Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade.

BACKGROUND: Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing. METHODS: ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies. RESULTS: Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells. CONCLUSIONS: These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.

Discovery of BAY-390, a Selective CNS Penetrant Chemical Probe as Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonist.

Transient receptor potential ankyrin 1 (TRPA1) is a voltage-dependent, ligand-gated ion channel, and activation thereof is linked to a variety of painful conditions. Preclinical studies have demonstrated the role of TRPA1 receptors in a broad range of animal models of acute, inflammatory, and neuropathic pain. In addition, a clinical study using the TRPA1 antagonist GRC-17536 (Glenmark Pharmaceuticals) demonstrated efficacy in a subgroup of patients with painful diabetic neuropathy. Consequently, there is an increasing interest in TRPA1 inhibitors as potential analgesics. Herein, we report the identification of a fragment-like hit from a high-throughput screening (HTS) campaign and subsequent optimization to provide a novel and brain-penetrant TRPA1 inhibitor (compound 18, BAY-390), which is now being made available to the research community as an open-source in vivo probe.

Insulin-like growth factor 1 reduces coronary atherosclerosis in pigs with familial hypercholesterolemia.

Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque's fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis, consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress, and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis showed that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1's effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.

Vertebral Artery Interventions: A Comprehensive Updated Review.

Patients with posterior circulation ischemia due to vertebral artery stenosis account for 20 to 25% of ischemic strokes and have an increased risk of recurrent stroke. In patients treated with medical therapy alone, the risk of recurrence is particularly increased in the first few weeks after symptoms occur, with an annual stroke rate of 10 to 15%. Additionally, obstructive disease of the vertebrobasilar system carries a worse prognosis, with a 30% mortality at 2-years if managed medically without additional surgical or endovascular intervention. Percutaneous transluminal angioplasty and stenting of symptomatic vertebral artery stenosis are promising options widely used in clinical practice with good technical results; however, the improved clinical outcome has been examined in various clinical trials without a sufficient sample size to conclusively determine whether stenting is better than medical therapy. Surgical revascularization is an alternative approach for the treatment of symptomatic vertebral artery stenosis that carries a 10-20% mortality rate. Despite the advances in medical therapy and endovascular and surgical options, symptomatic vertebral artery stenosis continues to impose a high risk of stroke recurrence with associated high morbidity and mortality. This review aims to provide a focused update on the percutaneous treatment of vertebral artery stenosis, its appropriate diagnostic approach, and advances in medical therapies.

Self-diffusion in inhomogeneous granular shearing flows.

In this Letter, we discuss how flow inhomogeneity affects the self-diffusion behavior in granular flows. Whereas self-diffusion scalings have been well characterized in the past for homogeneous shearing, the effect of shear localization and nonlocality of the flow has not been studied. We, therefore, present measurements of self-diffusion coefficients in discrete numerical simulations of steady, inhomogeneous, and collisional shearing flows of nearly identical, frictional, and inelastic spheres. We focus on a wide range of dense solid volume fractions, that correspond to geophysical and industrial shearing flows that are dominated by collisional interactions. We compare the measured values first with a scaling based on shear rate and, then, on a scaling based on the granular temperature. We find that the latter does much better than the former in collapsing the data. The results lay the foundations of diffusion models for inhomogeneous shearing flows, which should be useful in treating problems of mixing and segregation.

Watchman FLX Implantation for Challenging Left Atrial Appendage Anatomy: Case-Based Discussion.

Left atrial appendage (LAA) occlusion devices provided an acceptable and valid alternative to anticoagulation among patients with atrial fibrillation who carry high bleeding risk. Watchman device is non-inferior to oral anticoagulation to prevent cerebrovascular accidents. The presence of a longer distal portion of the older generation Watchman led to exclusion of patients with prohibitive anatomy of the LAA such as chicken-wing morphology or shallow LAA. Watchman FLX provides a wider range of sizes and can be implanted with complex anatomy or shallow LAA. In the case series, we discuss 3 patients with challenging LAA anatomy that underwent successful Watchman FLX implantation.

How vertical oscillatory motion above a saturated sand bed leads to heap formation.

