The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn.

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception.

Unrestrained cleavage of Roquin-1 by MALT1 induces spontaneous T cell activation and the development of autoimmunity.

Constitutive activation of the MALT1 paracaspase in conventional T cells of Malt1TBM/TBM (TRAF6 Binding Mutant = TBM) mice causes fatal inflammation and autoimmunity, but the involved targets and underlying molecular mechanisms are unknown. We genetically rendered a single MALT1 substrate, the RNA-binding protein (RBP) Roquin-1, insensitive to MALT1 cleavage. These Rc3h1Mins/Mins mice showed normal immune homeostasis. Combining Rc3h1Mins/Mins alleles with those encoding for constitutively active MALT1 (TBM) prevented spontaneous T cell activation and restored viability of Malt1TBM/TBM mice. Mechanistically, we show how antigen/MHC recognition is translated by MALT1 into Roquin cleavage and derepression of Roquin targets. Increasing T cell receptor (TCR) signals inactivated Roquin more effectively, and only high TCR strength enabled derepression of high-affinity targets to promote Th17 differentiation. Induction of experimental autoimmune encephalomyelitis (EAE) revealed increased cleavage of Roquin-1 in disease-associated Th17 compared to Th1 cells in the CNS. T cells from Rc3h1Mins/Mins mice did not efficiently induce the high-affinity Roquin-1 target IκBNS in response to TCR stimulation, showed reduced Th17 differentiation, and Rc3h1Mins/Mins mice were protected from EAE. These data demonstrate how TCR signaling and MALT1 activation utilize graded cleavage of Roquin to differentially regulate target mRNAs that control T cell activation and differentiation as well as the development of autoimmunity.

Exposure to endocrine-disrupting plasticisers and lung function in children and adolescents: A systematic review and meta-analysis.

Exposure to endocrine-disrupting plasticisers (EDPs), such as phthalates and bisphenols, has been associated with reduced lung function in children and adolescents. However, the existing literature yields conflicting results. This systematic review and meta-analysis aimed to assess the epidemiologic evidence investigating the association between EDP exposure and lung function in children and adolescents. A comprehensive search of five databases identified 25 relevant studies. We employed a random-effects meta-analysis on spirometry measures. The effect size of interest was the change in lung function in standard deviation (SD) units resulting from a two-fold increase in exposure levels. We found that certain phthalates marginally reduced lung function in children. Forced expiratory volume in 1 s (FEV1) was reduced by a two-fold increase in mono-benzyl phthalate (MBzP) (ß = -0.025 SD, 95%CI: 0.042, -0.008), mono-ethyl-oxo-hexyl phthalate (MEOHP) (ß = -0.035 SD, 95%CI: 0.057, -0.014) and mono-carboxy-nonyl phthalate (MCNP) (ß = -0.024 SD, 95%CI: 0.05, -0.003). Forced vital capacity (FVC) was decreased by a two-fold increase in MBzP (ß = -0.022 SD, 95%CI: 0.036, -0.008) and MEOHP (ß = -0.035 SD, 95%CI: 0.057, -0.014) levels. A two-fold increase in MCNP levels was associated with lower FEV1/FVC (ß = -0.023 SD, 95%CI: 0.045, -0.001). Furthermore, a two-fold increase in MEOHP levels reduced forced mid-expiratory flow (FEF25-75) (ß = -0.030 SD, 95%CI: 0.055, -0.005) and peak expiratory flow (PEF) (ß = -0.056 SD, 95%CI: 0.098, -0.014). Notably, associations were more pronounced in males. Given the potential for reverse causation bias, the association between childhood exposure to EDPs and lung function remains uncertain. Overall, our meta-analysis showed small reductions in lung function with higher phthalate exposure. However, future studies are warranted in younger age groups.

The Clinical Applications of Left Atrial Strain: A Comprehensive Review.

