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The cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for priming adaptive antitumour immunity through antigen-presenting cells (APCs). Natural agonists, such as cyclic dinucleotides (CDNs), activate the cGAS-STING pathway, but their clinical translation is impeded by poor cytosolic entry and serum stability, low specificity and rapid tissue clearance. Here we developed an ultrasound (US)-guided cancer immunotherapy platform using nanocomplexes composed of 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) electrostatically bound to biocompatible branched cationic biopolymers that are conjugated onto APC-targeting microbubbles (MBs). The nanocomplex-conjugated MBs engaged with APCs and efficiently delivered cGAMP into the cytosol via sonoporation, resulting in activation of cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This bridging of innate and adaptive immunity inhibited tumour growth in both localized and metastatic murine cancer models. Our findings demonstrate that targeted local activation of STING in APCs under spatiotemporal US stimulation results in systemic antitumour immunity and improves the therapeutic efficacy of checkpoint blockade, thus paving the way towards novel image-guided strategies for targeted immunotherapy of cancer.

To assess the effectiveness and safety of combined pulsed-dye laser (PDL) and NAFL for treatment of surgical scars.PDL and NAFL have not been compared to healing by time alone.Randomized controlled, single-blinded clinical trial at an urban, university hospital. Healthy adults' status post skin surgery with primary closure were randomized to either 3 sessions of combination PDL and NAFL every 2 to 8 weeks, or control of no treatment. At baseline and 36-week follow-up, Patient and observer Scar Assessment Scale and Scar Cosmesis Assessment and Rating were completed by participants and blinded physicians. The primary outcome was scar improvement, as measured by the score difference over time.Of 76 participants, 52 completed the study (July 2017 to June 2019). No severe adverse events were reported. Patient and observer Scar Assessment Scale assessments demonstrated improvement in total score in the laser group compared to controls, as reported by patients [mean difference (standard deviation), laser: 12.86 (6.91) vs control: 7.25 (6.34); P = 0.004] and blinded physicians [18.32 (8.69) vs 13.08 (9.63); P = 0.044]. Patients observed a greater improvement in scar thickness [3.68 (2.04) vs 1.88 (1.85); P = 0.002] and stiffness [3.57 (2.78) vs 1.50 (2.11); P = 0.004] with lasers, and physicians reported greater improvement in vascularity [3.71 (1.98) vs 1.71 (1.52); P = 0.0002]. The live Scar Cosmesis Assessment and Rating subscore for erythema improved significantly with lasers [1.04 (0.79) vs 0.42 (0.50); P = 0.001].Combined PDL and NAFL resulted in scar improvement. Scar thickness, stiffness, and erythema were improved.ClinicalTrials.gov (NCT03057964).

Background Treatment options for patients with melanoma brain metastasis (MBM) have changed significantly in the last decade. Few studies have evaluated changes in outcomes and factors associated with survival in MBM patients over time. The aim of this study is to evaluate changes in clinical features and overall survival (OS) for MBM patients. Methods Patients diagnosed with MBMs from 1/1/2009 to 12/31/2013 (Prior Era; PE) and 1/1/2014 to 12/31/2018 (Current Era; CE) at The University of Texas MD Anderson Cancer Center were included in this retrospective analysis. The primary outcome measure was OS. Log-rank test assessed differences between groups; multivariable analyses were performed with Cox proportional hazards models and recursive partitioning analysis (RPA). Results A total of 791 MBM patients (PE, n = 332; CE, n = 459) were included in analysis. Median OS from MBM diagnosis was 10.3 months (95% CI, 8.9–12.4) and improved in the CE vs PE (14.4 vs 10.3 months, P Conclusions OS and factors associated with OS have changed for MBM patients. This information can inform contemporary patient management and clinical investigations.