We show how oscillations in fluid flow over a fluid-saturated and porous sediment bed leads to the development of a bedform. To understand the role of pressure fluctuations on the bed associated with flow oscillations, we analyze how the flow penetrates into and through the bed. We then calculate the corresponding vertical pressure gradients within the bed that tend to expand the bed along the vertical direction. When these pressure gradients are large enough, they facilitate small irreversible rearrangements of the grains within the bed, and so cause granular creep. We conjecture that this granular creep alternates with jamming to produce a granular ratchet that slowly lifts the surface of the bed locally where pressure gradients dominate, and depresses the surface where shear stresses dominate. We observe that the shape of the resulting heap exhibits a constant characteristic width. The height of this heap evolves approximately as the square root of time, in agreement with dimensional arguments predicated on a coarse-grained viscous deformation of the bed. The surface of the heap contracts initially with the square root of time, consistent with an incompressible analysis of the flow of grains within the heap. Near its peak the heap grows due to a dilatation of the bed, to inward radial flux, or to a combination of the two.

Self-diffusion scalings in dense granular flows.

We report on measurements of self-diffusion coefficients in discrete numerical simulations of steady, homogeneous, collisional shearing flows of nearly identical, frictional, inelastic spheres. We focus on a range of relatively high solid volume fractions that are important in those terrestrial gravitational shearing flows that are dominated by collisional interactions. Diffusion over this range of solid fraction has not been well characterized in previous studies. We first compare the measured values with an empirical scaling based on shear rate previously proposed in the literature, and highlight the presence of anisotropy and the solid fraction dependence. We then compare the numerical measurements with those predicted by the kinetic theory for shearing flows of inelastic spheres and offer an explanation for why the measured and predicted values differ.

Evolutionary temperature compensation of carbon fixation in marine phytoplankton.

The efficiency of carbon sequestration by the biological pump could decline in the coming decades because respiration tends to increase more with temperature than photosynthesis. Despite these differences in the short-term temperature sensitivities of photosynthesis and respiration, it remains unknown whether the long-term impacts of global warming on metabolic rates of phytoplankton can be modulated by evolutionary adaptation. We found that respiration was consistently more temperature dependent than photosynthesis across 18 diverse marine phytoplankton, resulting in universal declines in the rate of carbon fixation with short-term increases in temperature. Long-term experimental evolution under high temperature reversed the short-term stimulation of metabolic rates, resulting in increased rates of carbon fixation. Our findings suggest that thermal adaptation may therefore have an ameliorating impact on the efficiency of phytoplankton as primary mediators of the biological carbon pump.

A low-mass planet candidate orbiting Proxima Centauri at a distance of 1.5 AU.

Our nearest neighbor, Proxima Centauri, hosts a temperate terrestrial planet. We detected in radial velocities evidence of a possible second planet with minimum mass m c sin i c = 5.8 ± 1.9M ⊕ and orbital period P c = 5.21 - 0.22 + 0.26 years. The analysis of photometric data and spectro-scopic activity diagnostics does not explain the signal in terms of a stellar activity cycle, but follow-up is required in the coming years for confirming its planetary origin. We show that the existence of the planet can be ascertained, and its true mass can be determined with high accuracy, by combining Gaia astrometry and radial velocities. Proxima c could become a prime target for follow-up and characterization with next-generation direct imaging instrumentation due to the large maximum angular separation of ~1 arc second from the parent star. The candidate planet represents a challenge for the models of super-Earth formation and evolution.

Chest computed tomography for staging renal tumours: validation and simplification of a risk prediction model from a large contemporary retrospective cohort.

