Comparison of Magnetic Resonance Imaging and Endoscopic Ultrasound in the Sizing of Intraductal Papillary Mucinous Neoplasia of the Pancreas.

OBJECTIVES: Because IPMNs are potentially malignant, surveillance of IPMN is recommended by magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS). The aim of the study was the evaluation of the concordance between EUS and MRI regarding cyst size. METHODS: Retrospective data analysis was done for patients with IPMN in whom EUS and MRI were performed simultaneously (≤60 days). The measured cyst size of both procedures was compared by Bland-Altman plots. Agreement of cyst localization and dilation of main pancreatic duct was assessed using kappa statistics. RESULTS: Fifty-nine cases were evaluated (median age, 71 years; 65% female; median time interval between both investigations, 17 days). The mean difference of IPMN maximal diameter between EUS and MRI was 0.55 mm with a prediction interval of -9.20 to +10.29 mm for 95% of the expected differences. There was strong interobserver agreement regarding cyst localization ( κ = 0.669, P = 1.06e -13 ) and the width of main pancreatic duct (<5, 5-9, and ≥10 mm; κ = 0.676 caput, κ = 0.823 corpus). CONCLUSIONS: We found a clinically relevant difference in cyst size comparing EUS and MRI. Therefore, alternating EUS and MRI for follow-up of the "worrisome feature" size growth is not reasonable.

Genetic Disruption of Cilia-Associated Signaling Pathways in Patients with VACTERL Association.

VACTERL association is a rare malformation complex consisting of vertebral defects, anorectal malformation, cardiovascular defects, tracheoesophageal fistulae with esophageal atresia, renal malformation, and limb anomalies. According to current knowledge, VACTERL is based on a multifactorial pathogenesis including genomic alterations. This study aimed to improve the understanding of the genetic mechanisms in the development of VACTERL by investigating the genetic background with a focus on signaling pathways and cilia function. The study was designed as genetic association study. For this, whole-exome sequencing with subsequent functional enrichment analyses was performed for 21 patients with VACTERL or a VACTERL-like phenotype. In addition, whole-exome sequencing was performed for three pairs of parents and Sanger-sequencing was performed for ten pairs of parents. Analysis of the WES-data revealed genetic alteration in the Shh- and Wnt-signaling pathways. Additional performed functional enrichment analysis identified an overrepresentation of the cilia, including 47 affected ciliary genes with clustering in the DNAH gene family and the IFT-complex. The examination of the parents showed that most of the genetic changes were inherited. In summary, this study indicates three genetically determined damage mechanisms for VACTERL with the potential to influence each other, namely Shh- and Wnt-signaling pathway disruption, structural cilia defects and disruption of the ciliary signal transduction.

MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer.

KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2'3'-cyclic GMP-AMP (2'3'-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.

Genetic Evidence for Congenital Vascular Disorders in Patients with VACTERL Association.

INTRODUCTION: The VACTERL association is a rare malformation complex, showing at least three anomalies of the following organ systems: vertebra, anorectum, heart and vessels, trachea and esophagus, genitourinary tract, and limbs. In addition to a multifactorial event, congenital vascular disorders are also discussed as triggers for the VACTERL association. The aim of this study was to determine whether there is a genetic background for vascular disorders triggering VACTERL association. MATERIALS AND METHODS: We performed a functional analysis on whole exome sequencing data of 21 patients with VACTERL or VACTERL-like phenotype using the online analysis tool "Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8." The study was approved by the institutional ethics committee (approval no. 026-13). Written informed consent was obtained from all patients or their parents. RESULTS: We identified a total of 86 genetic variants (in 75 genes) classified as damaging (including probably damaging missense, nonsense, and frameshift variants), which are associated to cardiovascular development. Each investigated patient showed at least one damaging variant in genes associated to cardiovascular development. These variants were further reduced by significance in cardiovascular development to 39 genetic variants (in 33 genes). Of note, a pair of siblings, both presenting with cardiac and renal defects, had the same damaging variant in two different genes. CONCLUSION: Our results indicate a genetic background for congenital vascular disorders in patients with VACTERL association. In line with the literature, our data suggest that genetic mutation led to vascular diseases, which in turn may cause malformations similar to the VACTERL association.

