We sought to identify potential radiologic and serologic markers of pancreatic tumor response to therapy, using pathologic major response (pMR) as the objective endpoint.
We previously demonstrated ...that a pMR to preoperative therapy, defined as detection of <5% viable cancer cells in the surgical specimen on histopathological analysis, is an important prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC).
Pretreatment and posttreatment computed tomography scans of consecutive patients who received preoperative chemotherapy and/or (chemo)radiation before pancreatectomy for PDAC between January 2010 and December 2018 were rereviewed. Response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, other radiographic changes in tumor size and anatomic extent, and posttreatment CA 19-9 levels were compared between patients who did and did not have a pMR on final histopathologic analysis of their surgical specimens.
A total of 290 patients with localized PDAC underwent pancreatectomy between 2010 and 2018 after receiving preoperative chemotherapy (n = 36; 12%), (chemo)radiation (n = 87; 30%), or both (n = 167; 58%). Among them, 28 (10%) experienced pMR, including 9 (3.1%) who experienced pathologic complete response. On multivariable logistic regression, low posttreatment CA 19-9 level, RECIST partial response, and reduction in tumor volume were confirmed to be independently associated with pMR (P < 0.01).
We identified serologic and radiographic indicators of pMR that could help inform the delivery of preoperative therapy to patients with PDAC.
During development, progenitors progress through transition states. The cardiac epicardium contains progenitors of essential non-cardiomyocytes. The Hippo pathway, a kinase cascade that inhibits the ...Yap transcriptional co-factor, controls organ size in developing hearts. Here, we investigated Hippo kinases Lats1 and Lats2 in epicardial diversification. Epicardial-specific deletion of Lats1/2 was embryonic lethal, and mutant embryos had defective coronary vasculature remodeling. Single-cell RNA sequencing revealed that Lats1/2 mutant cells failed to activate fibroblast differentiation but remained in an intermediate cell state with both epicardial and fibroblast characteristics. Lats1/2 mutant cells displayed an arrested developmental trajectory with persistence of epicardial markers and expanded expression of Yap targets Dhrs3, an inhibitor of retinoic acid synthesis, and Dpp4, a protease that modulates extracellular matrix (ECM) composition. Genetic and pharmacologic manipulation revealed that Yap inhibits fibroblast differentiation, prolonging a subepicardial-like cell state, and promotes expression of matricellular factors, such as Dpp4, that define ECM characteristics.
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•Single-cell transcriptomic analysis of 18,166 cells from E13.5 and E14.5 heart•Characterization of rare cardiac cell types•Lats1/2 are required for subepicardial transition into cardiac fibroblasts•Lats1/2 are required for proper extracellular milieu and coronary vessel formation
The epicardium, the outermost cell layer of the heart, contains progenitors that contribute to non-cardiomyocytes. How epicardial progenitors transition to a mature cell type is unknown. Xiao et al. demonstrate that Hippo kinases Lats1/2 promote epicardial-fibroblast transition, which is essential for maintaining proper extracellular milieu and coronary vessel development.
Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing ...pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.
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•Autoreactive CD27- IgD- CXCR5- CD11c+ (DN2) B cells expand in lupus patients•DN2 cells derive from naive cells and are poised to generate plasmablasts•DN2 B cells are hyper-responsive to Toll-like receptor-7 signaling•The properties of SLE DN2 B cells stem from distinct transcriptional networks
The role of extrafollicular B cells in human systemic lupus is unknown. Jenks et al. define the main components of this pathway and its prominence in severe disease. Its activation is mediated by hyper-responsiveness to Toll-like receptor-7 and leads to the generation of autoreactive antibody-secreting plasmablasts.
Living in an enriched environment with complex physical and social stimulation leads to improved cognitive and metabolic health. In white fat, enrichment induced the upregulation of the brown fat ...cell fate determining gene Prdm16, brown fat-specific markers, and genes involved in thermogenesis and β-adrenergic signaling. Moreover, pockets of cells with prototypical brown fat morphology and high UCP1 levels were observed in the white fat of enriched mice associated with resistance to diet-induced obesity. Hypothalamic overexpression of BDNF reproduced the enrichment-associated activation of the brown fat gene program and lean phenotype. Inhibition of BDNF signaling by genetic knockout or dominant-negative trkB reversed this phenotype. Our genetic and pharmacologic data suggest a mechanism whereby induction of hypothalamic BDNF expression in response to environmental stimuli leads to selective sympathoneural modulation of white fat to induce “browning” and increased energy dissipation.