OBJECTIVES: To externally validate a nomogram recently proposed by Larcher et al. (BJU Int. 2017; 120: 490) and to develop a simplified model with comparable accuracy to guide on the need for staging chest computed tomography (CT) for patients with new renal masses. PATIENTS AND METHODS: We analysed the data of 1082 consecutive patients with unilateral enhancing renal masses referred to urology multidisciplinary team meetings at two centres between 2011 and 2017. All patients underwent a staging chest CT at diagnosis. We fitted multivariable logistic regression models and tested the Larcher model performance using area under the receiver-operating curve (AUC), calibration and decision curve analysis. RESULTS: Forty-two patients (3.9%) had a positive chest CT. The Larcher nomogram had an AUC of 83.8% (95% confidence interval [CI] 77.1-90.6), but was only moderately well calibrated (calibration-in-the-large = -0.61, slope = 0.82). Specifically, the nomogram overestimated the risk of positive chest CT, and the magnitude of miscalibration increased with increasing predicted risks. Using a stepwise backward approach, a new model was developed including tumour size, nodal stage and systemic symptoms. Compared with the Larcher model, the new model had a similar AUC (82.7% [95% CI 75.5-90.0]), but improved calibration and clinical net benefit. The predicted risk of positive chest CT was <1% in the low-risk group and 1.9-79.9% in the high-risk group. CONCLUSION: The Larcher nomogram is an accurate prediction tool that was moderately well calibrated with our dataset. However, our simplified model has similar accuracy and uses more objective variables available from referral, so may be easier to incorporate into clinical practice. The low-risk group from our model (tumour size ≤4 cm and no systemic symptoms) had a risk of positive chest CT <1%, suggesting these patients may forego chest CT.

Efficacy and Safety of Transcarotid Transcatheter Aortic Valve Replacement: A Systematic Review.

BACKGROUND: In patients who are not suitable for traditional access routes for transcatheter aortic valve replacement (TAVR) due to severe peripheral vascular disease (PVD) or prohibitive surgical risk, carotid artery (CA) access is an emerging route for TAVR. This study represents the most up to date on outcomes of carotid access TAVR. METHODS: A systematic review was conducted as per the Preferred Reporting Instructions for Systematic Reviews and Meta-analysis (PRISMA). We performed a thorough electronic search through Pubmed, SCOPUS and Embase databases. Statistical analyses were performed using SPSS version 24 (IBM Corporation, Armonk, New York, USA). RESULTS: A total of 15 non-randomized studies were included in this systematic review comprising of patients that received TAVR via 4 vascular access sites, transcarotid (TC) (N = 1035), transfemoral (TF) (N = 1116), transapical (TAP) (N = 307), transaortic (TAO) (N = 176) and transaxillary (TAX) (N = 90). In the Transcarotid cases, device success was achieved in 95.6% of patients (n = 748). The 30-day and 1-yr mortality was 4.2% and 10.5% respectively. 15.3% of patients required new pacemaker implantation. In-hospital stroke or TIA occurred in 4% of cases. 30-day stroke or TIA occurred in 5% of cases. There were no hemorrhagic strokes. 30-day Mortality was significantly higher in the Transaortic group (12.1%) compared to the Transcarotid group (2.6%) [RR = 2.93 95% CI = 1.15-7.58; p = 0.027]. There were no differences in outcomes between the Transcarotid group and the Transapical or Transaxillary groups. CONCLUSION: The most contemporary data on Carotid access TAVR shows impressive device success, low rates of stroke and pacemaker implantation and an acceptable 30-day and 1-year mortality. 30-day mortality was significantly lower in TC compared to TAO patients.

Percutaneous endovascular abdominal aneurysm repair: State-of-the art.

Endovascular repair of abdominal aortic aneurysms emerged initially as an alternative treatment strategy for patients considered to be inoperable or high risk for surgery. The evolution of endovascular techniques has made this technology a safe and less invasive alternative to open surgery for patients with suitable aortic anatomy. This manuscript reviews the current state of the art for endovascular AAA repair techniques, clinical outcomes, guideline recommendations, and future applications.

The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality.

Tissue-resident memory CD8+ T (Trm) cells share core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic, and epigenetic regulation of Trm cell and TIL development and function is largely undefined. Here, we found that the transcription factor Bhlhe40 was specifically required for Trm cell and TIL development and polyfunctionality. Local PD-1 signaling inhibited TIL Bhlhe40 expression, and Bhlhe40 was critical for TIL reinvigoration following anti-PD-L1 blockade. Mechanistically, Bhlhe40 sustained Trm cell and TIL mitochondrial fitness and a functional epigenetic state. Building on these findings, we identified an epigenetic and metabolic regimen that promoted Trm cell and TIL gene signatures associated with tissue residency and polyfunctionality. This regimen empowered the anti-tumor activity of CD8+ T cells and possessed therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights into the local regulation of Trm cell and TIL function.

