Purpose: Heritable genetic variations can affect the inflammatory tumor microenvironment, which can ultimately affect cancer susceptibility and clinical outcomes. Recent evidence indicates that IDO2, a positive modifier in inflammatory disease models, is frequently upregulated in pancreatic ductal adenocarcinoma (PDAC). A unique feature of IDO2 in humans is the high prevalence of two inactivating singlenucleotide polymorphisms (SNP), which affords the opportunity to carry out loss-of-function studies directly in humans. In this study, we sought to address whether genetic loss of IDO2 may influence PDAC development and responsiveness to treatment.Experimental Design: Transgenic Ido2 þ/þ and Ido2 À/À mice in which oncogenic KRAS is activated in pancreatic epithelial cells were evaluated for PDAC. Two patient data sets (N ¼ 200) were evaluated for the two IDO2-inactivating SNPs together with histologic, RNA expression, and clinical survival data.Results: PDAC development was notably decreased in the Ido2 À/À mice (30% vs. 10%, P < 0.05), with a female predominance similar to the association observed for one of the human SNPs. In patients, the biallelic occurrence of either of the two IDO2-inactivating SNPs was significantly associated with markedly improved disease-free survival in response to adjuvant radiotherapy (P < 0.01), a treatment modality that has been highly debated due to its variable efficacy.Conclusions: The results of this study provide genetic support for IDO2 as a contributing factor in PDAC development and argue that IDO2 genotype analysis has the immediate potential to influence the PDAC care decision-making process through stratification of those patients who stand to benefit from adjuvant radiotherapy.

We genetically characterized the synaptic role of the Drosophila homologue of human DCAF12, a putative cofactor of Cullin4 (Cul4) ubiquitin ligase complexes. Deletion of Drosophila DCAF12 impairs larval locomotion and arrests development. At larval neuromuscular junctions (NMJs), DCAF12 is expressed presynaptically in synaptic boutons, axons, and nuclei of motor neurons. Postsynaptically, DCAF12 is expressed in muscle nuclei and facilitates Cul4-dependent ubiquitination. Genetic experiments identified several mechanistically independent functions of DCAF12 at larval NMJs. First, presynaptic DCAF12 promotes evoked neurotransmitter release. Second, postsynaptic DCAF12 negatively controls the synaptic levels of the glutamate receptor subunits GluRIIA, GluRIIC, and GluRIID. The down-regulation of synaptic GluRIIA subunits by nuclear DCAF12 requires Cul4. Third, presynaptic DCAF12 is required for the expression of synaptic homeostatic potentiation. We suggest that DCAF12 and Cul4 are critical for normal synaptic function and plasticity at larval NMJs.

Introduction: Repair of inguinal hernia is a common procedure, but there is a lack of consensus as to the optimal repair technique along with the use of mesh and methods of mesh fixation. The objective of this study was to evaluate the efficacy and safety of fibrin sealant for mesh fixation in laparoscopic totally extraperitoneal (TEP) inguinal hernia repair.Materials and Methods: A study was conducted of the first 200 patients undergoing TEP hernia repair with mesh fixation using fibrin sealant between March 2012 and January 2014. The primary outcome measures were (1) chronic pain (persisting for >3 months), (2) persistence of hernia (recurrence identified within first 2 weeks postoperatively), (3) hernia recurrence, and (4) any additional perioperative complications. The mean follow-up in the series was 34.4 ± 6.1 months (range 22.2–44.1).Results: Of the 278 hernias repaired in 204 patients (74 bilateral, 130 unilateral), 38 were recurrent and 240 were primary. Three patients (1.5%) had a persistent hernia, including one with a planned return to the operating room the next day due to poor visualization. Three patients (1.5%) had a hernia recurrence. Twelve patients (5.9%) reported experiencing chronic pain. The remaining complications were minor and resolved over time.Conclusions: TEP repair of inguinal hernia using mesh secured with fibrin sealant can be effectively used to treat primary, recurrent, unilateral, and bilateral inguinal hernias in adults with minimal recurrence rates and complications during almost 3 years of follow-up.

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