Phosphorylation of RAB7 by TBK1/IKKε Regulates Innate Immune Signaling in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease enriched for mutations in PTEN and dysregulation of innate immune signaling. Here, we demonstrate that Rab7, a recently identified substrate of PTEN phosphatase activity, is also a substrate of the innate immune signaling kinases TANK-binding kinase 1 (TBK1)/IκB kinase ε (IKKε) on the same serine-72 (S72) site. An unbiased search for novel TBK1/IKKε substrates using stable isotope labeling with amino acids in cell culture phosphoproteomic analysis identified Rab7-S72 as a top hit. PTEN-null TNBC cells expressing a phosphomimetic version of Rab7-S72 exhibited diffuse cytosolic Rab7 localization and enhanced innate immune signaling, in contrast to a kinase-resistant version, which localized to active puncta that promote lysosomal-mediated stimulator of interferon genes (STING) degradation. Thus, convergence of PTEN loss and TBK1/IKKε activation on Rab7-S72 phosphorylation limited STING turnover and increased downstream production of IRF3 targets including CXCL10, CCL5, and IFNß. Consistent with this data, PTEN-null TNBC tumors expressed higher levels of STING, and PTEN-null TNBC cell lines were hyperresponsive to STING agonists. Together, these findings begin to uncover how innate immune signaling is dysregulated downstream of TBK1/IKKε in a subset of TNBCs and reveals previously unrecognized cross-talk with STING recycling that may have implications for STING agonism in the clinic. SIGNIFICANCE: These findings identify Rab7 as a substrate for TBK1 for regulation of innate immune signaling, thereby providing important insight for strategies aimed at manipulating the immune response to enhance therapeutic efficacy in TNBC.

Development of a solvent-free polylactide/calcium carbonate composite for selective laser sintering of bone tissue engineering scaffolds.

Since large bone defects cannot be healed by the body itself, continuous effort is put into the development of 3D scaffolds for bone tissue engineering. One method to fabricate such scaffolds is selective laser sintering (SLS). However, there is a lack of solvent-free prepared microparticles suitable for SLS. Hence, the aim of this study was to develop a solvent-free polylactide/calcium carbonate composite powder with tailored material properties for SLS. Four composite powders with a composition of approximately 75 wt% polylactide (PLLA as well as PDLLA) and 25 wt% calcium carbonate (calcite) were prepared by a milling process based on GMP standards. Four different grades of polylactide were chosen to cover a broad inherent viscosity range of 1.0-3.6 dl/g. The composite material with the lowest inherent viscosity (1.0 dl/g) showed the best processability by SLS. This was caused by the small polymer particle diameter (50 µm) and the small zero-shear melt viscosity (400 Pa·s), which led to fast sintering. The SLS process parameters were developed to achieve low micro-porosity (approx. 2%) and low polymer degradation (no measurable decrease of the inherent viscosity). A biaxial bending strength of up to 75 MPa was achieved. Cell culture assays indicated good viability of MG-63 osteoblast-like cells on the SLS specimens. Finally, the manufacture of 3D scaffolds with interconnected pore structure was demonstrated. After proving the biocompatibility of the material, the developed scaffolds could have great potential to be used as patient-specific bone replacement implants.

Neisseria gonorrhoeae-Induced Inflammatory Pyroptosis in Human Macrophages is Dependent on Intracellular Gonococci and Lipooligosaccharide.

Neisseria gonorrhoeae, the human obligate pathogen responsible for the sexually transmitted disease gonorrhea, has evolved several mechanisms to evade the host immune response. One such mechanism is the modulation of host cell death pathways. In this study, we defined cell death pathways induced by N gonorrhoeae in human monocyte-derived macrophages (MDMs). In a dose-dependent manner, N gonorrhoeae stimulation of MDMs resulted in caspase 1 and 4-dependent cell deaths, indicative of canonical and noncanonical pyroptosis, respectively. Internalization of bacteria or stimulation with lipooligosaccharide (LOS) specifically induced pyroptosis in MDMs and increased secretion of IL-1ß. Collectively, our results demonstrate that N gonorrhoeae induces inflammatory pyroptosis in human macrophages due in part to intracellular LOS. We propose that this in turn may exacerbate inflammatory outcomes observed during mucosal infection.

