Label-free mapping of cetuximab in multi-layered tumor oral mucosa models by atomic force-microscopy-based infrared spectroscopy.

Sensitive mapping of drugs and drug delivery systems is pivotal for the understanding and improvement of treatment options. Since labeling alters the physicochemical and potentially the pharmacological properties of the molecule of interest, its label-free detection by photothermal expansion is investigated. We report on a proof-of-concept study to map the cetuximab distribution by atomic-force microscopy-based infrared spectroscopy (AFM-IR). The monoclonal antibody cetuximab was applied to a human tumor oral mucosa model, consisting of a tumor epithelium on a lamina propria equivalent. Hyperspectral imaging in the wavenumber regime between 903 cm-1 and 1312 cm-1 and a probing distance between the data points down to 10 × 10 nm are used for determining the local drug distribution. The local distinction of cetuximab from the tissue background is gained by linear combination modeling making use of reference spectra of the drug and untreated models. The results from this approach are compared to principal component analyses, yielding comparable results. Even single molecule detection appears feasible. The results indicate that cetuximab penetrates the cytosol of tumor cells but does not bind to structures in the cell membrane. In conclusion, AFM-IR mapping of cetuximab proved to sensitively determine drug concentrations at an unprecedented spatial resolution without the need for drug labeling.

Reproductive isolation between diploid and tetraploid individuals in mixed-cytotype populations of Lycium australe.

PREMISE: Whole-genome duplication is considered a major mechanism of sympatric speciation due to the creation of strong and instantaneous reproductive barriers. Although postzygotic reproductive isolation between diploids and polyploids is often expected, the extent of reproductive incompatibility must be empirically determined and compared to patterns of genetic isolation to fully characterize the reproductive dynamics between cytotypes. METHODS: We investigated reproductive compatibility between diploid and tetraploid Lycium australe in two mixed-cytotype populations using (1) controlled crossing experiments to evaluate fruit and seed production and (2) germination trials to test seed viability following homoploid and heteroploid crosses. We contrast these experiments with a single-nucleotide polymorphism (SNP) data set to measure genetic isolation between cytotypes and explore whether cytotype or population origin better explains patterns of genetic variation. Finally, we explore mating patterns using the observed germination rates of naturally produced seeds in each population. RESULTS: Although homoploid and heteroploid crosses resulted in similar fruit and seed production, reproductive isolation between co-occurring diploids and tetraploids was nearly complete, due to low seed viability following heteroploid crosses. Of 191,182 total SNPs, 21,679 were present in ≥90% of individuals and replicate runs using unlinked SNPs revealed strong clustering by cytotype and differentiation of tetraploids based on population origin. CONCLUSIONS: As often reported, diploid and tetraploid L. australe experience strong postzygotic isolation via hybrid seed inviability. Consistent with this result, cytotype explained a greater amount of variation in the SNP data set than population origin, despite some evidence of historical introgression.

Comparison of criteria for determining appropriateness of antibiotic prescribing in nursing homes.

BACKGROUND: Measuring the appropriateness of antibiotic prescribing in nursing homes remains a challenge. The revised McGeer criteria, which are widely used to conduct infection surveillance in nursing homes, were not designed to assess antibiotic appropriateness. The Loeb criteria were explicitly designed for this purpose but are infrequently used outside investigational studies. The extent to which the revised McGeer and Loeb criteria overlap and can be used interchangeably for tracking antibiotic appropriateness in nursing homes remains insufficiently studied. METHODS: We conducted a cross-sectional chart review study in 5 Wisconsin nursing homes and applied the revised McGeer and Loeb criteria to all nursing home-initiated antibiotic treatment courses. Kappa (κ) statistics were employed to assess level of agreement overall and by treatment indications. RESULTS: Overall, 734 eligible antibiotic courses were initiated in participating nursing homes during the study period. Of 734 antibiotic courses, 372 (51%) satisfied the Loeb criteria, while only 211 (29%) of 734 satisfied the revised McGeer criteria. Only 169 (23%) of 734 antibiotic courses satisfied both criteria, and the overall level of agreement between them was fair (κ = 0.35). When stratified by infection type, levels of agreement between the revised McGeer and Loeb criteria were moderate for urinary tract infections (κ = 0.45), fair for skin and soft-tissue infections (0.36), and slight for respiratory tract infections (0.17). CONCLUSIONS: Agreement between the revised McGeer and Loeb criteria is limited, and nursing homes should employ the revised McGeer and Loeb criteria for their intended purposes. Studies to establish the best method for ongoing monitoring of antibiotic appropriateness in nursing homes are needed.

