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Objective: The study objective was to assess the role of CCL19+ lymph node stromal cells of the joint‐draining popliteal lymph node (pLN) for the development of arthritis. Methods: CCL19+ lymph node stromal cells were spatiotemporally depleted for five days in the pLN before the onset of collagen‐induced arthritis (CIA) using Ccl19‐Cre × iDTR mice. In addition, therapeutic treatment with recombinant CCL19–immunoglobulin G (IgG), locally injected in the footpad, was used to confirm the results. RNA sequencing of lymph node stromal cells combined with T cell coculture assays using tropomyosin receptor kinase (Trk) family inhibitors together with in vivo local pLN small interfering RNA (siRNA) treatments were used to elucidate the pathway by which CCL19+ lymph node stromal cells initiate the onset of arthritis. Results: Spatiotemporal depletion of CCL19+ lymph node stromal cells prevented disease onset in CIA mice. These inhibitory effects could be mimicked by local CCL19‐IgG treatment. The messenger RNA sequencing analyses showed that CCL19+ lymph node stromal cells down‐regulated the expression of the tropomyosin receptor kinase A (TrkA) just before disease onset. Blocking TrkA in lymph node stromal cells led to increased T cell proliferation in in vitro coculture assays. Similar effects were observed with the pan‐Trk inhibitor larotrectinib in cocultures of lymph node stromal cells of patients with rheumatoid arthritis and T cells. Finally, local pLN treatment with TrkA inhibitor and TrkA siRNA led to exacerbated arthritis scores. Conclusion: CCL19+ lymph node stromal cells are crucially involved in the development of inflammatory arthritis. Therefore, targeting of CCL19+ lymph node stromal cells via TRK could provide a tool to prevent arthritis. [ABSTRACT FROM AUTHOR]

Progress in magnetoelectric materials is hindered by apparently contradictory requirements for time‐reversal symmetry broken and polar ferroelectric electronic structure in common ferromagnets and antiferromagnets. Alternative routes can be provided by recent discoveries of a time‐reversal symmetry breaking anomalous Hall effect (AHE) in noncollinear magnets and altermagnets, but hitherto reported bulk materials are not polar. Here, the authors report the observation of a spontaneous AHE in doped AgCrSe2, a layered polar semiconductor with an antiferromagnetic coupling between Cr spins in adjacent layers. The anomalous Hall resistivity 3 μΩcm$\mu \Omega \, \textnormal {cm}$ is comparable to the largest observed in compensated magnetic systems to date, and is rapidly switched off when the angle of an applied magnetic field is rotated to ≈80° from the crystalline c‐axis. The ionic gating experiments show that the anomalous Hall conductivity magnitude can be enhanced by modulating the p‐type carrier density. They also present theoretical results that suggest the AHE is driven by Berry curvature due to noncollinear antiferromagnetic correlations among Cr spins, which are consistent with the previously suggested magnetic ordering in AgCrSe2. The results open the possibility to study the interplay of magnetic and ferroelectric‐like responses in this fascinating class of materials. [ABSTRACT FROM AUTHOR]

Aim: Pilocytic astrocytomas (PA) in adults are rare and may be challenging to identify based only on histomorphology. Compared to their paediatric counterparts, they are reportedly molecularly more diverse and associated with a worse prognosis. We aimed to describe the characteristics of adult PAs more precisely by comprehensively profiling a series of 79 histologically diagnosed adult cases (≥18 years). Methods: We performed global DNA methylation profiling and DNA and RNA panel sequencing and integrated the results with clinical data. We further compared the molecular characteristics of adult and paediatric PAs that had a significant match to one of the established PA methylation classes in the Heidelberg brain tumour classifier. Results: The mean age in our cohort was 33 years, and 43% of the tumours were located supratentorially. Based on methylation profiling, only 39% of the cases received a significant match to a PA methylation class. Sixteen per cent matched a different tumour type, and 45% had a Heidelberg classifier score <0.9 with an affiliation to diverse established methylation classes in t‐SNE analyses. Although the KIAA1549::BRAF fusion was found in 98% of paediatric PAs, this was true for only 27% of histologically defined and 55% of adult PAs defined by methylation profiling. Conclusions: A particularly high fraction of adult tumours with histological features of PA do not match current PA methylation classes, indicating ambiguous histology and an urgent need for molecular profiling. Moreover, even in adult PAs with a match to a PA methylation class, the distribution of genetic drivers differs significantly from their paediatric counterparts (p < 0.01). [ABSTRACT FROM AUTHOR]

Objective: The current study was performed to evaluate the incidence of positive lymph nodes (LNs) in relation to known pathological risk factors, specifically among patients with apparent low‐grade, small tumors. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to retrospectively identify patients with vulvar squamous cell carcinoma (SCC) diagnosed between January 1, 2000, and December 31, 2019, with known tumor size and regional LN examined. A comparison between patients who had positive and negative LNs was conducted to identify risk factors for LN metastases in relation to survival. Subgroup analysis was conducted in patients with diagnosed grade 1 vulvar SCC and tumor size up to 2 cm according to the status of LNs. Results: Multivariate analysis found that both grade of disease and tumor size were significant factors in predicting LN status. Among patients with low‐grade small tumors up to 2 cm, the odds ratio for positive LNs was 2.5 for those with tumor size larger than 1 cm. In a multivariate survival analysis, older age, larger tumor size, and positive LNs were independently associated with decreased survival. Conclusions: The current study confirms that among small tumors, those larger than 1 cm have a significantly increased risk for positive nodes compared with those smaller than 1 cm, and, among this specific group, patients with positive nodes have decreased survival. Future studies are needed to answer the question of whether, in the era of the sentinel node procedure, it is safe to omit LN evaluation altogether. Synopsis: Patients with small vulvar cancer tumors up to 1 cm present with decreased rates of lymph node metastases, and patients with positive nodes have decreased survival. [ABSTRACT FROM AUTHOR]

Photochromic supramolecular hydrogels are versatile materials that show macroscopic effects upon irradiation, like liquefaction or shape changes. Here, we demonstrate a simple photochromic cyclic dipeptide (2,5‐diketopiperazine‐based) supergelator, composed of (S)‐lysine and an azobenzene analogue of phenylalanine, that forms supramolecular hydrogels even at 0.1 wt% loading. The gels can physically encapsulate cargo molecules and release them to the environment in a controllable manner upon irradiation with red light, thus working as a "molecular syringe". As the material is biocompatible and operational in the "therapeutic window" of light (>650 nm) that deeply penetrates soft human tissues, it is applicable to smart drug‐delivery systems. [ABSTRACT FROM AUTHOR]