Erodible, granular beds are fragile.

Geophysical flows that involve the transport of grains and the shearing of colloids and non-Brownian suspensions often take place above a substrate composed of the same particles that can be incorporated into the flow. Despite the importance of understanding such erodible beds to the phrasing of appropriate boundary conditions for the solution of continuum models, a rigorous definition of the erodible bed and the constitutive relations for the stresses within it are still lacking. Here, we use discrete-element simulations to show that the intense, intermittent forming and breaking of contact chains marks the transition to the erodible bed at a critical solid volume fraction, as in shear jamming of steady, homogeneous flows. However, the compressible, collisional flow that confines the bed is not strong enough to insure the stability of the contact network, resulting in a bulk stiffness that is three orders of magnitude less than in shear jamming.

Bedforms Produced on a Particle Bed by Vertical Oscillations of a Plate.

We describe a new mechanism that produces bedforms and characterize the conditions under which it operates. The mechanism is associated with pressure gradients generated in a fluid saturated particle bed by a plate oscillating in the water above it. These vertical pressure gradients cause oscillatory bed failure. This facilitates particle displacement in its interior and transport at and near its surface that contribute to the formation of a heap under the plate. Flows over erodible beds generally cause shear stresses on the bed and these induce bed failure. Failure driven by pressure gradients is different from this. We report on bedforms in a bed of glass beads associated with such fluctuating pressure gradients. We measure the development of the profiles of heaps as a function of time and determine the tangential and normal motion of areas on the beds surface and estimate the depth of penetration of the tangential transport. The measurements compare favorably with a simple model that describes the onset of failure due to oscillations in pressure.

Unintentional removal of a developing permanent premolar during primary molar extraction: a 10-year case report.

A 14-year-old girl underwent extraction of an ankylosed primary left second molar as requested by her orthodontist. The developing mandibular left second premolar (tooth 20) was unintentionally removed during extraction of the primary molar. Immediate measures were taken to reimplant tooth 20. Recall appointments over the next 10 years included monitoring of tooth 20. The patient also was followed up closely by her orthodontist during this time. Tooth 20 was monitored for proper eruption, root development, and pulpal vitality. The tooth erupted normally, and the results of pulp testing continued to be within normal limits over the course of 10 years (with the exception of a single higher electric pulp test reading than that for adjacent teeth). Root formation was completed and appeared to be within normal limits. Pulpal calcification also occurred. At the most recent recall, the tooth remained asymptomatic. Monitoring will continue during the patient's regular recall appointments. The success of this case 10 years after reimplantation supports quick action to optimize the potential for long-term clinical success. The fact that tooth 20 was at a developmental stage also likely had a favorable impact on the outcome of this case.

Myosin efflux promotes cell elongation to coordinate chromosome segregation with cell cleavage.

Chromatid segregation must be coordinated with cytokinesis to preserve genomic stability. Here we report that cells clear trailing chromatids from the cleavage site by undergoing two phases of cell elongation. The first phase relies on the assembly of a wide contractile ring. The second phase requires the activity of a pool of myosin that flows from the ring and enriches the nascent daughter cell cortices. This myosin efflux is a novel feature of cytokinesis and its duration is coupled to nuclear envelope reassembly and the nuclear sequestration of the Rho-GEF Pebble. Trailing chromatids induce a delay in nuclear envelope reassembly concomitant with prolonged cortical myosin activity, thus providing forces for the second elongation. We propose that the modulation of cortical myosin dynamics is part of the cellular response triggered by a "chromatid separation checkpoint" that delays nuclear envelope reassembly and, consequently, Pebble nuclear sequestration when trailing chromatids are present at the midzone.Chromatid segregation must be coordinated with cytokinesis to preserve genomic stability. Here the authors show that cells clear trailing chromatids from the cleavage site in a two-step cell elongation and demonstrate the role of myosin efflux in the second phase.