Left atrial (LA) strain imaging, which measures the deformation of the LA using speckle-tracing echocardiography (STE), has emerged recently as an exciting tool to help provide diagnostic and prognostic information for patients with a broad range of cardiovascular (CV) pathologies. Perhaps due to the LA's relatively thin-walled architecture compared with the more muscular structure of the left ventricle (LV), functional changes in the left atrium often precede changes in the LV, making LA strain (LAS) an earlier marker for underlying pathology than many conventional echocardiographic parameters. LAS imaging is typically divided into three phases according to the stage of the cardiac cycle: reservoir strain, which is characterized by LA filling during systole; conduit strain, which describes LA deformation during passive LV filling; and booster strain, which provides information on the LA atrium during LA systole in late ventricular diastole. While additional large-population studies are still needed to further solidify the role of LAS in routine clinical practice, this review will discuss the current evidence of its use in different pathologies and explore the possibilities of its applications in the future.

TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity.

Mast cells and basophils are main drivers of allergic reactions and anaphylaxis, for which prevalence is rapidly increasing. Activation of these cells leads to a tightly controlled release of inflammatory mediators stored in secretory granules. The release of these granules is dependent on intracellular calcium (Ca2+) signals. Ca2+ release from endolysosomal compartments is mediated via intracellular cation channels, such as two-pore channel (TPC) proteins. Here, we uncover a mechanism for how TPC1 regulates Ca2+ homeostasis and exocytosis in mast cells in vivo and ex vivo. Notably, in vivo TPC1 deficiency in mice leads to enhanced passive systemic anaphylaxis, reflected by increased drop in body temperature, most likely due to accelerated histamine-induced vasodilation. Ex vivo, mast cell-mediated histamine release and degranulation was augmented upon TPC1 inhibition, although mast cell numbers and size were diminished. Our results indicate an essential role of TPC1 in endolysosomal Ca2+ uptake and filling of endoplasmic reticulum Ca2+ stores, thereby regulating exocytosis in mast cells. Thus, pharmacological modulation of TPC1 might blaze a trail to develop new drugs against mast cell-related diseases, including allergic hypersensitivity.

Should employees be required to return to the office?

Expectations for where and when work should take place changed radically for workers through the COVID-19 global pandemic. Now that COVID-19 no longer poses a significant safety threat for the typical worker, executives at many organizations are now expecting their employees to return to the office. The issues seem to revolve around perceived barriers to culture, collaboration, and innovation when employees are not present together in the office. Yet, many employees strongly resist a return to the office. They have experienced well-being, productivity, and autonomy benefits from a remote and hybrid work arrangement. Rigid return to office rules feel outdated, manipulative, and controlling to many employees. In the current article we explore expert opinion on the issues of culture, collaboration, and innovation. Specifically, we ask whether a return to office will improve these aspects of organizational functioning and we outline evidence that leads us to provide an answer these questions. Executives and managers may find these expert opinions useful in their consideration of workplace policies and guidelines for the use of remote, hybrid, and in office work arrangements in their organizations.

Decorin evokes reversible mitochondrial depolarization in carcinoma and vascular endothelial cells.

Decorin, a small leucine-rich proteoglycan with multiple biological functions, is known to evoke autophagy and mitophagy in both endothelial and cancer cells. Here, we investigated the effects of soluble decorin on mitochondrial homeostasis using live cell imaging and ex vivo angiogenic assays. We discovered that decorin triggers mitochondrial depolarization in triple-negative breast carcinoma, HeLa, and endothelial cells. This bioactivity was mediated by the protein core in a time- and dose-dependent manner and was specific for decorin insofar as biglycan, the closest homolog, failed to trigger depolarization. Mechanistically, we found that the bioactivity of decorin to promote depolarization required the MET receptor and its tyrosine kinase. Moreover, two mitochondrial interacting proteins, mitostatin and mitofusin 2, were essential for downstream decorin effects. Finally, we found that decorin relied on the canonical mitochondrial permeability transition pore to trigger tumor cell mitochondrial depolarization. Collectively, our study implicates decorin as a soluble outside-in regulator of mitochondrial dynamics.

Oncosuppressive roles of decorin through regulation of multiple receptors and diverse signaling pathways.