Molecular signatures of long-distance oceanic dispersal and the colonization of Pacific islands in Lycium carolinianum.

PREMISE: Long-distance dispersal has been important in explaining the present distributions of many plant species. Despite being infrequent, such dispersal events have considerable evolutionary consequences, because bottlenecks during colonization can result in reduced genetic diversity. We examined the phylogeographic history of Lycium carolinianum, a widespread taxon that ranges from southeastern North America to several Pacific islands, with intraspecific diversity in sexual and mating systems. METHODS: We used Bayesian, likelihood, and coalescent approaches with nuclear and plastid sequence data and genome-wide single nucleotide polymorphisms to reconstruct the dispersal history of this species. We also compared patterns of genetic variation in mainland and island populations using single nucleotide polymorphisms and allelic diversity at the S-RNase mating system gene. RESULTS: Lycium carolinianum is monophyletic and dispersed once from the North American mainland, colonizing the Pacific islands ca. 40,100 years ago. This dispersal was accompanied by a loss of genetic diversity in SNPs and the S-RNase locus due to a colonization bottleneck and the loss of self-incompatibility. Additionally, we documented at least two independent transitions to gynodioecy: once following the colonization of the Hawaiian Islands and loss of self-incompatibility, and a second time associated with polyploidy in the Yucatán region of Mexico. CONCLUSIONS: Long-distance dispersal via fleshy, bird dispersed fruits best explains the unusually widespread distribution of L. carolinianum. The collapse of diversity at the S-RNase locus in island populations suggests that self-fertilization may have facilitated the subsequent colonization of Pacific islands following a single dispersal from mainland North America.

The Proving Ground: Colombo Plan Fellowships and the Changing Landscape of Health Education in Canada, 1951-69.

This article examines the history of the Colombo Plan fellowship program in Canada during the 1950s and 1960s. It will argue that this program had a visible impact on Canadian institutions of learning and health care for three reasons. First, it brought an unprecedented number of students and health care professionals from South and Southeast Asia to Canada; second, it fostered a sense of mission within Canadian institutions about the role education should play in contributing to health and international development overseas; and third, it revealed the challenges and tensions inherent in fulfilling this mission in the context of differences between the objectives of Canadian officials and those of the fellows themselves. With its focus on South and Southeast Asia, the Colombo Plan fellowship program anticipated broader trends regarding the international migration of health workers from that region in later years.

Automated Real-Time Tumor Pharmacokinetic Profiling in 3D Models: A Novel Approach for Personalized Medicine.

Cancer treatment often lacks individual dose adaptation, contributing to insufficient efficacy and severe side effects. Thus, personalized approaches are highly desired. Although various analytical techniques are established to determine drug levels in preclinical models, they are limited in the automated real-time acquisition of pharmacokinetic profiles. Therefore, an online UHPLC-MS/MS system for quantitation of drug concentrations within 3D tumor oral mucosa models was generated. The integration of sampling ports into the 3D tumor models and their culture inside the autosampler allowed for real-time pharmacokinetic profiling without additional sample preparation. Docetaxel quantitation was validated according to EMA guidelines. The tumor models recapitulated the morphology of head-and-neck cancer and the dose-dependent tumor reduction following docetaxel treatment. The administration of four different docetaxel concentrations resulted in comparable courses of concentration versus time curves for 96 h. In conclusion, this proof-of-concept study demonstrated the feasibility of real-time monitoring of drug levels in 3D tumor models without any sample preparation. The inclusion of patient-derived tumor cells into our models may further optimize the pharmacotherapy of cancer patients by efficiently delivering personalized data of the target tissue.

Pediatric blunt abdominal trauma: recognition and management in the emergency department

Blunt abdominal trauma is the third most common cause of pediatric deaths from trauma, but it is the most common unrecog­nized fatal injury. The history and physical examination, combined with the mecha­nism of injury, should be used to develop a thoughtful and directed diagnostic workup. The mainstays of diagnostic evaluation in­clude laboratory testing, sonography, and computed tomography. However, due to the concern for radiation exposure and other risks, the routine use of these studies may not be necessary, and controversy exists as to which studies are beneficial and which are less valuable. This supplement discusses common mechanisms and injuries seen in children with blunt abdominal trauma and takes a closer look at evaluation and man­agement techniques.