Mucosal melanoma remains a rare cancer with high mortality and a paucity of therapeutic options. This is due in significant part to its low incidence leading to limited patient access to expert care and downstream clinical/basic science data for research interrogation. Clinical challenges such as delayed and at times inaccurate diagnoses, and lack of consensus tumor staging have added to the suboptimal outcomes for these patients. Clinical trials, while promising, have been difficult to activate and accrue. While individual institutions and investigators have attempted to seek solutions to such problems, international, national, and local partnership may provide the keys to more efficient and innovative paths forward. Furthermore, a mucosal melanoma coalition would provide a potential network for patients and caregivers to seek expert opinion and advice. The Melanoma Research Foundation Mucosal Melanoma Meeting (December 16, 2022, New York, USA) highlighted the current clinical challenges faced by patients, providers, and scientists, identified current and future clinical trial investigations in this rare disease space, and aimed to increase national and international collaboration among the mucosal melanoma community in an effort to improve patient outcomes. The included proceedings highlight the clinical challenges of mucosal melanoma, global clinical trial experience, basic science advances in mucosal melanoma, and future directions, including the creation of shared rare tumor registries and enhanced collaborations. [ABSTRACT FROM AUTHOR]

Objective: In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis. Methods: Fecal samples were collected from 38 healthy individuals and 53 high‐risk RA individuals with anti–citrullinated protein antibody (ACPA) positivity (Pre‐RA), 12 of 53 Pre‐RA individuals developed RA within 5 years of follow‐up. The differences in intestinal microbial composition between the healthy controls and Pre‐RA individuals or among Pre‐RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic‐pretreated mice that received GM from the healthy control or Pre‐RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen‐induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre‐RA individuals on arthritis severity in mice. Results: Stool microbial diversity was lower in Pre‐RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre‐RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre‐RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre‐RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre‐RA group increased intestinal permeability in FMT mice and zonula occludens‐1 expression in the small intestine and Caco‐2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre‐RA feces compared to healthy controls. The changes in intestinal permeability and Th17‐cell activation prior to arthritis induction enhanced CIA severity in PreRA‐FMT mice compared with HC‐FMT mice. Conclusion: Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis. [ABSTRACT FROM AUTHOR]

Blood‐brain‐barrier (BBB) disruption has been associated with a variety of central‐nervous‐system diseases. In vitro BBB models enable to investigate how the barrier reacts to external injury events, commonly referred to as insults. Here, a human‐cell‐based BBB platform with integrated, transparent electrodes to monitor barrier tightness in real time at high resolution is presented. The BBB model includes human cerebral endothelial cells and primary pericytes and astrocytes in a 3D arrangement within a pump‐free, open‐microfluidic platform. With this platform, this study demonstrates that oxygen‐glucose deprivation (OGD), which mimics the characteristics of an ischemic insult, induces a rapid remodeling of the cellular actin structures and subsequent morphological changes in the endothelial cells. High‐resolution live imaging shows the formation of large actin stress‐fiber bundles in the endothelial layer during OGD application, which ultimately leads to cell shrinkage and barrier breakage. Simultaneous electrical measurements evidence a rapid decrease of the barrier electrical resistance before the appearance of stress fibers, which indicates that the barrier function is compromised already before the appearance of drastic morphological changes. The results demonstrate that the BBB platform recapitulates the main barrier functions in vitro and can be used to investigate rapid reorganization of the BBB upon application of external stimuli. [ABSTRACT FROM AUTHOR]

Summary: We report a case of a 47‐year‐old woman with a history of acral lentiginous melanoma, left great toe subungual primary, metastatic to the lungs, brain, and spleen, presenting with lower urinary tract symptoms. She had also palpated and removed a dark mass from her vaginal canal. Magnetic resonance imaging (MRI) showed polypoidal lesions within the urinary bladder and the endometrium. The suspected differential diagnosis was endometrial and bladder melanoma metastases, based on her cancer history and MRI findings. The patient underwent cystoscopy with transurethral resection of the bladder tumor and endometrial biopsy, and pathology was consistent with metastatic melanoma. Bladder and endometrial metastatic lesions are exceedingly rare. Herein, we describe an unusual case of metastatic melanoma concurrent to the urinary bladder and endometrium. [ABSTRACT FROM AUTHOR]

Traditional West African pearl millet couscous products are popular; however, their preparation is laborious, time‐consuming and energy‐demanding, involving agglomeration, steaming, drying and sieving steps. In this study, a process was developed to produce millet couscous using a high pressure, high temperature and low‐cost single‐screw extruder. The innovation was to directly process the cooked low‐moisture extrudate to a couscous product by drying and milling to the appropriate particle size (ranging between 1 and 2 mm). Throughput for the traditional process as prepared for commercial sale is 50 kg per day, but with the same amount of labour, the extrusion process yields ~350 kg per day. A consumer sensory study held in Niamey (Niger) showed that the extruded millet couscous was comparable to traditional couscous, though this was dependent on selection of the proper millet variety. This novel extrusion process could stimulate small‐ to medium‐scale manufacturing of couscous and couscous‐type products in West Africa. [ABSTRACT FROM AUTHOR]

Phytophthora capsici is a highly destructive pathogen of crops. Although chemical pesticides are the most widely used strategy to counter phytopathogens, they have been inefficient to combat P. capsici and have produced significant environmental and health problems. Therefore, sustainable alternatives to control soilborne pathogens, such as the inhibitory effect of self‐extracellular DNA (eDNA), have been proposed. This inhibition phenomenon has been attributed to the action of self‐eDNA as a damage‐associated molecular pattern (DAMP). Here, we describe the effect of self‐eDNA on P. capsici zoospore germination rate, antioxidant enzymes activity and MAPK gene expression. Also, the effect of P. capsici eDNA on the protection of chilli pepper (Capsicum annuum) plants against P. capsici was investigated. The results highlight that P. capsici can sense 2–500 µg/ml self‐eDNA and induce stress‐related responses like SAK1 gene expression, and superoxide dismutase and catalase activities. Moreover, in vitro zoospore germination rate was suppressed with self‐eDNA concentrations ranging from 50 to 500 µg/ml. Interestingly, drench applications of P. capsici eDNA at 60 and 100 µg/ml on chilli pepper plants did not show any protective effect against the phytopathogen, whereas 2 µg/ml of P. capsici eDNA drench application showed a lower percentage of plants with symptoms and lower disease severity. Moreover, phenols and total flavonoids were increased in chilli pepper plants, therefore inducing plant immunity. This study showed that self‐eDNA acts as a DAMP in P. capsici and provides insight into the use of eDNA for the protection of crops of agronomic interest. [ABSTRACT FROM AUTHOR]