Background A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline. Methods In this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment. Results The APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014). Conclusions Patients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

The incidence of liver cirrhosis is increasing worldwide. Patients with cirrhosis are generally at a higher risk of harbouring hepatic and non-hepatic malignancies, including bladder cancer, likely due to the presence of related risk factors such as smoking. Cirrhosis can complicate both the operative and non-surgical management of bladder cancer. For example, cirrhotic patients undergoing abdominal surgery generally demonstrate worse postoperative outcomes, and chemotherapy in patients with cirrhosis often requires dose reduction due to its direct hepatotoxic effects and reduced hepatic clearance. Multiple other considerations in the peri-operative management for cirrhosis patients with muscle-invasive bladder cancer must be taken into account to optimize outcomes in these patients. Unfortunately, the current literature specifically related to the treatment of cirrhotic bladder cancer patients remains sparse. We aim to review the literature on treatment considerations for this patient population with respect to perioperative, surgical, and adjuvant management.

Nodule formation after autologous fat grafting to the breast is the most common complication. In the reconstructive population, this generates significant patient anxiety and presents a diagnostic challenge. The authors characterized palpable nodule occurrence after autologous fat grafting in breast reconstruction and compared benign versus malignant nodule characteristics.Chart review of the senior author's experience with breast fat grafting was performed. Data extracted included demographics, intraoperative details, nodule data, radiographic characteristics, and biopsy results. Logistic regression identified risk factors for nodule formation. Unpaired t tests and Fisher exact tests compared characteristics of benign versus malignant nodules.In total, 775 breasts were identified that underwent 1158 fat grafting procedures, of which 67 (8.6 percent) developed palpable nodules. Sonographic characterization of nodules included presumed fat necrosis (38.2 percent), benign lesions (27.6 percent), presumed oil cysts (17.1 percent), indeterminate (8.9 percent), and concerning for malignancy (8.1 percent). Lesions concerning for malignancy were more often irregular (10.0 percent versus 0 to 2.9 percent of benign nodules) and more often larger than 0.8 cm in greatest dimension (80 percent versus 42.9 to 61.8 percent of benign nodules). Six patients developed a palpable local recurrence. Malignant nodules tended to be larger (1.45 cm versus 0.70 cm; p = 0.03), were more often vascular (50 percent versus 3.8 percent; p = 0.03), and tended to occur later (17.5 months versus 10.0 months; p = 0.60). Benign nodules occurred in the setting of larger fat graft volumes (64.2 cc versus 40.0 cc; p = 0.008).This study provides the first comparison of radiographic and clinical characteristics between benign and malignant palpable nodules after autologous fat grafting in breast reconstruction.Risk, III.

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer's disease.

Quick and reliable mass testing of infected people is an effective tool for the contingency of SARS-CoV-2. During the COVID-19 pandemic, Point-of-Care (POC) tests using Loop-Mediated Isothermal Amplification (LAMP) arose as a useful diagnostic tool. LAMP tests are a robust and fast alternative to Polymerase Chain Reaction (PCR), and their isothermal property allows easy incorporation into POC platforms. The main drawback of using colorimetric LAMP is the reported short-term stability of the pre-mixed reagents, as well as the relatively high rate of false-positive results. Also, low-magnitude amplification can produce a subtle color change, making it difficult to discern a positive reaction. This paper presents Hilab Molecular, a portable device that uses the Internet of Things and Artificial Intelligence to pre-analyze colorimetric data. In addition, we established manufacturing procedures to increase the stability of colorimetric RT-LAMP tests. We show that ready-to-use reactions can be stored for up to 120 days at −20 °C. Furthermore, we validated both the Hilab Molecular device and the Hilab RT-LAMP test for SARS-CoV-2 using 581 patient samples without any purification steps. We achieved a sensitivity of 92.93% and specificity of 99.42% (samples with CT ≤ 30) when compared to RT-qPCR.