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► A complex environment (EE) leads to decreased adiposity and resistance to obesity ► EE switches white fat to brown fat and thereby increases energy expenditure ► Activation of a hypothalamic-adipocyte axis mediates the browning of white fat
Physically transient forms of electronics enable unique classes of technologies, ranging from biomedical implants that disappear through processes of bioresorption after serving a clinical need to ...internet-of-things devices that harmlessly dissolve into the environment following a relevant period of use. Here, we develop a sustainable manufacturing pathway, based on ultrafast pulsed laser ablation, that can support high-volume, cost-effective manipulation of a diverse collection of organic and inorganic materials, each designed to degrade by hydrolysis or enzymatic activity, into patterned, multi-layered architectures with high resolution and accurate overlay registration. The technology can operate in patterning, thinning and/or cutting modes with (ultra)thin eco/bioresorbable materials of different types of semiconductors, dielectrics, and conductors on flexible substrates. Component-level demonstrations span passive and active devices, including diodes and field-effect transistors. Patterning these devices into interconnected layouts yields functional systems, as illustrated in examples that range from wireless implants as monitors of neural and cardiac activity, to thermal probes of microvascular flow, and multi-electrode arrays for biopotential sensing. These advances create important processing options for eco/bioresorbable materials and associated electronic systems, with immediate applicability across nearly all types of bioelectronic studies.
Exploring robust catalysts for water oxidation in acidic electrolyte is challenging due to the limited material choice. Iridium (Ir) is the only active element with a high resistance to the acid ...corrosion during water electrolysis. However, Ir is rare, and its large-scale application could only be possible if the intrinsic activity of Ir could be greatly enhanced. Here, a pseudo-cubic SrCo
Ir
O
perovskite, containing corner-shared IrO6 octahedrons, is designed. The Ir in the SrCo
Ir
O
catalyst shows an extremely high intrinsic activity as reflected from its high turnover frequency, which is more than two orders of magnitude higher than that of IrO
. During the electrochemical cycling, a surface reconstruction, with Sr and Co leaching, over SrCo
Ir
O
occurs. Such reconstructed surface region, likely contains a high amount of structural domains with corner-shared and under-coordinated IrO
octahedrons, is responsible for the observed high activity.
The suspension plasma spray (SPS) process was used to produce coatings from yttria-stabilized zirconia (YSZ) powders with median diameters of 15 μm and 80 nm. The powder-ethanol suspensions made with ...15-μm diameter YSZ particles formed coatings with microstructures typical of the air plasma spray (APS) process, while suspensions made with 80-nm diameter YSZ powder yielded a coarse columnar microstructure not observed in APS coatings. To explain the formation mechanisms of these different microstructures, a hypothesis is presented which relates the dependence of YSZ droplet flight paths on droplet diameter to variations in deposition behavior. The thermal conductivity (
k
th
) of columnar SPS coatings was measured as a function of temperature in the as-sprayed condition and after a 50 h, 1200 °C heat treatment. Coatings produced from suspensions containing 80 nm YSZ particles at powder concentrations of 2, 8, and 11 wt.% exhibited significantly different
k
th
values. These differences are connected to microstructural variations between the SPS coatings produced by the three suspension formulations. Heat treatment increased the
k
th
of the coatings generated from suspensions containing 2 and 11 wt.% of 80 nm YSZ powder, but this
k
th
increase was less than has been observed in APS coatings.
Colorectal cancer (CRC) development has been associated with increased proportions of Bacteroides fragilis and certain Streptococcus, Fusobacterium, and Peptostreptococcus species in the intestinal ...microbiota. We investigated associations between bacteremia from specific intestinal microbes and occurrence of CRC.
We performed a retrospective study after collecting data on 13,096 adult patients (exposed group) in Hong Kong hospitalized with bacteremia (identified by blood culture test) without a previous diagnosis of cancer from January 1, 2006 through December 31, 2015. We collected data on intestinal microbes previously associated with CRC (genera Bacteroides, Clostridium, Filifactor, Fusobacterium, Gemella, Granulicatella, Parvimonas, Peptostreptococcus, Prevotella, Solobacterium, and Streptococcus). Clinical information, including patient demographics, comorbid medical conditions, date of bacteremia, and bacterial species identified, were collected. The incidence of biopsy-proved CRC was compared between the exposed and unexposed (patients without bacteremia matched for age, sex, and comorbidities) groups.