It is commonly accepted that species should move toward higher elevations and latitudes to track shifting isotherms as climate warms. However, temperature might not be the only limiting factor determining species distribution. Species might move to opposite directions to track changes in other climatic variables. Here, we used an extensive occurrence data set and an ensemble modelling approach to model the climatic niche and to predict the distribution of the seven baobab species (genus Adansonia) present in Madagascar. Using climatic projections from three global circulation models, we predicted species' future distribution and extinction risk for 2055 and 2085 under two representative concentration pathways (RCPs) and two dispersal scenarios. We disentangled the role of each climatic variable in explaining species range shift looking at relative variable importance and future climatic anomalies. Four baobab species (Adansonia rubrostipa, Adansonia madagascariensis, Adansonia perrieri¸ and Adansonia suarezensis) could experience a severe range contraction in the future (>70% for year 2085 under RCP 8.5, assuming a zero‐dispersal hypothesis). For three out of the four threatened species, range contraction was mainly explained by an increase in temperature seasonality, especially in the North of Madagascar, where they are currently distributed. In tropical regions, where species are commonly adapted to low seasonality, we found that temperature seasonality will generally increase. It is, thus, very likely that many species in the tropics will be forced to move equatorward to avoid an increase in temperature seasonality. Yet, several ecological (e.g., equatorial limit, or unsuitable deforested habitat) or geographical barriers (absence of lands) could prevent species to move equatorward, thus increasing the extinction risk of many tropical species, like endemic baobab species in Madagascar. [ABSTRACT FROM AUTHOR]

Summary: We present the experimental performance analysis of a fire protection fabric for cars designed to protect people's life in case of fire entrapment. Two experimental burns were executed to simulate heat and smoke exposure conditions in case of vehicle entrapment in a rural road. For the first experimental burn, a 2‐m high fuel bed of pine slash was arranged in a 13 m × 6 m area. Fire was ignited at one end of the fuel bed and spread wind driven (3 m/s midflame wind speed). 2.8 m away from the other fuel bed end, a car covered with the fabric was placed parallel to the fire. Data analysis provided values of fire behavior and flame characteristics, being typical of wildfires of moderate intensity (1800 kW/m). Maximum air temperatures inside the vehicle ranged around 41°C to 42.5°C, providing evidence of the fabric's good performance. To evaluate the degree of protection against smoke, air change rates were estimated with and without the fabric covering the car. Also, an experimental burn similar to the previous one was executed to monitor CO2 and CO concentrations inside the car. Tenable conditions for these gases were maintained during the whole test according to reviewed exposure criteria. [ABSTRACT FROM AUTHOR]

Three‐dimensional food printing (3DFP) uses additive manufacturing concepts to fabricate customized designed products with food ingredients in powder, liquid, dough, or paste presentations. In some cases, it uses additives, such as hydrocolloids, starch, enzymes, and antibrowning agents. Chocolate, cheese, sugar, and starch‐based materials are among the most used ingredients for 3DFP, and there is a broad and growing interest in meat‐, fruit‐, vegetable‐, insect‐, and seaweed‐based alternative raw materials. Here, we reviewed the most recent published information related to 3DFP for novel uses, including personalized nutrition and health‐oriented applications, such as the use of 3D‐printed food as a drug vehicle, and four‐dimensional food printing (4DFP). We also reviewed the use of this technology in aesthetic food improvement, which is the most popular use of 3DFP recently. Finally, we provided a prospective and perspective view of this technology. We also reflected on its multidisciplinary character and identified aspects in which social and regulatory affairs must be addressed to fulfill the promises of 3DFP in human health improvement. [ABSTRACT FROM AUTHOR]

The persistence of Helicobacter pylori in the human gastric mucosa implies that the immune response fails to clear the infection. We found that H. pylori compromises the antigen presentation ability of macrophages, because of the decline of the presenting molecules HLA‐II. Here, we reveal that the main bacterial factor responsible for this effect is ADP‐heptose, an intermediate metabolite in the biosynthetic pathway of lipopolysaccharide (LPS) that elicits a pro‐inflammatory response in gastric epithelial cells. In macrophages, it upregulates the expression of miR146b which, in turn, would downmodulate CIITA, the master regulator for HLA‐II genes. Hence, H. pylori, utilizing ADP‐heptose, exploits a specific arm of macrophage response to establish its survival niche in the face of the immune defense elicited in the gastric mucosa. [ABSTRACT FROM AUTHOR]

To avoid autoimmunity, it is essential to keep the balance between the defence against pathogens and the maintenance of tolerance to self‐antigens. Mucosal inflammation may lead to breakdown of tolerance and activation of autoreactive cells. Growing evidence suggests a major contribution of gut microbiota to the onset of chronic, autoimmune inflammatory diseases including rheumatoid arthritis (RA). RA patients show significant differences in the composition of gut microbiota compared to healthy controls, and in murine arthritis models certain bacteria can induce inflammatory Th17 responses or autoantibody production. The gut microbiota plays an important role in regulating the balance between immunogenic and tolerogenic immune responses. The intestinal barrier is the site of the body where most host–microbiota interaction takes place. Certain microbiota or their metabolites can cause a break in homeostasis by affecting the intestinal barrier integrity and permeability. However, an intact intestinal barrier is essential to separate the intestinal epithelium from toxins, microorganisms, and antigens in the gut lumen. This review will focus on the correlation between a leaky gut and the onset of arthritis. Furthermore, it will be discussed how targeting the intestinal barrier function by dietary changes might provide an opportunity to modulate the development of RA. [ABSTRACT FROM AUTHOR]