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington’s disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined in silico and in vitro cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model. In particular, not only APQ reduced H3K9me3 levels in the striatum but it also improved motor function and neuropathological symptoms such as neuronal size and activity in HD transgenic (YAC128) mice with minimal toxicity. Using H3K9me3-ChIP and genome-wide sequencing, we also confirmed that APQ modulates H3K9me3-landscaped epigenomes in YAC128 mice. These data provide that APQ, a novel small molecule SETDB1 inhibitor, coordinates H3K9me-dependent heterochromatin remodelling and can be an epigenetic drug for treating HD, leading with hope in clinical trials of HD., Graphical Abstract

1. Moulting is a natural physiological process in birds when they shed their old feathers and replace them with new ones, and it is followed by reproductive quiescence resulting in reduced egg production. Different birds undergo moulting at different points in their life. Some birds have seasonal moulting while some moult at the end of their breeding cycle. This review will mainly focus on moulting practices associated with commercial layer birds because, in all other bird types, this is not managed.2. Commercial farms commonly analyse the cost-benefit ratio to decide the time and method to adopt for moulting. Commercial layer farms adopt different practices to force birds out of moult and restart the production cycle. Animal welfare groups consider this as stressful and against animal welfare, raising questions about the ethics of this practice.3. Many studies have been conducted using complete or partial feed withdrawal and non-feed withdrawal programs to measure their effectiveness in maintaining animal welfare, economy, and post-moult performance in mind.4. Animal welfare should not be compromised during moulting. The United States Egg Producers and other such groups from the United Kingdom and Europe have decided to sell eggs produced only through a non-feed withdrawal moulting programs.

Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer's disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H2O2) originated from monoamine oxidase B in severe reactive astrocytes causes glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which are significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2--induced pathological features of AD in GiDs are consistently recapitulated in a three-dimensional culture AD model, virus-infected APP/PS1 mice and the brains of patients with AD. Our study identifies H2O2 from severe but not mild reactive astrocytes as a key determinant of neurodegeneration in AD.

The nematic phase in iron based superconductors (IBSs) has attracted attention with a notion that it may provide important clue to the superconductivity. A series of angle-resolved photoemission spectroscopy (ARPES) studies were performed to understand the origin of the nematic phase. However, there is lack of ARPES study on LaFeAsO nematic phase. Here, we report the results of ARPES studies of the nematic phase in LaFeAsO. Degeneracy breaking between the $$d_{xz}$$ d xz and $$d_{yz}$$ d yz hole bands near the $$\Gamma$$ Γ and M point is observed in the nematic phase. Different temperature dependent band splitting behaviors are observed at the $$\Gamma$$ Γ and M points. The energy of the band splitting near the M point decreases as the temperature decreases while it has little temperature dependence near the $$\Gamma$$ Γ point. The nematic nature of the band shift near the M point is confirmed through a detwin experiment using a piezo device. Since a momentum dependent splitting behavior has been observed in other iron based superconductors, our observation confirms that the behavior is a universal one among iron based superconductors.

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma that has remained a challenge for oncologic and reconstructive surgeons due to a high rate of local recurrence. The objective of this study is to investigate the oncologic and reconstructive benefits of employing a multidisciplinary two-step approach to the treatment of DFSP. A retrospective review was conducted using a prospectively collected database of all patients who underwent resection and reconstruction of large DFSPs by a multidisciplinary team, including a Mohs micrographic surgeon, surgical oncologist, dermatopathologist, and plastic and reconstructive surgeon, at one academic institution from 1998–2018. Each patient underwent Mohs micrographic surgery for peripheral margin clearance (Step 1) followed by wide local excision (WLE) of the deep margin by surgical oncology and immediate reconstruction by plastic surgery (Step 2). 57 patients met inclusion criteria. Average defect size after WLE (Step 2): 87.3 cm2 (range 8.5–1073.5 cm2). Mean follow-up time was 37 months (range 0–138 months). There were no cases of recurrence. A two-step multidisciplinary surgical treatment approach for DFSP minimizes risk of recurrence, decreases patient discomfort, and allows immediate reconstruction after deep margin clearance.