Coral Reefs and People in a High-CO2 World: Where Can Science Make a Difference to People?

REEFS AND PEOPLE AT RISK: Increasing levels of carbon dioxide in the atmosphere put shallow, warm-water coral reef ecosystems, and the people who depend upon them at risk from two key global environmental stresses: 1) elevated sea surface temperature (that can cause coral bleaching and related mortality), and 2) ocean acidification. These global stressors: cannot be avoided by local management, compound local stressors, and hasten the loss of ecosystem services. Impacts to people will be most grave where a) human dependence on coral reef ecosystems is high, b) sea surface temperature reaches critical levels soonest, and c) ocean acidification levels are most severe. Where these elements align, swift action will be needed to protect people's lives and livelihoods, but such action must be informed by data and science. AN INDICATOR APPROACH: Designing policies to offset potential harm to coral reef ecosystems and people requires a better understanding of where CO2-related global environmental stresses could cause the most severe impacts. Mapping indicators has been proposed as a way of combining natural and social science data to identify policy actions even when the needed science is relatively nascent. To identify where people are at risk and where more science is needed, we map indicators of biological, physical and social science factors to understand how human dependence on coral reef ecosystems will be affected by globally-driven threats to corals expected in a high-CO2 world. Western Mexico, Micronesia, Indonesia and parts of Australia have high human dependence and will likely face severe combined threats. As a region, Southeast Asia is particularly at risk. Many of the countries most dependent upon coral reef ecosystems are places for which we have the least robust data on ocean acidification. These areas require new data and interdisciplinary scientific research to help coral reef-dependent human communities better prepare for a high CO2 world.

Splenectomy improves survival by increasing arterial blood supply in a rat model of reduced-size liver.

Prevention of acute portal hyperperfusion in small-for-size livers by inflow modulation results in beneficial postoperative outcome. The objective of this study was to unravel the underlying mechanism, emphasizing the intimate relationship between portal venous (PV) and hepatic arterial (HA) blood flow (BF). Rats underwent partial hepatectomy (pHx), splenectomy before pHx or splenectomy and ligation of the A. hepatica before pHx. Portal venous blood flow (PVBF), hepatic arterial blood flow (HABF), and tissue pO2 were assessed during stepwise resection from 30% to 90%. Hepatic regeneration and hypoxia-responsive gene expression were analyzed in each group after nonlethal 85% pHx. 90% pHx caused a fourfold rise in PVBF, a slight decrease in HABF with a 50% reduction in pO2, and high mortality. Splenectomy before pHx reduced the PVBF and caused a rise in HABF with doubling in tissue pO2. An attenuation of hypoxia-responsive gene expression turned into enhanced hepatocellular regeneration and improved survival. A. hepatica ligation abolished the beneficial effect of splenectomy on tissue oxygenation, proliferation, and outcome. In conclusion, the beneficial effect of splenectomy in small-for-size livers can be attributed to a rise in HABF with sufficient oxygen supply rather than to a reduced portal venous hyperperfusion to the remnant liver.

A national study predicting licensed social workers' levels of political participation: the role of resources, psychological engagement, and recruitment networks.

The social work literature is replete with studies evaluating social workers' direct practice interventions, but strikingly few have assessed how well social workers are faring in the political arena. This study tests a major theoretical model, the civic voluntarism model, developed to explain why some citizens become involved in politics, whereas others do not. The study sample consisted of 396 randomly selected social workers licensed in 11 states, all of whom completed a 25-minute telephone survey. Social workers were surveyed to determine the role of the following variables in explaining social workers' political activity levels-resources needed to participate, psychological engagement, and attachment to recruitment networks. The results indicate that the civic voluntarism model was significant and accounted for 42 percent of the variance. The strongest predictors of social workers' political activity were NASW membership and political interest. This study provides empirical support for the idea that being connected to social networks and having a psychological engagement with politics are crucial factors in explaining social workers' political participation. Implications for social work education are included.