The risk of CRC was increased in patients with bacteremia from B fragilis (hazard ratio HR = 3.85, 95% CI = 2.62–5.64, P = 5.5 × 10−12) or Streptococcus gallolyticus (HR = 5.73, 95% CI = 2.18–15.1, P = 4.1 × 10−4) compared with the unexposed group. In addition, the risk of CRC was increased in patients with bacteremia from Fusobacterium nucleatum (HR = 6.89, 95% CI = 1.70–27.9, P = .007), Peptostreptococcus species (HR = 3.06, 95% CI = 1.47–6.35, P = .003), Clostridium septicum (HR = 17.1, 95% CI = 1.82–160, P = .013), Clostridium perfringens (HR = 2.29, 95% CI = 1.16–4.52, P = .017), or Gemella morbillorum (HR = 15.2, 95% CI = 1.54–150, P = .020). We observed no increased risk in patients with bacteremia caused by microbes not previously associated with colorectal neoplasms.
In a retrospective analysis of patients hospitalized for bacteremia, we associated later diagnosis of CRC with B fragilis and S gallolyticus and other intestinal microbes. These bacteria might have entered the bloodstream from intestinal dysbiosis and perturbed barrier function. These findings support a model in which specific members of the intestinal microbiota promote colorectal carcinogenesis. Clinicians should evaluate patients with bacteremia from these species for neoplastic lesions in the colorectum.
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Outdoor air pollution is a major killer worldwide and the fourth largest contributor to the burden of disease in China. China is the most populous country in the world and also has the largest number ...of air pollution deaths per year, yet the spatial resolution of existing national air pollution estimates for China is generally relatively low. We address this knowledge gap by developing and evaluating national empirical models for China incorporating land-use regression (LUR), satellite measurements, and universal kriging (UK). Land use, traffic and meteorological variables were included for model building. We tested the resulting models in several ways, including (1) comparing models developed using forward variable selection vs. partial least squares (PLS) variable reduction, (2) comparing models developed with and without satellite measurements, and with and without UK, and (3) 10-fold cross-validation (CV), Leave-One-Province-Out CV (LOPO-CV), and Leave-One-City-Out CV (LOCO-CV). Satellite data and kriging are complementary in making predictions more accurate: kriging improved the models in well-sampled areas; satellite data substantially improved performance at locations far away from monitors. Variable-selection models performed similarly to PLS models in 10-fold CV, but better in LOPO-CV. Our best models employed forward variable selection and UK, with 10-fold CV R2 of 0.89 (for both 2014 and 2015) for PM2.5 and of 0.73 (year-2014) and 0.78 (year-2015) for NO2. Population-weighted concentrations during 2014–2015 decreased for PM2.5 (58.7 μg/m3 to 52.3 μg/m3) and NO2 (29.6 μg/m3 to 26.8 μg/m3). We produced the first high resolution national LUR models for annual-average concentrations in China. Models were applied on 1 km grid to support future research. In 2015, >80% of the Chinese population lived in areas that exceeded the Chinese national PM2.5 standard, 35 μg/m3. Results here will be publicly available and may be useful for epidemiology, risk assessment, and environmental justice research.
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•First high spatial resolution national LUR models for both NO2 and PM2.5 in China•Satellite data and kriging are complementary in making predictions more accurate.•Variable selection models perform similar or better than PLS models.•1 km2 resolution prediction maps will be publicly available for future research.
Particle breakage alters particle-scale properties of granular soils including particle size, shape, and contact conditions, and changes macroscale properties including soil compressibility, shear ...strength, and permeability. This study monitors the crushing of natural quartz sands under one-dimensional compression with in situ X-ray tomography, i.e., X-ray scans during loading. We use the assembly-scale and particle-scale images to characterize particle failure patterns, e.g., chipping, major splitting, and comminution. Image processing and analysis enable us to determine the failure patterns around the yield stress, and the influence of initial density and particle morphology on the particle survival probability. We further quantify the degree of particle breakage with fractal dimension, breakage factor, and specific surface. Particle shape and coordination number both show a scale-dependent evolution pattern.
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