Here it is reported on the fabrication of a carbon‐gold micro/nano hierarchical platform using a stimuli‐responsive wrinkling technology. The approach exploits the generation of depth wise photo‐crosslinking gradient in SU8 thin films doped with a UV light absorbing gold precursor. Wrinkled films are then pyrolyzed at 900 °C, resulting in well preserved carbonized wrinkle patterns along with the growth of GNPs. The wrinkling phenomenon is explained using a theoretical model that includes the influence of the film thickness, the gold precursor concentration, and the exposure gradient that sets the theoretical intermolecular distance of free monomers along the film's depth direction. The predicted evolution of the wrinkle patterns is supported by experimental results. Surface roughness and wetting properties of the resulting topographies are studied in detail. GNPs act as potential anchor points for cell adhesion whereas mechanical topographies controls the cellular alignment as a result of contact guidance. Fibronectin functionalization significantly improves cell attachment, biocompatibility, and provides highly aligned cell cultures. This whole strategy of fabricating non‐planar carbon/gold‐based cell culture platform has great potential for their use in lab on a chip and tissue engineering based applications. [ABSTRACT FROM AUTHOR]

Schistosomiasis is an acute and chronic disease caused by tropical parasitic worms of the genus Schistosoma, which parasitizes annually over 200 million people worldwide. Screening of antischistosomal compounds is hampered by the low throughput and potential subjectivity of the visual evaluation of the parasite phenotypes, which affects the current drug assays. Here, an impedance‐based platform, capable of assessing the viability of Schistosoma mansoni schistosomula exposed to drugs, is presented. This automated and parallelized platform enables unbiased and continuous measurements of dose–response relationships for more than 48 h. The platform performance is established by exposure of schistosomula to three test compounds, praziquantel, oxethazaine, and mefloquine, which are known to affect the larvae phenotypes. The system is thereafter used to investigate the response of schistosomula to methiothepine, an antipsychotic compound, which causes complex drug‐induced effects. Continuous monitoring of the parasites reveals transient behavioral phenotypes and allows for extracting temporal characteristics of dose–response curves, which are essential for selecting drugs that feature high activity and fast kinetics of action. These measurements demonstrate that impedance‐based detection provides a wealth of information for the in vitro characterization of candidate antischistosomals and, represents a promising tool for the identification of new lead compounds. [ABSTRACT FROM AUTHOR]

This approach involves the synthesis of gold nanoparticles (GNPs) within the carbonizing photoresist (SU8) to achieve GNPs trapped glassy carbon (GNPs‐GC) substrates. Surface size distribution and interparticle separation of GNPs is primarily controlled by changing the metal precursor concentration. Chemical stability and fabrication control are achieved by selecting sodium tetrachloroaurate (NaAuCl4) over a more conventional aurochloric acid (HAuCl4) as the gold precursor. Seeding of gold nuclei in a photocrosslinking polymer is a classical representation of simultaneous homogeneous and heterogeneous nucleation. GNPs growth during the carbonization process is tracked and explained using pertinent mechanisms. With the nanoparticle spacing ranging from 260 to 50 nm, GNPs‐GC thin films are employed as interfaces for fibroblast cell adhesion. GNPs act as potential anchor points for cell adhesion and their nanoscale arrangement regulates the structural behavior of the cells. GNPs' density‐dependent fibronectin physisorption significantly improves cell adhesion and proliferation. Intraparticle spacing around 160 nm offers ideal biointerface for fibroblast attachment and spreading. Fabrication of 3D GNPs composite carbon microelectromechanical systems is achieved as a demonstration of the studied GNPs‐GC synthesis mechanism. Sub‐micron patterning of GNPs‐GC combined with its biofunctional nature presents vast opportunities in the field of bioelectronics, biophotonics, and lab/organ‐on‐a‐chip technology. [ABSTRACT FROM AUTHOR]

Meteorological extreme events have a major impact on water resources, economic development, and ecosystem health. In this study, maximum precipitation and maximum temperature indices were derived for Isfahan province, in central Iran, over the historical (1992–2017) and future (2020–2100) periods. Precipitation and maximum temperature data from the REMO model under RCP4.5 scenario were used to investigate changes in extreme values over the future period. The results showed that extreme precipitation in the historical and future periods has respectively a decreasing and increasing trend. Based on the extreme indices, temperature in the study area has a significant increasing trend in the baseline and future period. Various combinations of extreme precipitation indicators were created for joint modeling by copula theory. Copula modeling for the three weather stations for which REMO had satisfactory performance in simulating extremes over the historic period showed that the average return period of extreme precipitation combinations will be reduced in the future period compared to the historical period at Daran and Shahreza, while the average return period of combinations will have both increasing and decreasing trends at Naeen. Recommendations for Resource Managers Knowing information about the probability of occurrence of extreme precipitation with a certain value that exceeds a certain threshold will help planning for water resource systems under drought conditions and future increasing temperature.The joint return period of extreme precipitation can help to know the return period of extreme events such as floods and droughts.The findings of this study are important to assess the prediction of climate extreme. Also, these results can be useful to provide the appropriate strategies for water resources managers in drought conditions under future increasing temperature. [ABSTRACT FROM AUTHOR]

A strong mesoscale convective system affected northeastern Italy on August 8, 2008. Notable damage and two casualties resulted, mainly due to the strong wind gusts. The event is analysed using observations, including surface data from a meso‐network of meteorological stations, radar reflectivity and velocity data from a C‐band Doppler radar, polar satellite images, lightning measurements from a lightning detection network and the ambient thermodynamic conditions derived from local radiosoundings. The role of the cold front is investigated; in particular, the associated strong wind descending from the Alps, which interacted with the preexisting convection in the plain, is analysed to understand the way it affected the storm development. A simple density current model is applied to describe the flow characteristics and to identify the mechanisms that could support the development of such a high wind speed. Lastly, observed wind speeds are compared with the theoretical estimates from the proposed model. The results show that different factors contribute to the very strong wind gusts registered by surface stations. The main contributor to the windstorm is a density current (a) driven by the cold front, (b) maintained by the interaction between the cold air impinging on the Friuli Venezia Giulia plain from the north and the strong regional density gradient and (c) eventually enhanced by the storm cold pool. This study highlights the complex evolution of severe storms in a region on the lee side of the Alpine chain, and emphasizes the role of the orography in the enhancement of storm. [ABSTRACT FROM AUTHOR]