Obtaining spatially continuous, high resolution thermal images is crucial in order to effectively analyze heat-related phenomena in urban areas and the inherent high spatial and temporal variations. Spatiotemporal Fusion (STF) methods can be applied to enhance spatial and temporal resolutions simultaneously, but most STF approaches for the generation of Land Surface Temperature (LST) have not focused specifically on urban regions. This study therefore proposes a two-phase approach using Landsat 8 and MODIS images acquired on a study area in Beijing to first, investigate the sharpening of the fine resolution image input with urban-related spectral indices and second, to explore the potential of implementing the sharpened results into the Spatiotemporal Adaptive Data Fusion Algorithm for Temperature Mapping (SADFAT) to generate high spatiotemporal resolution LST images in urban areas. For this test, five urban indices were selected based on their correlation with brightness temperature. In the thermal sharpening phase, the Fractional Urban Cover (FUC) index was able to delineate spatial details in urban regions whilst maintaining its correlation with the original brightness temperature image. In the STF phase however, FUC sharpened results returned relatively high levels of correlation coefficient values up to 0.689, but suffered from the highest Root Mean Squared Error (RMSE) and Average Absolute Difference (AAD) values of 4.260 K and 2.928 K, respectively. In contrast, Normalized Difference Building Index (NDBI) sharpened results recorded the lowest RMSE and AAD values of 3.126 K and 2.325 K, but also the lowest CC values. However, STF results were effective in delineating fine spatial details, ultimately demonstrating the potential of using sharpened urban or built-up indices as a means to generate sharpened thermal images for urban areas, as well as for input images in the SADFAT algorithm. The results from this study can be used to further improve STF approaches for daily and spatially continuous mapping of LST in urban areas.

Light Detection and Ranging (LiDAR) is a primary sensor for autonomous vehicles to recognize surroundings. It detects near-infrared (NIR) light pulses, typically at 905nm, which is emitted and reflected by surrounding objects. Here, the fact of the matter is that conventional black or dark-tone cars with extremely low NIR reflection are hard to be detected by LiDAR and endanger the future highway. In this work, we propose to use platelet-shaped effect pigments with visible absorption and NIR reflectivity. Copper(II) oxide and Silicon dioxide multilayer are theoretically investigated with different numbers of layers and thicknesses. The optimized structures appear various dark-tone colors with high NIR-reflectivity over 90%.

Triple-negative breast cancer (TNBC) is the most lethal subtypes of breast cancer. Although chemotherapy is considered the most effective strategy for TNBC, most chemotherapeutics in current use are cytotoxic, meaning they target antiproliferative activity but do not inhibit tumor cell metastasis. Here, a TNBC-specific targeted liposomal formulation of epalrestat (EPS) and doxorubicin (DOX) with synergistic effects on both tumor cell proliferation and metastasis is described. These liposomes are biocompatible and effectively target tumor cells owing to hyaluronic acid (HA) modification on their surface. This active targeting, mediated by CD44-HA interaction, allows DOX and EPS to be delivered simultaneously to tumor cells in vivo, where they suppress not only TNBC tumor growth and the epithelial-mesenchymal transition, but also cancer stem cells, which collectively suppress tumor growth and metastasis of TNBC and may also act to prevent relapse of TNBC.

The spatial and angular organization of biological macromolecules is a key determinant, as well as informative readout, of their function. Correlative imaging of the dynamic spatio-angular architecture of cells and organelles is valuable, but remains challenging with current methods. Correlative imaging of spatio-angular dynamics requires fast polarization-, depth-, and wavelength-diverse measurement of intrinsic optical properties and fluorescent labels. We report a multimodal instant polarization microscope (miPolScope) that combines a broadband polarization-resolved detector, automation, and reconstruction algorithms to enable label-free imaging of phase, retardance, and orientation, multiplexed with fluorescence imaging of concentration, anisotropy, and orientation of molecules at diffraction-limited resolution and high speed. miPolScope enabled multimodal imaging of myofibril architecture and contractile activity of beating cardiomyocytes, cell and organelle architecture of live HEK293T and U2OS cells, and density and anisotropy of white and grey matter of mouse brain tissue across the visible spectrum. We anticipate these developments in joint quantitative imaging of density and anisotropy to enable new studies in tissue pathology, mechanobiology, and imaging-based screens.