Colonization, Baker's law, and the evolution of gynodioecy in Hawaii: implications from a study of Lycium carolinianum.

PREMISE: As Baker's law suggests, the successful colonization of oceanic islands is often associated with uniparental reproduction (self-fertility), but the high incidence of dimorphism (dioecy, gynodioecy) on islands complicates this idea. Lycium carolinianum is widespread, occurring on the North American mainland and the Hawaiian Islands. We examined Baker's ideas for mainland and island populations of L. carolinianum and examined inbreeding depression as a possible contributor to the evolution of gynodioecy on Maui. METHODS: Controlled crosses were conducted in two mainland populations and two populations in Hawaii. Treatments included self and cross pollination, unmanipulated controls, and autogamy/agamospermy. Alleles from the self-incompatibility S-RNase gene were isolated and compared between mainland and island populations. Given self-compatibility in Hawaii, we germinated seeds from self- and cross- treatments and estimated inbreeding depression using seven traits and a measure of cumulative fitness. RESULTS: Mainland populations of Lycium carolinianum are predominately self-incompatible with some polymorphism for self-fertility, whereas Hawaiian populations are self-compatible. Concordantly, S-RNase allelic diversity is reduced in Hawaii compared to the mainland. Hawaiian populations also exhibit significant inbreeding depression. CONCLUSIONS: Self-compatibility in Hawaii and individual variation in self-fertility in mainland populations suggests that a colonization filter promoting uniparental reproduction may be acting in this system. Comparison of S-RNase variation suggests a collapse of allelic diversity and heterozygosity at the S-RNase locus in Hawaii, which likely contributed to mate limitation upon arrival to the Pacific. Inbreeding depression coupled with autonomous self-fertilization may have led to the evolution of gynodioecy on Maui.

Combined Pathology-Driven Algorithmic Testing and Integrated Reporting for Bone Marrow Examination.

CONTEXT.­: The College of American Pathologists published guideline recommending bone marrow synoptic reporting for hematologic neoplasms. OBJECTIVE.­: To evaluate the impact of pathology-driven algorithmic testing (PDAT) with integrated reporting for bone marrow examination on test utilization, ability to render a specific World Health Organization diagnosis, and clinician satisfaction 1 year after implementation. DESIGN.­: We reviewed the hematopathology reports, integrated synoptic reports, and ancillary test results generated during a 12-month period. The initial diagnosis from the hematopathology report was compared with the final diagnosis on the integrated synoptic reports. Test utilization data were compared with a previous year in which ancillary testing was ordered at clinician discretion. Clinicians were anonymously surveyed to assess their satisfaction with PDAT and integrated reporting. RESULTS.­: Integrated reporting resulted in a World Health Organization diagnosis for 80 of 85 cases (94%) compared with 54 (64%) for the hematopathology report alone. Unnecessary testing decreased from 45% pre-PDAT (124 of 274 cases) to 0.7% PDAT (2 of 268 cases), and PDAT resulted in fewer omissions of necessary tests. Clinicians preferred PDAT and valued integrated reporting for a variety of reasons, including the ease of finding relevant prognostic information. CONCLUSIONS.­: Pathology-driven algorithmic testing with integrated reporting improves the pathologist's ability to render a specific World Health Organization diagnosis and improves test utilization. Clinicians prefer PDAT to clinician-ordered testing. This is the first study to examine how synoptic reporting can modify hematologic diagnoses.

Gastric Emphysema: A Cannot-Miss Emergency Medicine Diagnosis.

The radiographic finding of gastric emphysema with portal venous gas is classically an ominous finding, associated with a high rate of mortality. Although classically the case, this imaging finding must be quickly correlated with the overall clinical picture, allowing for the essential differentiation between the highly lethal emphysematous gastritis and the much more benign gastric emphysema, each of which has drastically different management strategies. We report a case of gastric emphysema with portal venous gas likely attributable to a gastric outlet obstruction and gastric mucosal defect in a 17-year-old girl with a chief complaint of syncope that was diagnosed in the emergency department and treated conservatively.