The study was carried out to assess meteorological drought on the basis of the standardized precipitation index (SPI) and standardized precipitation evapotranspiration index (SPEI) evaluated in future climate scenarios. Yazd province, located in an arid region in the centre of Iran, was chosen for analysis. The study area has just one synoptic station with a long‐term record (56 years). The impact of climate change on future drought was examined by using the CanESM2 of the CMIP5 model under three scenarios, that is, representative concentration pathways RCP2.6, RCP4.5 and RCP8.5. Given that a drought is defined by several dependent variables, the evaluation of this phenomenon should be based on a multivariate analysis. For this purpose, two main characteristics of drought (severity and duration) were extracted by run theory in a past (1961–2016) and future (2017–2100) period based on the SPI and SPEI, and studied using copula theory. Three functions, that is, Frank, Gaussian and Gumbel copula, were selected to fit with drought severity and duration. The results of the bivariate analysis using copula showed that, according to both indicators, the study area will experience droughts with greater severity and duration in future as compared with the historical period, and the drought represented by the SPEI is more severe than that associated with the SPI. Also, drought simulated using the RCP8.5 scenario was more severe than when using the other two scenarios. Finally, droughts with a longer return period will become more frequent in future. [ABSTRACT FROM AUTHOR]

Background: KIT-directed tyrosine kinase inhibitors such as imatinib have demonstrated benefits in KIT-mutant (KIT+) mucosal, acral, vulvovaginal, and chronically sun-damaged (CSD) melanoma. Dasatinib has superior preclinical activity in comparison with other tyrosine kinase inhibitors against cells with the most common KIT mutation, exon 11L576P . The ECOG-ACRIN E2607 trial assessed dasatinib in patients with these melanoma subtypes.Methods: Patients received 70 mg of oral dasatinib twice daily. The primary objective for this 2-stage phase 2 trial was response rate. Stage I was open to KIT+ and wild-type KIT (KIT-) mucosal, acral, and CSD melanoma (n = 57). Stage II accrued only KIT+ tumors (n = 30). To enrich the trial for KIT+ tumors, vulvovaginal melanoma was added, and CSD melanoma was removed from eligibility. Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety.Results: From May 2009 to December 2010, the first stage enrolled 57 patients. Among the evaluable patients, 3 of 51 (5.9%) achieved a partial response: all were KIT-. Stage II closed early because of slow accrual (November 2011 to December 2015). In stage II, 4 of 22 evaluable patients (18.2%) had a partial response; the median duration was 4.2 months. The median PFS was 2.1 months (n = 73; 95% confidence interval [CI], 1.5-2.9 months). The median OS was 7.5 months (95% CI, 6.0-11.9 months). In exploratory analyses, no differences were seen in PFS or OS with the KIT status or subtype. Dasatinib was discontinued because of adverse events in 9 of 75 patients (12%).Conclusions: The dasatinib response rate among KIT+ melanoma patients was low. In view of its clinical activity, it is recommended that imatinib remain the KIT tyrosine kinase inhibitor of choice for unresectable KIT+ melanoma. Cancer 2017;123:2688-97. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective: The association between inflammation and dysregulated bone remodeling is apparent in rheumatoid arthritis and is recapitulated in the human tumor necrosis factor transgenic (hTNFtg) mouse model. We investigated whether extracellular binding immunoglobulin protein (BiP) would protect the hTNFtg mouse from both inflammatory arthritis as well as extensive systemic bone loss and whether BiP had direct antiosteoclast properties in vitro. Methods: hTNFtg mice received a single intraperitoneal administration of BiP at onset of arthritis. Clinical disease parameters were measured weekly. Bone analysis was performed by microcomputed tomography and histomorphometry. Mouse bone marrow macrophage and human peripheral blood monocyte precursors were used to study the direct effect of BiP on osteoclast differentiation and function in vitro. Monocyte and osteoclast signaling was analyzed by Western blotting, flow cytometry, and imaging flow cytometry. Results: BiP‐treated mice showed reduced inflammation and cartilage destruction, and histomorphometric analysis revealed a decrease in osteoclast number with protection from systemic bone loss. Abrogation of osteoclast function was also observed in an ex vivo murine calvarial model. BiP inhibited differentiation of osteoclast precursors and prevented bone resorption by mature osteoclasts in vitro. BiP also induced downregulation of CD115/c‐Fms and Receptor Activator of NF‐κB (RANK) messenger RNA and protein, causing reduced phosphorylation of the p38 mitogen–activated protein kinases, extracellular signal–regulated kinases 1/2 and p38, with suppression of essential osteoclast transcription factors, c‐Fos and NFATc1. BiP directly inhibited TNF‐α– or Receptor Activator of NF–κB Ligand (RANKL)–induced NF‐κB nuclear translocation in THP‐1 monocytic cells and preosteoclasts by the canonical and noncanonical pathways. Conclusion: BiP combines an anti‐inflammatory function with antiosteoclast activity, which establishes it as a potential novel therapeutic for inflammatory disorders associated with bone loss. [ABSTRACT FROM AUTHOR]

Objectives: Although the reliability of frozen sections for the intraoperative assessment of complete tumour excision has been established, the best location for collection and the impact of the type of sampling are still debated. We retrospectively investigated the reliability of frozen sections when collected from the surgical bed as tissue strips representative of the whole superficial margin and as a bowl of tissue underlying the resection site for deep margin, and the possibility of relying on frozen section negativity to consider resections complete. Materials and Methods: Frozen section reliability was calculated by comparing histology before and after formalin embedding and then categorised by sampling type, in 182 patients undergoing transoral resection of oral cancer. Results: Comparing frozen and permanent histology, sensitivity, specificity and accuracy were 69%, 98% and 96%, respectively; categorisation by sampling type failed to produce statistically significant differences. Based on frozen section negativity after formalin embedding, complete resections were obtained in 91.7% of patients with multiple‐strip and bowl frozen sections. Conclusion: Frozen sections collected as tissue strips and bowl are as reliable as point sampling in the intraoperative guidance of surgical resections. They effectively provide for margin enlargement, thereby increasing the surgeon's confidence that negative margins are clear. [ABSTRACT FROM AUTHOR]

BACKGROUND: Characterizing lethal and sublethal control of soil‐based pests with plant protection products is particularly challenging due to the complex and dynamic interplay of the system components. Here, we present two types of studies: acute toxcity experiments (homogenous exposure of individuals in soil) and rhizotron experiments (heterogeneous exposure of individuals in soil) to investigate their ability to strengthen our understanding of mechanisms driving the effectivness of the plant protection product. Experiments were conducted using larvae of the western corn rootworm Diabrotica virgifera LeConte and three pesticide active ingredients: clothianidin (neonicotinoid), chlorpyrifos (organophosphate) and tefluthrin (pyrethroid). RESULTS: The order of compound concentrations needed to invoke a specific effect intensity (EC50 values) within the acute toxicity tests was chlorpyrifos > tefluthrin > clothianidin. This order changed for the rhizotron experiments because application type, fate and transport of the compounds in the soil profile, and sublethal effects on larvae also influence their effectiveness in controlling larval feeding on corn roots. CONCLUSION: Beyond the pure measurement of efficacy through observing relative changes in plant injury to control plants, the tests generate mechanistic understanding for drivers of efficacy apart from acute toxicity. The experiments have the potential to enhance efficacy testing and product development, and might be useful tools for assessing resistance development in the future. © 2018 Society of Chemical Industry Assessing the efficacy of products to combat soil‐based pests is challenging. We present laboratory and greenhouse experiments and investigate their ability to assess the mechanism driving efficacy prior to conducting field trials. [ABSTRACT FROM AUTHOR]

The proteomic analysis of complex body fluids by liquid chromatography tandem mass spectrometry (LC‐MS/MS) analysis requires the selection of suitable sample preparation techniques and optimal parameter settings in data analysis software packages to obtain reliable results. Proteomic analysis of follicular fluid, as a representative of a complex body fluid similar to serum or plasma, is difficult as it contains a vast amount of high abundant proteins and a variety of proteins with different concentrations. However, the accessibility of this complex body fluid for LC‐MS/MS analysis is an opportunity to gain insights into the status, the composition of fertility‐relevant proteins including immunological factors or for the discovery of new diagnostic and prognostic markers for, for example, the treatment of infertility. In this study, we compared different sample preparation methods (FASP, eFASP and in‐solution digestion) and three different data analysis software packages (Proteome Discoverer with SEQUEST, Mascot and MaxQuant with Andromeda) combined with semi‐ and full‐tryptic databank search options to obtain a maximum coverage of the follicular fluid proteome. We found that the most comprehensive proteome coverage is achieved by the eFASP sample preparation method using SDS in the initial denaturing step and the SEQUEST‐based semi‐tryptic data analysis. In conclusion, we have developed a fractionation‐free methodical workflow for in depth LC‐MS/MS‐based analysis for the standardized investigation of human follicle fluid as an important representative of a complex body fluid. Taken together, we were able to identify a total of 1392 proteins in follicular fluid. [ABSTRACT FROM AUTHOR]

Abstract: Adjuvant chemotherapy is recommended for patients with resected high‐risk adult granulosa cell tumors (GCT), although strong data to support this are lacking. The objective of this study was to assess the outcomes of GCT patients, with the specific focus on patients that received adjuvant chemotherapy with curative intent (stage I‐III), reported in a large national cancer registry. Data from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2013 were used for analysis. Patient and disease characteristics were extracted and analyzed for association with administration of chemotherapy. Impact on disease‐specific survival (DSS) was analyzed using log‐rank test. A total of 739 patients with surgically treated adult GCT were identified. Median age was 51 years. 570 (77%) patients were stage I, 87 (12%) were stage II, and 82 (11%) were stage III. Adjuvant chemotherapy was administered to 176 (24%) patients. Young age, higher stage, and hysterectomy were associated with chemotherapy administration. Higher disease stage was associated with decreased five‐year DSS (IA/B 98.5%, IC 95.1%, II 86.1%, III 83.5%, P < 0.01). Notably, administration of adjuvant chemotherapy was not associated with improved five‐year DSS (P = 0.45) regardless of disease stage (stage IA/B: 96% with chemotherapy vs. 99% without chemotherapy; P = 0.64), (stage IC: 97% with chemotherapy vs. 94% without chemotherapy; P = 0.49), (stage II: 89% with chemotherapy vs. 83% without chemotherapy; P = 0.56), (stage III: 73% with chemotherapy vs. 93% without chemotherapy; P = 0.18). In this analysis, chemotherapy was not found to be associated with improved DSS of patients with operable disease regardless of stage, questioning the role for adjuvant chemotherapy in GCT. [ABSTRACT FROM AUTHOR]

Abstract: In neuro Behçet disease with multiple sclerosis‐like features, diagnosis could be challenging. Here, we studied the cerebrospinal fluid and serum inflammatory profile of 11 neuro Behçet and 21 relapsing‐remitting multiple sclerosis patients. Between the soluble factors analyzed (MMP9, TNFα, IL6, CXCL13, CXCL10, CXCL8, IFNγ, IL10, IL17, IL23, and others) we found MMP9 increased in neuro Behçet serum compared to multiple sclerosis and decreased in cerebrospinal fluid. Furthermore, neuro Behçet analysis of circulating natural killer CD56DIM subset suggests their potential involvement in increased MMP9 production. We believe that these findings may have a translational utility in clinical practice. [ABSTRACT FROM AUTHOR]

Dietary fibre intake can help to improve the health of the population. Cookies are one of the most consumed bakery products. The aim of this study was to investigate the influence of different fibres on cookie quality. Soluble fibres (nutriose, inulin and polydextrose) decreased dough consistency favoured cookie spread during baking and produced wider and thinner cookies. In contrast, insoluble fibres (elongated and rounded) showed an opposite trend increasing dough consistency and giving rise to cookies with higher moisture, lower spread factor and higher hardness. Long insoluble fibres gave rise to harder cookies and with lower spread factor. Cookies made with soluble fibres were darker than the control cookie and cookies containing insoluble fibres. Therefore, solubility and shape of insoluble fibres play an important role in cookie quality. Fibre selection will be key to enriched cookies development. [ABSTRACT FROM AUTHOR]