Decorin is a stromal-derived prototype member of the small leucine-rich proteoglycan gene family. In addition to its functions as a regulator of collagen fibrillogenesis and TGF-ß activity soluble decorin acts as a pan-receptor tyrosine kinase (RTK) inhibitor. Decorin binds to various RTKs including EGFR HER2 HGFR/Met VEGFR2 TLR and IGFR. Although the molecular mechanism for the action of decorin on these receptors is not entirely elucidated overall decorin evokes transient activation of these receptors with suppression of downstream signaling cascades culminating in growth inhibition followed by their physical downregulation via caveosomal internalization and degradation. In the case of Met decorin leads to decreased ß-catenin signaling pathway and growth suppression. As most of these RTKs are responsible for providing a growth advantage to cancer cells the result of decorin treatment is oncosuppression. Another decorin-driven mechanism to restrict cancer growth and dissemination is by impeding angiogenesis via vascular endothelial growth factor receptor 2 (VEGFR2) and the concurrent activation of protracted endothelial cell autophagy. In this review we will dissect the multiple roles of decorin in cancer biology and its potential use as a next-generation protein-based adjuvant therapy to combat cancer.

Sorption of Strontium to Uraninite and Uranium(IV)-Silicate Nanoparticles.

Spent nuclear fuel contains both uranium (U) and high yield fission products, including strontium-90 (90Sr), a key radioactive contaminant at nuclear facilities. Both U and 90Sr will be present where spent nuclear fuel has been processed, including in storage ponds and tanks. However, the interactions between Sr and U phases under ambient conditions are not well understood. Over a pH range of 4-14, we investigate Sr sorption behavior in contact with two nuclear fuel cycle relevant U(IV) phases: nano-uraninite (UO2) and U(IV)-silicate nanoparticles. Nano-UO2 is a product of the anaerobic corrosion of metallic uranium fuel, and UO2 is also the predominant form of U in ceramic fuels. U(IV)-silicates form stable colloids under the neutral to alkaline pH conditions highly relevant to nuclear fuel storage ponds and geodisposal scenarios. In sorption experiments, Sr had the highest affinity for UO2, although significant Sr sorption also occurred to U(IV)-silicate phases at pH ≥ 6. Extended X-ray absorption fine structure (EXAFS) spectroscopy, transmission electron microscopy, and desorption data for the UO2 system suggested that Sr interacted with UO2 via a near surface, highly coordinated complex at pH ≥ 10. EXAFS measurements for the U(IV)-silicate samples showed outer-sphere Sr sorption dominated at acidic and near-neutral pH with intrinsic Sr-silicates forming at pH ≥ 12. These complex interactions of Sr with important U(IV) phases highlight a largely unrecognized control on 90Sr mobility in environments of relevance to spent nuclear fuel management and storage.

Hydrotalcite Colloidal Stability and Interactions with Uranium(VI) at Neutral to Alkaline pH.

In the United Kingdom, decommissioning of legacy spent fuel storage facilities involves the retrieval of radioactive sludges that have formed as a result of corrosion of Magnox nuclear fuel. Retrieval of sludges may re-suspend a colloidal fraction of the sludge, thereby potentially enhancing the mobility of radionuclides including uranium. The colloidal properties of the layered double hydroxide (LDH) phase hydrotalcite, a key product of Magnox fuel corrosion, and its interactions with U(VI) are of interest. This is because colloidal hydrotalcite is a potential transport vector for U(VI) under the neutral-to-alkaline conditions characteristic of the legacy storage facilities and other nuclear decommissioning scenarios. Here, a multi-technique approach was used to investigate the colloidal stability of hydrotalcite and the U(VI) sorption mechanism(s) across pH 7-11.5 and with variable U(VI) surface loadings (0.01-1 wt %). Overall, hydrotalcite was found to form stable colloidal suspensions between pH 7 and 11.5, with some evidence for Mg2+ leaching from hydrotalcite colloids at pH ≤ 9. For systems with U present, >98% of U(VI) was removed from the solution in the presence of hydrotalcite, regardless of pH and U loading, although the sorption mode was affected by both pH and U concentrations. Under alkaline conditions, U(VI) surface precipitates formed on the colloidal hydrotalcite nanoparticle surface. Under more circumneutral conditions, Mg2+ leaching from hydrotalcite and more facile exchange of interlayer carbonate with the surrounding solution led to the formation of uranyl carbonate species (e.g., Mg(UO2(CO3)3)2-(aq)). Both X-ray absorption spectroscopy (XAS) and luminescence analysis confirmed that these negatively charged species sorbed as both outer- and inner-sphere tertiary complexes on the hydrotalcite surface. These results demonstrate that hydrotalcite can form pseudo-colloids with U(VI) under a wide range of pH conditions and have clear implications for understanding the uranium behavior in environments where hydrotalcite and other LDHs may be present.