Extracellular signal regulated kinase 5 and inflammasome in progression of mesothelioma.

Malignant mesothelioma is an aggressive cancer in desperate need of treatment. We have previously shown that extracellular signaling regulated kinase 5 (ERK5) plays an important role in mesothelioma pathogenesis using ERK5 silenced human mesothelioma cells exhibiting significantly reduced tumor growth in immunocompromised mice. Here, we used a specific ERK 5 inhibitor, XMD8-92 in various in vitro and in vivo models to demonstrate that inhibition of ERK5 can slow down mesothelioma tumorigenesis. First, we show a dose dependent toxicity of XMD8-92 to 2 human mesothelioma cell lines growing as a monolayer. We also demonstrate the inhibition of ERK5 phosphorylation in various human mesothelioma cell lines by XMD8-92. We further confirmed the toxicity of XMD8-92 towards mesothelioma cell lines grown as spheroids in a 3-D model as well as in intraperitoneal (immune-competent) and intrapleural (immune-deficient) mouse models with and without chemotherapeutic drugs. To ascertain the mechanism, we explored the role of the nod-like receptor family member containing a pyrin domain 3 (NLRP3) inflammasome in the process. We found XMD8-92 attenuated naïve and chemotherapeutic-induced inflammasome priming and activation in mesothelioma cells. It can thus be concluded that ERK5 inhibition attenuates mesothelioma tumor growth and this phenomenon in part is regulated by the inflammasome.

Floral size and shape evolution following the transition to gender dimorphism.

PREMISE OF THE STUDY: Floral morphology is expected to evolve following the transition from cosexuality to gender dimorphism in plants, as selection through male and female function becomes dissociated. Specifically, male-biased dimorphism in flower size can arise through selection for larger flowers through male function, selection for smaller flowers through female function, or both. The evolutionary pathway to floral dimorphism can be most effectively reconstructed in species with intraspecific variation in sexual system. We examined the evolution of flower size and shape in Lycium californicum, whose populations are either gender dimorphic with male and female plants, or cosexual with hermaphroditic plants. METHODS: Floral morphology was characterized in populations spanning the species' complete range. For a subset of the range where cosexual and dimorphic populations are in close proximity, we compared the size and shape of flowers from female and male plants in dimorphic populations to hermaphrodites in cosexual populations, accounting for variation associated with abiotic environmental conditions. KEY RESULTS: The magnitude of flower size dimorphism varied across dimorphic populations. After controlling for environmental variation across cosexual and dimorphic populations, flowers on males were larger than flowers on females and hermaphrodites, whereas flower size did not differ between females and hermaphrodites. Flower shape differences were associated with mating type, sexual system, and environmental variation. CONCLUSIONS: While abiotic environmental gradients shape both overall flower size and shape, male-biased flower size dimorphism in L. californicum appears to arise through selection for larger flowers in males but not smaller flowers in females.

Correlated polymorphism in cytotype and sexual system within a monophyletic species, Lycium californicum.

BACKGROUND AND AIMS: Polyploidy has important effects on reproductive systems in plants and has been implicated in the evolution of dimorphic sexual systems. In particular, higher ploidy is associated with gender dimorphism across Lycium species (Solanaceae) and across populations within the species Lycium californicum. Previous research on the association of cytotype and sexual system within L. californicum sampled a limited portion of the species range, and did not investigate evolutionary transitions between sexual systems. Lycium californicum occurs in arid regions on offshore islands and mainland regions in the south-western United States and Mexico, motivating a more comprehensive analysis of intraspecific variation in sexual system and cytotype across the full range of this species. METHODS: Sexual system (dimorphic vs. cosexual) was determined for 34 populations across the geographical range of L. californicum using field observations of pollen production, and was confirmed using morphological measurements and among-plant correlations of primary sexual traits. Ploidy was inferred using flow cytometry in 28 populations. DNA sequence data from four plastid and two nuclear regions were used to reconstruct relationships among populations and to map transitions in sexual system and ploidy. KEY RESULTS: Lycium californicum is monophyletic, ancestrally diploid and cosexual, and the association of gender dimorphism and polyploidy appears to have two evolutionary origins in this species. Compared with cosexual populations, dimorphic populations had bimodal anther size distributions, negative correlations between male and female floral traits, and larger coefficients of variation for primary sexual traits. Flow cytometry confirmed tetraploidy in dimorphic populations, whereas cosexual populations were diploid. CONCLUSIONS: Tetraploidy and gender dimorphism are perfectly correlated in L. californicum, and the distribution of tetraploid-dimorphic populations is restricted to populations in Arizona and the Baja California peninsula. The analysis suggests that tetraploidy and dimorphism likely established in Baja California and may have evolved multiple times.