One of the main problems with gluten-free breads is their texture and their rapid staling. Fats are widely used for the improvement of texture and other quality parameters in gluten-free breads. The effect of oil and shortening in rice-breads quality and its correlation with dough rheology has been analyzed. The inclusion of oil increased the specific volume of the breads and reduced their hardness, particularly with lower levels of hydration, whereas shortening did not modify specific volume or reduced it when hydration levels were higher. Oil, at levels of up to 30%, reduced the cohesiveness, springiness and resilience of breads, as well as the brightness of the crust, and increased the a* and b* values. Breads with oil also exhibited a greater number of pores per cm2, especially in doughs with higher levels of hydration. An inverse correlation between G′ and G′′ and bread specific volume has been observed, being the reciprocal-Y model a better predictor than the linear model to relate the bread specific volume. Practical applications This study showed that the type and quantity of fat added in rice based breads affect the bread quality in a different way. In general, it can be said that the incorporation of up to 20% oil improved rice based breads. Oil increased the specific volume, the a* and b* parameters of the crust and the cell density. It also decreases hardness, cohesiveness, springiness, resilience, and the L* parameter. Converse to breads made with oil, the addition of shortening can negatively affect the quality of the breads. Moreover, the correlation analysis has demonstrated that the study of dough rheology could be a good predictor of gluten-free bread quality. [ABSTRACT FROM AUTHOR]

There were an estimated 19.3 million new cases of cancer worldwide in 2020 alone - a number that continues to rise year after year [1]. Within this larger pocket of global cancers, the incidence and mortality rates of specific cancers can vary widely across societies and cultures, especially among the less populous and poorer nations and territories. [ABSTRACT FROM AUTHOR]

The diffusion of moisture in soybean grains is usually followed by two physical facts related to the presence of water: the increase in grain size due to water accumulation and the increase in permeability, as more water is absorbed. In order to increase the physical meaning of the proposed model those two phenomenological facts were inserted in the classical Fick's Second Law of Diffusion. The increase of the grains was taken into account by considering the radius of the grains as a moving boundary of the diffusion system (characterizing a Stefan problem). The increase in permeability was taken into account by considering an exponential dependence of the diffusivity with the moisture content. The behaviour of the main parameters was analyzed with the temperatures. The moisture profiles were calculated for the moving boundary problem as well as the behaviour of the radius of the grains as a function of time. The results showed good agreement with experimental reality of soybean hydration process. [ABSTRACT FROM AUTHOR]

Dynamic synapses facilitate activity-dependent remodeling of neural circuits, thereby providing the structural substrate for adaptive behaviors. However, the mechanisms governing dynamic synapses in adult brain are still largely unknown. Here, we demonstrate that in the cortex of adult amyloid precursor protein knockout ( APP- KO) mice, spine formation and elimination were both reduced while overall spine density remained unaltered. When housed under environmental enrichment, APP- KO mice failed to respond with an increase in spine density. Spine morphology was also altered in the absence of APP. The underlying mechanism of these spine abnormalities in APP- KO mice was ascribed to an impairment in D-serine homeostasis. Extracellular D-serine concentration was significantly reduced in APP- KO mice, coupled with an increase of total D-serine. Strikingly, chronic treatment with exogenous D-serine normalized D-serine homeostasis and restored the deficits of spine dynamics, adaptive plasticity, and morphology in APP- KO mice. The cognitive deficit observed in APP- KO mice was also rescued by D-serine treatment. These data suggest that APP regulates homeostasis of D-serine, thereby maintaining the constitutive and adaptive plasticity of dendritic spines in adult brain. [ABSTRACT FROM AUTHOR]

The principal focus of this paper is the formulation of a general approach to hyperelastic strain energy functions that does not rely on the use of scalar invariants of tensors. We call this an invariant-free formulation of hyperelasticity. This essentially requires the conversion of the strain energy function from one of scalar products of scalar tensor invariants (all zeroth-order) into one of quadruple contractions between fourth-order tensors, thus preserving directional distinctions through to energy. We begin with an analysis of a range of hyperelastic properties in order to eliminate some non-physical models. In the section after, we are left with the Simo and Pister model and the Compressible neo-Hookean model, and decide on Simo and Pister's model for further study. Presented is a general form of invariant-free hyperelasticity (the so-called generalized strain energy function), and the fitting of the Simo and Pister model into that framework. The novelty of this invariant-free formulation is threefold: first allowing the presentation of strain energy as a fourth-order tensor that explicitly provides the origin of energy contributions from a possible 81 combinations through the simple exchange of the quadruple contraction operator with the Hadamard product; second is a new ability to seamlessly integrate micropolar effects into existing hyperelastic functions (a cursory look); and third is the direction-preserving nature of the formulation, which satisfies the original charter of this work in providing a primer for the natural extension of advanced conventional hyperelastic functions from isotropic materials to anisotropic materials. [ABSTRACT FROM AUTHOR]

Roasting improves the palatability of barley grains. After processing, the resulting powder is widely used to elaborate beverages such as coffee and tea. The objective of this research was to evaluate the influence of roasting on the characteristics of barley grains and the derived powder. The kinetics of release of soluble solids during the powder hydration at 80°C, performed to produce beverages such as tea, was also determined. In addition, the influence of roasting and rehydration temperatures on the physical composition of the beverages and on the release of soluble solids was investigated. After roasting, barley was ground and sieved. The powder retained in the 0.425 mm sieve was used in the analyses. Owing to roasting, the average protein content of barley increased from 10.56 to 12.88 g/100 g, and the sugar content decreased from 730 to 12.99 mg/mL, which is ascribed to the high process temperature. The phenolic compounds increased from 105.33 to 253.07 mg of ferulic acid per milliliter between the nonprocessed sample and the one roasted at 240°C, respectively. The antioxidant activity decreased with the roasting temperature rise (160-240°C) from 11.60 to 5.30 pg of 2,2- diphenyl-1-picrylhydrazyl per milliliter. In the production of beverages such as tea, higher roasting temperatures led to a greater release of soluble solids in water. [ABSTRACT FROM AUTHOR]