Characteristics and progression of childhood-onset and adult-onset eosinophilic esophagitis.

BACKGROUND AND AIM: The prevalence and incidence of eosinophilic esophagitis (EoE) has been increasing over recent years. However, the natural history remains incompletely understood particularly the differences in disease characteristics and progression of childhood-onset and adult-onset EoE. The aim of this study was to evaluate the disease characteristics and progression of childhood-onset and adult-onset EoE. METHODS: A cross-sectional, questionnaire-based study, on 87 adults and 67 children from 2 major tertiary hospitals in South Australia was conducted. Data of those who were diagnosed with EoE between 1999 and 2018 were collected and correlated with medical records. RESULTS: Of the 87 adults with EoE, 34 (39%) were diagnosed at the age of < 18 years (childhood-onset EoE). Reflux symptoms were more common in childhood-onset EoE, whereas asthma was more common in adult-onset EoE. The median duration of symptoms prior to diagnosis of EoE was > 1-4 years in childhood-onset disease (44%) and ≥ 10 years in adult-onset disease (34%). Food impaction was significantly more common on initial presentation in those with adult-onset EoE, whereas weight loss was more common in childhood-onset EoE. At the time of questionnaire, regurgitation, abdominal pain, and bloating were more common in childhood-onset EoE. Those with childhood-onset EoE were more likely to have multiple symptoms at questionnaire when compared with their adult-onset counterparts. In both groups, 15% (5/34 childhood-onset EoE and 8/53 adult-onset EoE) were asymptomatic at the time of questionnaire. CONCLUSION: Childhood-onset EoE appears to be a progressive disease from childhood to adulthood, however with more inflammatory-type symptoms post transition compared to those with adult-onset EoE.

Oxacillin plus ertapenem rapidly clears persistent left ventricular assist device-related methicillin-susceptible Staphylococcus aureus bacteremia.

There is an increasing use of left ventricular assist devices (LVADs) as bridge to transplantation or permanent destination therapy in the heart failure patient population. Infection remains a common complication in LVADs, with Gram-positive skin flora as predominant pathogens implicated, including Staphylococcus aureus. While there is emerging evidence for synergistic antibiotic combinations with methicillin resistant S. aureus, there remains a significant gap in the literature for persistent methicillin susceptible S. aureus bacteremia. In this article, we describe the first successful treatment of persistent LVAD-related bacteremia with salvage oxacillin plus ertapenem. The salvage therapy described here must be balanced by the risks for toxicity, impact on resistance, microbiota disruption, drug shortages, and patient costs. This combination warrants further evaluation in the clinical setting to better establish its role in our expanding patient population.

Human-Autonomy Teaming: A Review and Analysis of the Empirical Literature.

OBJECTIVE: We define human-autonomy teaming and offer a synthesis of the existing empirical research on the topic. Specifically, we identify the research environments, dependent variables, themes representing the key findings, and critical future research directions. BACKGROUND: Whereas a burgeoning literature on high-performance teamwork identifies the factors critical to success, much less is known about how human-autonomy teams (HATs) achieve success. Human-autonomy teamwork involves humans working interdependently toward a common goal along with autonomous agents. Autonomous agents involve a degree of self-government and self-directed behavior (agency), and autonomous agents take on a unique role or set of tasks and work interdependently with human team members to achieve a shared objective. METHOD: We searched the literature on human-autonomy teaming. To meet our criteria for inclusion, the paper needed to involve empirical research and meet our definition of human-autonomy teaming. We found 76 articles that met our criteria for inclusion. RESULTS: We report on research environments and we find that the key independent variables involve autonomous agent characteristics, team composition, task characteristics, human individual differences, training, and communication. We identify themes for each of these and discuss the future research needs. CONCLUSION: There are areas where research findings are clear and consistent, but there are many opportunities for future research. Particularly important will be research that identifies mechanisms linking team input to team output variables.