Intraspecific variation in gender strategies in Lycium (Solanaceae): associations with ploidy and changes in floral form following the evolution of gender dimorphism.

UNLABELLED: • PREMISE OF THE STUDY: An association between polyploidy and gender dimorphism has been noted in several plant lineages. Whereas the majority of Lycium species are diploid and have hermaphroditic flowers in cosexual populations, gender dimorphism (gynodioecy, dioecy) has been shown to be uniformly associated with polyploidy in previous studies. Preliminary field observations suggested that some populations of Lycium carolinianum were dimorphic, providing a test of this association.• METHODS: We assessed sexual systems and cytotype variation (to infer ploidy) across 17 populations of L. carolinianum. Comparison of flowers in cosexual and dimorphic populations were used to infer changes in reproductive morphology associated with the evolution of gynodioecy.• KEY RESULTS: The majority of populations were cosexual in gender expression, but dimorphism was present in the Yucatán and in some populations in Hawaii. Populations varied in ploidy and were either diploid or tetraploid. Floral sexual dimorphism was present in all gynodioecious populations, though the magnitude differed and was cryptic in some cases. Our results are consistent with the hypothesis that following the evolution of gynodioecy, flowers on hermaphrodites increased in size.• CONCLUSIONS: Dimorphic sexual systems have likely evolved convergently in L. carolinianum. In contrast to previous studies, dimorphism is not perfectly associated with polyploidy. Although our sample from the Yucatán was both tetraploid and dimorphic, all populations in Hawaii were diploid regardless of sexual system. Ongoing phylogeographic and mating system studies will contribute to our understanding of reproductive evolution in this widespread, polymorphic species.

CREB-induced inflammation is important for malignant mesothelioma growth.

Malignant mesothelioma (MM) is an aggressive tumor with no treatment regimen. Previously we have demonstrated that cyclic AMP response element binding protein (CREB) is constitutively activated in MM tumor cells and tissues and plays an important role in MM pathogenesis. To understand the role of CREB in MM tumor growth, we generated CREB-inhibited MM cell lines and performed in vitro and in vivo experiments. In vitro experiments demonstrated that CREB inhibition results in significant attenuation of proliferation and drug resistance of MM cells. CREB-silenced MM cells were then injected into severe combined immunodeficiency mice, and tumor growth in s.c. and i.p. models of MM was followed. We observed significant inhibition in MM tumor growth in both s.c. and i.p. models and the presence of a chemotherapeutic drug, doxorubicin, further inhibited MM tumor growth in the i.p. model. Peritoneal lavage fluids from CREB-inhibited tumor-bearing mice showed a significantly reduced total cell number, differential cell counts, and pro-inflammatory cytokines and chemokines (IL-6, IL-8, regulated on activation normal T cell expressed and secreted, monocyte chemotactic protein-1, and vascular endothelial growth factor). In vitro studies showed that asbestos-induced inflammasome/inflammation activation in mesothelial cells was CREB dependent, further supporting the role of CREB in inflammation-induced MM pathogenesis. In conclusion, our data demonstrate the involvement of CREB in the regulation of MM pathogenesis by regulation of inflammation.

Extracellular signal-regulated kinase 5 and cyclic AMP response element binding protein are novel pathways inhibited by vandetanib (ZD6474) and doxorubicin in mesotheliomas.