Background and Purpose: The Kv 7 channel activator flupirtine is a clinical analgesic characterized as 'selective neuronal potassium channel opener'. Flupirtine was found to exert comparable actions at GABAA receptors and Kv 7 channels in neurons of pain pathways, but not in hippocampus.Experimental Approach: Expression patterns of GABAA receptors were explored in immunoblots of rat dorsal root ganglia, dorsal horns and hippocampi using antibodies for 10 different subunits. Effects of flupirtine on recombinant and native GABAA receptors were investigated in patch clamp experiments and compared with the actions on Kv 7 channels.Key Results: Immunoblots pointed towards α2, α3, β3 and γ2 subunits as targets, but in all γ2-containing receptors the effects of flupirtine were alike: leftward shift of GABA concentration-response curves and diminished maximal amplitudes. After replacement of γ2S by δ, flupirtine increased maximal amplitudes. Currents through α1β2δ receptors were more enhanced than those through Kv 7 channels. In hippocampal neurons, flupirtine prolonged inhibitory postsynaptic currents, left miniature inhibitory postsynaptic currents (mIPSCs) unaltered and increased bicuculline-sensitive tonic currents; penicillin abolished mIPSCs, but not tonic currents; concentration-response curves for GABA-induced currents were shifted to the left by flupirtine without changes in maximal amplitudes; in the presence of penicillin, maximal amplitudes were increased; GABA-induced currents in the presence of penicillin were more sensitive towards flupirtine than K(+) currents. In dorsal horn neurons, currents evoked by the δ-preferring agonist THIP (gaboxadol) were more sensitive towards flupirtine than K(+) currents.Conclusions and Implications: Flupirtine prefers δ-containing GABAA receptors over γ-containing ones and over Kv 7 channels. [ABSTRACT FROM AUTHOR]

Aims The purpose of this study was too describe the associated baseline features of AF patients with heart failure ( HF) with reduced and preserved ejection fraction ( HFrEF and HFpEF). Secondly, we assessed symptomatic status and their clinical correlates. Finally, we examined independent predictors for 'heart failure' at the 1-year follow-up period. Methods and results A survey of European cardiologists from nine countries, participating in the EURObservational Research Programme Pilot survey on Atrial Fibrillation ( EORP-AF Pilot), was carried out. Of the whole cohort of 2972 patients, 1411 (47.5%) had a diagnosis of HF. Of the AF patients with HF, oral anticoagulants were prescribed to 82.1% and antiarrhythmic drugs in 36.7%. Independent predictors of HFpEF were high body mass index, high heart rate, high systolic blood pressure, low diastolic blood pressure, high CHA2DS2-VASc score, and absence of chronic kidney disease, sleep apnoea, or ischaemic cardiomyopathy. On multivariate stepwise regression analysis, independent predictors of the development of HF were mode of AF presentation, diuretic use, prior HF, COPD, and valvular disease. At 1 year, HF was associated with a greater risk of all-cause mortality (log-rank test, P < 0.001). When HFrEF was compared with HFpEF at 1 year, crude rates were significant for the composite endpoint of 'stroke/thrombo-embolism/transient ischaemic attack and death' (15.9% vs. 11.1%, P = 0.043). Conclusion We provide insights into the clinical characteristics and outcomes in AF patients with HF, who were managed by European cardiologists. Despite a high prevalence of oral anticoagulant use, 1-year mortality and morbidity remained high in AF patients with HF, whether HFrEF or HFpEF. Such patients require a holistic approach to cardiovascular risk management. [ABSTRACT FROM AUTHOR]

ABSTRACT The aim of this study is to gain further understanding of the structure of the marine atmospheric boundary layer ( MABL) and its interaction with synoptic-scale forcing. A possible application of this study is to simulate mean and turbulent spatial and temporal structure of the marine boundary layer in order to optimize the structural design of offshore large wind turbines that today reach heights up to 200 m. Large-eddy simulations ( LESs) have been performed and compared with offshore experimental data collected during the LASIE campaign performed in the Mediterranean during summer 2007. Two simulations are performed: one where the LES is left free to evolve without any external forcing, and one where a force restoration nudging technique has been implemented in LES in order to force the model to the evolving large-scale situation. Model results have been compared against experimental soundings. Results show that for all the calculated fields the nudged LES outperforms the simulation without nudging, demonstrating that incorporating changes in the large-scale features is necessary in order to provide a realistic evolution of the modelled meteorological fields at local scale. Thus, appropriately nudged LES appears as a promising technique to be applied to the simulation of offshore cases, particularly suitable for wind energy applications. [ABSTRACT FROM AUTHOR]

Helicobacter pylori colonizes mucosa, activates Toll-like and Nod-like receptors, and usually elicits a gastric T-helper 1/17 (Th1/Th17) type of immune response. Among several bacterial factors, the secreted peptidyl prolyl cis, trans-isomerase of H. pylori represents a key factor driving Th17 inflammation. A complex and fascinating balance between H. pylori and host factors takes part in the gastric niche and is responsible for the chronicity of the infection. Novel insights into the innate and adaptive responses against H. pylori, dealing with gastric epithelial cells, cytokines, and immune evasion have been elucidated over the past year and are discussed for the development of an effective vaccine. [ABSTRACT FROM AUTHOR]

Aims Lymph node involvement affects prognosis/treatment in endometrial carcinoma patients. We assessed various histological features associated with nodal metastasis in patients with grade I, stage I endometrial endometrioid carcinoma ( EEC). Methods and results Eighteen stage I EECs with occult positive lymph nodes and 36 controls were assessed for depth of myoinvasion; microcystic, elongated and fragmented ( MELF) pattern of myometrial invasion; lymphovascular invasion ( LVI); and epithelial metaplasia. Nodal metastases were subclassified as isolated tumour cells ( ITCs; ≤0.2 mm), micrometastasis (>0.2 mm and <2 mm), or macrometastasis (≥2 mm). Node-positive cases had significantly higher rates of LVI ( P < 0.001) and MELF invasion ( P = 0.003) on univariate analysis. Only LVI was associated significantly with nodal metastasis on multivariate analysis ( P = 0.002). Tumours with MELF invasion demonstrated reduced E-cadherin expression. Macrometastases were identified in seven cases (39%) with or without micrometastasis/ ITCs. Eight (44%) contained only ITCs. Eleven (61%) had histiocyte-like nodal metastases. Biopsy material from four of six (67%) and five of 17 (29%) cases with and without nodal metastasis showed detached eosinophilic tumour cell buds. Of the former, three were associated with histiocyte-like nodal metastases - a feature absent in biopsies without tumour budding. Conclusions Lymph nodes from grade I EEC exhibiting cellular budding or LVI should be examined for occult metastases, especially in the form of histiocyte-like cells. [ABSTRACT FROM AUTHOR]