Extramammary Paget disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms.To develop recommendations for the care of adults with EMPD.A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD.The key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. (5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years.Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

Elucidating the wiring diagram of the human cell is a central goal of the postgenomic era. We combined genome engineering, confocal live-cell imaging, mass spectrometry, and data science to systematically map the localization and interactions of human proteins. Our approach provides a data-driven description of the molecular and spatial networks that organize the proteome. Unsupervised clustering of these networks delineates functional communities that facilitate biological discovery. We found that remarkably precise functional information can be derived from protein localization patterns, which often contain enough information to identify molecular interactions, and that RNA binding proteins form a specific subgroup defined by unique interaction and localization properties. Paired with a fully interactive website (opencell.czbiohub.org), our work constitutes a resource for the quantitative cartography of human cellular organization.

In recent decades, the safety of ships at sea has become a major concern of the global maritime industries. Ships are rarely subject to severe accidents during their life cycle. Collision is one of the most hazardous accidents, with potentially serious consequences such as the loss of human life, structural damage and environmental damage, especially if large tankers, LNG and/or nuclear-powered vessels are involved. This study presents a Quantitative Risk Assessment (QRA) for double hull oil tankers that have collided with different types of ships. The methodology used to perform the QRA is based on the International Maritime Organization’s (IMO) definition of a Formal Safety Assessment (FSA). Using probabilistic approaches, ship-ship collision scenarios are randomly selected to create a representative sample of all possible scenarios. The collision frequency is then calculated for each scenario. As this is a virtual experiment, the LS-DYNA nonlinear finite element method (NLFEM) is used to predict the structural consequences of each scenario selected. In addition, the environmental consequences are estimated by calculating the size of each scenario’s oil spill. To assess the economic consequences, the property and environmental damages are calculated in terms of monetary units. The total risk is then calculated as the sum of the resultant structural and environmental damages. Exceedance curves are established that can be used to define the collision design loads in association with various design criteria.

Background Women with cosmetic breast implants have significantly lower rates of subsequent breast cancer than the general population (relative risk, 0.63; 95 percent CI, 0.56 to 0.71). The authors hypothesize that breast implant-induced local inflammation stimulates immunosurveillance recognition of breast tumor antigen. Methods Sera were collected from two cohorts of healthy women: women with long-term breast implants (i.e., breast implants for >6 months) and breast implant-naive women. Antibody responses to breast tumor antigens were tested by enzyme-linked immunosorbent assay and compared between cohorts by unpaired t test. Of the implant-naive cohort, nine women underwent breast augmentation, and antibody responses before and after implant placement were compared by paired t test. Results Sera were collected from 104 women: 36 (34.6 percent) long-term breast implants and 68 (65.4 percent) implant-naive women. Women with long-term breast implants had higher antibody responses than implant-naive women to mammaglobin-A (optical density at 450 nm, 0.33 versus 0.22; p = 0.003) and mucin-1 (optical density at 450 nm, 0.42 versus 0.34; p = 0.02). There was no difference in antibody responses to breast cancer susceptibility gene 2, carcinoembryonic antigen, human epidermal growth factor receptor-2, or tetanus. Nine women with longitudinal samples preoperatively and 1 month postoperatively demonstrated significantly elevated antibody responses following implant placement to mammaglobin-A (mean difference, 0.13; p = 0.0002) and mucin-1 (mean difference 0.08; p = 0.02). There was no difference in postimplant responses to other breast tumor antigens, or tetanus. Conclusions Women with long-term breast implants have higher antibody recognition of mammaglobin-A and mucin-1. This study provides the first evidence of implant-related immune responses to breast cancer antigens. Clinical question/level of evidence Therapeutic, V.