Malignant mesothelioma (MM), lung cancers, and asbestosis are hyperproliferative diseases associated with exposures to asbestos. All have a poor prognosis; thus, the need to develop novel and effective therapies is urgent. Vandetanib (Van) (ZD6474, ZACTIMA) is a tyrosine kinase inhibitor that has shown equivocal results in clinical trials for advanced non-small cell lung cancer. However, tyrosine kinase inhibitors alone have shown no significant clinical activity in phase II trials of patients with unresectable MM. Using epithelioid (HMESO) and sarcomatoid (H2373) human MM lines, the efficacy of tumor cell killing and signaling pathways modulated by Van with and without doxorubicin (Dox) was examined. Van alone reduced total cell numbers in HMESO MM and synergistically increased the toxicity of Dox in HMESO and H2373 cells. Most importantly, we identified two novel cell survival/resistance pathways, ERK5 and cyclic AMP response element binding protein (CREB), that were inhibited by Van and Dox. After silencing of either ERK5 or CREB, significant decreases in cell numbers in the Dox-resistant sarcomatoid H2373 line were observed. Results suggest that a plethora of cell signaling pathways associated with cell survival are induced by Dox but inhibited by the addition of Van in MM. Data from our study support the combined efficacy of Van and Dox as a novel approach in the treatment of MM that is further enhanced by blocking ERK5 or CREB signaling cascades.

Absence of anaplastic lymphoma kinase translocations in signet ring cell carcinomas of the upper gastrointestinal tract.

BACKGROUND: Anaplastic lymphoma kinase (ALK) fusion oncogenes are present in multiple cancer types. The inversion of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes on chromosome 2 is present in a subset of patients with non-small-cell lung cancer (NSCLC). ALK-rearranged lung cancers demonstrate a significantly higher incidence of signet ring cell histology than do ALK-negative tumors. Based on the histologic similarities of ALK-rearranged NSCLC and signet ring cell carcinomas (SRCCs) of the gastrointestinal tract, we hypothesized that SRCC of the upper gastrointestinal (GI) tract may also harbor ALK translocations. METHODS: Thirty-five formalin-fixed, paraffin-embedded (FFPE) diagnostic tissue specimens of SRCC or poorly differentiated adenocarcinoma with greater than 10% signet ring cell features originating from the upper GI tract were obtained and confirmed by a board-certified, GI pathologist. SRCC specimens were analyzed by fluorescence in situ hybridization (FISH) analysis, with an ALK (2p23) break-apart probe. RESULTS: The FISH analysis revealed no evidence of ALK translocation. All 35 (100%) SRCC specimens showed intact ALK FISH signals. CONCLUSIONS: These data indicate that, despite histologic similarities between SRCC of the upper GI tract and ALK-positive NSCLC, ALK translocations are unlikely to be a significant contributor to the molecular etiology of SRCC. Further genomic investigations are ongoing.

Curcumin: a double hit on malignant mesothelioma.

Inflammation is a key mediator in the development of malignant mesothelioma, which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anticarcinogenic properties through its anti-inflammatory effects. Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of proinflammatory cytokines, interleukin (IL)-1ß and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of malignant mesothelioma cells. Using in vitro models with mouse and human malignant mesothelioma cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of high-mobility group box 1 (HMGB1) without processing of IL-1ß and IL-18. Absence of IL-1ß processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1ß priming through inhibition of the NF-κB pathway. Furthermore, curcumin's cytotoxicity in malignant mesothelioma cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death. We also demonstrate that curcumin-mediated caspase-1 activation is oxidant dependent by using N-acetyl-L-cysteine (NAC) to inhibit pyroptosis. PCR array analysis using the human inflammasome template revealed that curcumin significantly downregulated levels of inflammasome-related gene expression involved in inflammation, e.g., NF-κB, toll-like receptors (TLR), and IL-1ß. Our data indicate that curcumin has a double effect on malignant mesothelioma cells through induction of pyroptosis while subsequently protecting against inflammation.

Pediatric blunt abdominal trauma in the emergency department: evidence-based management techniques.

Blunt abdominal trauma is the third most common cause of pediatric trauma deaths, but it is the most common unrecognized fatal injury. This issue discusses common mechanisms and injuries seen in children with blunt abdominal trauma and takes a closer look at current evaluation and management techniques. The main-stays of diagnostic evaluation include laboratory, sonography, and computed tomography studies. However, the routine use of these studies may not be necessary, and controversy exists as to which studies are beneficial and which are less valuable. The concern for radiation-induced malignancy has led to increased efforts to limit radiation exposure by decreasing the use of unnecessary computed tomography scans. The history and physical examination, combined with the mechanism of injury, should be used to develop a thoughtful and directed diagnostic workup.

Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells.

BACKGROUND: Pleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear. RESULTS: We document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1ß, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model. CONCLUSIONS: These novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis.