exposure times. Intriguingly, the results show that inactivation using 400 nm lasers is substantially more efficient for MS2 compared to M13. In contrast, using 800 nm lasers, M13 was slightly more efficiently inactivated. For both viruses, the genome was exposed to a harmful environment upon fs-laser irradiation. However, in addition to the protection of the genome, the metastable capsids differ in many properties required for stepwise cell entry that may explain their dissimilar behavior after (partial) disassembly. For MS2, the dominant mechanism of fs-laser inactivation was the aggregation of the viral capsid proteins, whereas aggregation did not affect M13 inactivation, suggesting that the dominant mechanism of M13 inactivation was related to breaking of secondary protein links.

Plasmonic Enhancement of Two-Photon Excitation Fluorescence by Colloidal Assemblies of Very Small AuNPs Templated on M13 Phage.

In this study, an engineered M13 bacteriophage was examined as a biological template to create a well-defined spacing between very small gold nanoparticles (AuNPs 3-13 nm). The effect of the AuNP particle size on the enhancement of the nonlinear process of two-photon excitation fluorescence (2PEF) was investigated. Compared to conventional (one-photon) microscopy techniques, such nonlinear processes are less susceptible to scattering given that the density of background-scattered photons is too low to generate a detectable signal. Besides this, the use of very small AuNPs in 2PEF microscopy becomes more advantageous because individual "isolated" AuNPs of this size do not sufficiently enhance 2PEF to produce a detectable signal, resulting in even less background signal. To investigate the 2PEF of the AuNP-M13 assemblies, a variety of sample preparation approaches are tested, and surface-enhanced Raman spectroscopy (SERS) is employed to study the strength of plasmon coupling within the gaps of AuNPs assembled on the M13 template. Results indicate that assemblies prepared with 9-13 nm AuNP were able to clearly label Escherichia coli cells and produce a 2PEF signal that was orders of magnitude higher than the isolated AuNP (below the threshold of detection). This study thus provides a better understanding of the opportunities and limitations relevant to the use of such small AuNPs within colloidal plasmonic assemblies, for applications in biodetection or as imaging contrast agents.

Expression of SARS-CoV-2 receptor ACE2 and coincident host response signature varies by asthma inflammatory phenotype.

BACKGROUND: More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019. OBJECTIVE: We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection. METHODS: Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2-correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets. RESULTS: Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes. CONCLUSIONS: ACE2 expression is linked to upregulation of viral response genes in a subset of type 2-low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell-activating factors may therefore be of benefit in a subset of patients.

Towards extracellular matrix normalization for improved treatment of solid tumors.

It is currently challenging to eradicate cancer. In the case of solid tumors, the dense and aberrant extracellular matrix (ECM) is a major contributor to the heterogeneous distribution of small molecule drugs and nano-formulations, which makes certain areas of the tumor difficult to treat. As such, much research is devoted to characterizing this matrix and devising strategies to modify its properties as a means to facilitate the improved penetration of drugs and their nano-formulations. This contribution presents the current state of knowledge on the composition of normal ECM and changes to ECM that occur during the pathological progression of cancer. It also includes discussion of strategies designed to modify the composition/properties of the ECM as a means to enhance the penetration and transport of drugs and nano-formulations within solid tumors. Moreover, a discussion of approaches to image the ECM, as well as ways to monitor changes in the ECM as a function of time are presented, as these are important for the implementation of ECM-modifying strategies within therapeutic interventions. Overall, considering the complexity of the ECM, its variability within different tissues, and the multiple pathways by which homeostasis is maintained (both in normal and malignant tissues), the available literature - while promising - suggests that improved monitoring of ECM remodeling in vivo is needed to harness the described strategies to their full potential, and match them with an appropriate chemotherapy regimen.