Catabolic degradation of endothelial VEGFA via autophagy.

Extracellular matrix-evoked angiostasis and autophagy within the tumor microenvironment represent two critical, but unconnected, functions of the small leucine-rich proteoglycan, decorin. Acting as a partial agonist of vascular endothelial growth factor 2 (VEGFR2), soluble decorin signals via the energy sensing protein, AMP-activated protein kinase (AMPK), in the autophagic degradation of intracellular vascular endothelial growth factor A (VEGFA). Here, we discovered that soluble decorin evokes intracellular catabolism of endothelial VEGFA that is mechanistically independent of mTOR, but requires an autophagic regulator, paternally expressed gene 3 (PEG3). We found that administration of autophagic inhibitors such as chloroquine or bafilomycin A1, or depletion of autophagy-related 5 (ATG5), results in accumulation of intracellular VEGFA, indicating that VEGFA is a basal autophagic substrate. Mechanistically, decorin increased the VEGFA clearance rate by augmenting autophagic flux, a process that required RAB24 member RAS oncogene family (RAB24), a small GTPase that facilitates the disposal of autophagic compartments. We validated these findings by demonstrating the physiological relevance of this process in vivo Mice starved for 48 h exhibited a sharp decrease in overall cardiac and aortic VEGFA that could be blocked by systemic chloroquine treatment. Thus, our findings reveal a unified mechanism for the metabolic control of endothelial VEGFA for autophagic clearance in response to decorin and canonical pro-autophagic stimuli. We posit that the VEGFR2/AMPK/PEG3 axis integrates the anti-angiogenic and pro-autophagic bioactivities of decorin as the molecular basis for tumorigenic suppression. These results support future therapeutic use of decorin as a next-generation protein therapy to combat cancer.

Family presence during resuscitation: a needs assessment of education, policy, and opinion in Canada.

PURPOSE: Family presence during resuscitation (FPDR) has been widely endorsed. Nevertheless, there is limited information available on current education and training used to support FPDR implementation, including that of relevant policy. Understanding the current state of FPDR educational opportunities, policies, and practices across Canadian hospitals is crucial to advancing and standardizing these within our medical community. Our objective was to identify the current and desired state of education and policy on FPDR, as well as current practices and opinions of Canadian healthcare professionals. METHODS: We selected questionnaire topics and employed a modified Delphi consensus technique using a group of subject matter experts in resuscitation. We contacted a stratified sample of Canadian healthcare professionals via select listservs and surveyed the cohort using RedCAP™. We used descriptive statistics and conducted quantitative analyses to describe and test for significant differences among groups. RESULTS: In total, 635 surveys were completed. Only 46.3% of participants reported ever attending an educational opportunity involving learning how to manage FPDR; however, 92% wanted training. Only 11% knew if they had an official FPDR policy in their current hospital but 62.9% indicated they wanted one. In support of FPDR, 88% agreed that family members should be allowed to be present during a resuscitation. CONCLUSION: While opinions are mostly positive towards FPDR, there exists a gap between the current and desired state of education and policy supporting it within Canada.

RéSUMé: OBJECTIF: La présence de la famille pendant la réanimation est largement appuyée. Néanmoins, il existe peu d'informations disponibles sur l'éducation et la formation actuelles utilisées pour soutenir la mise en œuvre de la présence de la famille pendant la réanimation, y compris l'information touchant les politiques pertinentes. Il est essentiel de comprendre l'état actuel des opportunités de formation, des politiques et des pratiques en matière de présence familiale pendant la réanimation dans l'ensemble des hôpitaux canadiens afin de les faire progresser et de les standardiser au sein de la communauté médicale. Notre objectif était de déterminer l'état actuel et souhaité de la formation et des politiques en matière de présence familiale pendant la réanimation, ainsi que les pratiques et les opinions actuelles des professionnels de la santé canadiens. MéTHODE: Nous avons sélectionné un questionnaire et utilisé une technique de consensus Delphi modifiée afin d'obtenir les réponses d'un groupe d'experts en matière de réanimation. Nous avons communiqué avec un échantillon stratifié de professionnels de la santé canadiens par l'entremise de gestionnaires de liste sélectionnés et avons sondé notre cohorte à l'aide de l'application RedCAP™. Nous avons utilisé des statistiques descriptives et effectué des analyses quantitatives pour décrire et tester les différences significatives entre les groupes. RéSULTATS: Au total, 635 sondages ont été complétés. Seuls 46,3 % des participants ont déclaré avoir déjà assisté à une opportunité de formation portant sur l'apprentissage de la gestion de la présence familiale pendant la réanimation; toutefois, 92 % des répondants ont déclaré désirer une formation. Seulement 11 % des répondants savaient s'il existait une politique officielle de présence de la famille pendant la réanimation dans leur hôpital, mais 62,9 % ont indiqué qu'ils souhaitaient en avoir une. En faveur de la présence familiale, 88 % étaient d'avis que les membres de la famille devraient être autorisés à être présents lors d'une réanimation. CONCLUSION: Bien que les opinions soient pour la plupart positives à l'égard de la présence familiale pendant la réanimation, il existe un écart entre l'état actuel et souhaité de la formation et des politiques qui l'appuient au Canada.

Microrheology of DNA hydrogels.

A key objective in DNA-based material science is understanding and precisely controlling the mechanical properties of DNA hydrogels. We perform microrheology measurements using diffusing wave spectroscopy (DWS) to investigate the viscoelastic behavior of a hydrogel made of Y-shaped DNA (Y-DNA) nanostars over a wide range of frequencies and temperatures. We observe a clear liquid-to-gel transition across the melting temperature region for which the Y-DNA bind to each other. Our measurements reveal a cross-over between the elastic [Formula: see text] and loss modulus [Formula: see text] around the melting temperature [Formula: see text] of the DNA building blocks, which coincides with the systems percolation transition. This transition can be easily shifted in temperature by changing the DNA bond length between the Y shapes. Using bulk rheology as well, we further show that, by reducing the flexibility between the Y-DNA bonds, we can go from a semiflexible transient network to a more energy-driven hydrogel with higher elasticity while keeping the microstructure the same. This level of control in mechanical properties will facilitate the design of more sensitive molecular sensing tools and controlled release systems.

Hacking teamwork in health care: Addressing adverse effects of ad hoc team composition in critical care medicine.

BACKGROUND: The continued need for improved teamwork in all areas of health care is widely recognized. The present article reports on the application of a hackathon to the teamwork problems specifically associated with ad hoc team formation in rapid response teams. PURPOSES: Hackathons-problem-solving events pioneered in computer science-are on the rise in health care management. The focus of these events tends to be on medical technologies, however, with calls for improvements in management practices as general recommendations. The hackathon reported here contributes to health care management practice by addressing improvements in teamwork as the focal problem. METHODOLOGY: The hackathon event took place over 2.5 days in conjunction with an academic conference focused on group research. Three teams comprised of practicing healthcare professionals, academic researchers and students developed solutions to problems of ad hoc team formation in rapid response teams. FINDINGS: The event fulfilled several goals. The teams produced three distinct, yet complementary solutions that were backed by both field-based experience and solid research evidence. The event provided the opportunity for two-way translation of research and practice through direct collaboration among key stakeholders. The hackathon produced long term effects through establishing or strengthening collaborations, dissemination of the ideas through presentations, workshops, and publications, and changes in participantsâ work practices. PRACTICE IMPLICATION: The event demonstrated that hackathons, classically focused on technology, can also offer a spur to innovation around organizational processes. The article provides advice for organizing other hackathons focused on similar topics. The solutions offered by the participants in the event yields the clear insight that multipronged solutions for emergency-oriented teamwork are needed. The hackathon highlighted the scaled of collaboration and effort needed to tackle the many complexities in health care that impact outcomes for providers, patients, and health organizations.

Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy.

CD27 is a costimulatory molecule that provides a complementary target to the PD-1/PD-L1 checkpoint axis on T cells. Combining a CD27 agonist antibody with PD-1/PD-L1 blockade has shown synergistic antitumor activity in preclinical models, which led to clinical studies of the combination in cancer patients. We theorized that coupling CD27 costimulation with PD-1/PD-L1 blockade in a bispecific antibody (BsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced CD27 activation by cross-linking through PD-L1 and Fc receptors. To test this approach, we developed CDX-527, a tetravalent PD-L1xCD27 IgG1-scFv BsAb. CDX-527 potently inhibits PD-1 signaling and induces CD27-mediated T cell costimulation through PD-L1 cross-linking. In mixed lymphocyte reaction assays, CDX-527 is more potent than the combination of the parental antibodies, suggesting that cross-linking through both Fc receptors and PD-L1 results in enhanced CD27 agonist activity. CDX-527 was shown to mediate effector function against tumor cells overexpressing either CD27 or PD-L1. In human CD27 transgenic mice, we observed that antigen-specific T cell responses to a vaccine are greatly enhanced with a surrogate PD-L1xCD27 BsAb. Furthermore, the BsAb exhibits greater antitumor activity than the combination of the parental antibodies in a syngeneic lymphoma model. A pilot study of CDX-527 in cynomolgus macaques confirmed a mAb-like pharmacokinetic profile without noted toxicities. These studies demonstrate that CDX-527 effectively combines PD-1 blockade and CD27 costimulation into one molecule that is more potent than combination of the parental antibodies providing the rationale to advance this BsAb toward clinical studies in cancer patients.

Management of ventricular arrhythmias in patients with LVAD.

PURPOSE OF REVIEW: Left ventricular assist devices (LVADs) have extended the life expectancy of patients with heart failure. The hemodynamic support afforded by LVADs in this population has also resulted in patients having prolonged ventricular arrhythmias. The purpose of this article is to review the mechanisms of ventricular arrhythmias in LVADs and the available management strategies. RECENT FINDINGS: Recent evidence suggests that prolonged ventricular arrhythmias may result in increased mortality in patients with LVADs. SUMMARY: Successful management of ventricular arrhythmias in patients with LVAD requires interdisciplinary collaboration between electrophysiology and heart failure specialists. Medical management, including changes to LVAD changes, heart failure medication management, and antiarrhythmics constitute the initial treatment for ventricular arrhythmias. Surgical or endocardial ablation are reasonable options if VAs are refractory.

On the role of flexibility in linker-mediated DNA hydrogels.

Three-dimensional DNA networks, composed of tri- or higher valent nanostars with sticky, single-stranded DNA overhangs, have been previously studied in the context of designing thermally responsive, viscoelastic hydrogels. In this work, we use linker-mediated gels, where the sticky ends of two trivalent nanostars are connected through the complementary sticky ends of a linear DNA duplex. We can design this connection to be either rigid or flexible by introducing flexible, non-binding bases. The additional flexibility provided by these non-binding bases influences the effective elasticity of the percolating gel formed at low temperatures. Here we show that by choosing the right length of the linear duplex and non-binding flexible joints, we obtain a completely different phase behaviour to that observed for rigid linkers. In particular, we use dynamic light scattering as a microrheological tool to monitor the self-assembly of DNA nanostars with linear linkers as a function of temperature. While we observe classical gelation when using rigid linkers, the presence of flexible joints leads to a cluster fluid with a much-reduced viscosity. Using both the oxDNA model and a coarse-grained simulation to investigate the nanostar-linker topology, we hypothesise on the possible structure formed by the DNA clusters. Moreover, we present a systematic study of the strong viscosity increase of aqueous solutions in the presence of these DNA building blocks.