SUMMARYMembers of the 18 glycosyl hydrolase (GH 18) gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1), which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2) and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.

Background Adaptive magnetic resonance imaging‐guided radiation therapy (MRgRT) can escalate dose to tumors while minimizing dose to normal tissue. We evaluated outcomes of inoperable pancreatic cancer patients treated using MRgRT with and without dose escalation. Methods We reviewed 44 patients with inoperable pancreatic cancer treated with MRgRT. Treatments included conventional fractionation, hypofractionation, and stereotactic body radiation therapy. Patients were stratified into high‐dose (biologically effective dose [BED 10 ] >70) and standard‐dose groups (BED 10 ≤70). Overall survival (OS), freedom from local failure (FFLF) and freedom from distant failure (FFDF) were evaluated using Kaplan‐Meier method. Cox regression was performed to identify predictors of OS. Acute gastrointestinal (GI) toxicity was assessed for 6 weeks after completion of RT. Results Median follow‐up was 17 months. High‐dose patients (n = 24, 55%) had statistically significant improvement in 2‐year OS (49% vs 30%, P = 0.03) and trended towards significance for 2‐year FFLF (77% vs 57%, P = 0.15) compared to standard‐dose patients (n = 20, 45%). FFDF at 18 months in high‐dose vs standard‐dose groups was 24% vs 48%, respectively ( P = 0.92). High‐dose radiation (HR: 0.44; 95% confidence interval [CI]: 0.21‐0.94; P = 0.03) and duration of induction chemotherapy (HR: 0.84; 95% CI: 0.72‐0.98; P = 0.03) were significantly correlated with OS on univariate analysis but neither factor was independently predictive on multivariate analysis. Grade 3+ GI toxicity occurred in three patients in the standard‐dose group and did not occur in the high‐dose group. Conclusions Patients treated with dose‐escalated MRgRT demonstrated improved OS. Prospective evaluation of high‐dose RT regimens with standardized treatment parameters in inoperable pancreatic cancer patients is warranted.

PurposeDaily magnetic resonance (MR)–guided radiation has the potential to improve stereotactic body radiation therapy (SBRT) for tumors of the liver. Magnetic resonance imaging (MRI) introduces unique variables that are untested clinically: electron return effect, MRI geometric distortion, MRI to radiation therapy isocenter uncertainty, multileaf collimator position error, and uncertainties with voxel size and tracking. All could lead to increased toxicity and/or local recurrences with SBRT. In this multi-institutional study, we hypothesized that direct visualization provided by MR guidance could allow the use of small treatment volumes to spare normal tissues while maintaining clinical outcomes despite the aforementioned uncertainties in MR-guided treatment.Methods and materialsPatients with primary liver tumors or metastatic lesions treated with MR-guided liver SBRT were reviewed at 3 institutions. Toxicity was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4. Freedom from local progression (FFLP) and overall survival were analyzed with the Kaplan-Meier method and χ2 test.ResultsThe study population consisted of 26 patients: 6 hepatocellular carcinomas, 2 cholangiocarcinomas, and 18 metastatic liver lesions (44% colorectal metastasis). The median follow-up was 21.2 months. The median dose delivered was 50 Gy at 10 Gy/fraction. No grade 4 or greater gastrointestinal toxicities were observed after treatment. The 1-year and 2-year overall survival in this cohort is 69% and 60%, respectively. At the median follow-up, FFLP for this cohort was 80.4%. FFLP for patients with hepatocellular carcinomas, colorectal metastasis, and all other lesions were 100%, 75%, and 83%, respectively.ConclusionsThis study describes the first clinical outcomes of MR-guided liver SBRT. Treatment was well tolerated by patients with excellent local control. This study lays the foundation for future dose escalation and adaptive treatment for liver-based primary malignancies and/or metastatic disease.

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Purpose Melanoma is a heterogeneous disease where monotherapies are likely to fail due to variations in genomic signatures. B-RAF inhibitors have been clinically inadequate but response might be augmented with combination therapies targeting multiple signaling pathways. We investigate the pre-clinical efficacy of combining the multi-kinase inhibitor Sorafenib or mutated B-RAF inhibitor PLX4720 with Riluzole, an inhibitor of glutamate release that antagonizes GRM1 (metabotropic glutamate receptor1) signaling in melanoma cells. Experimental Design Melanoma cell lines that express GRM1 and either wild type B-RAF or mutated B-RAF were treated with Riluzole, Sorafenib, PLX4720 or the combination of Riluzole with Sorafenib or with PLX4720. Extra-cellular glutamate levels were determined by glutamate release assays. MTT assays and cell cycle analysis demonstrate effects of the compounds on proliferation, viability and cell cycle profiles. Western immunoblots and immunohistochemical staining showed apoptotic markers. Consequences on MAPK pathway were assessed by western immunoblots. Xenograft tumor models were used to determine the efficacy of the compounds in vivo. Results The combination of Riluzole with Sorafenib exhibited enhanced anti-tumor activities in GRM1 expressing melanoma cells harboring either wild type or mutated B-RAF. The combination of Riluzole with PLX4720 showed lessened efficacy compared with the Riluzole and Sorafenib combination in suppressing the growth of GRM1 expressing cells harboring the B-RAFV600E mutation. Conclusions The combination of Riluzole with Sorafenib appears potent in suppressing tumor proliferation in vitro and in vivo in GRM1 expressing melanoma cells regardless of B-RAF genotype and may be a viable therapeutic clinical combination.

The Wnt/β-catenin signaling pathway is frequently activated in hepatocellular carcinoma (HCC). Downstream signaling events involving the Wnt/β-catenin cascade occur through T-cell factor (TCF) proteins. The human TCF-4 gene is composed of 17 exons with multiple alternative splicing sites. However, the role of different TCF-4 isoforms in the pathogenesis of HCC is unknown. The purpose of this study was to identify and characterize TCF-4 isoforms in HCC. We identified 14 novel TCF-4 isoforms from four HCC cell lines. Functional analysis following transfection and expression in HCC cells revealed distinct effects on the phenotype. The TCF-4J isoform expression produced striking features of malignant transformation characterized by high cell proliferation rate, migration and colony formation even though its transcriptional activity was low. In contrast, the TCF-4K isoform displayed low TCF transcriptional activity; cell proliferation rate and colony formation were reduced as well. Interestingly, TCF-4J and TCF-4K differed by only five amino acids (the SxxSS motif). Thus, these studies suggest that conserved splicing motifs may have a major influence on the transcriptional activity and functional properties of TCF-4 isoforms and alter the characteristics of the malignant phenotype.

The goal of this study was to examine the effects of GRM1 blockade on melanoma anchorage independent growth and invasion. We performed colony and invasion assays using GRM1-expressing melanoma lines and the GRM1 negative UACC930 line. Using the glutamate-release inhibitor Riluzole or the noncompetitive GRM1 antagonist BAY36-7620 we were able to induced considerable inhibition of colony formation and invasion in GRM1-expressing melanoma lines. Neither pharmacological agent induced a significant reduction in colony formation or invasion in the GRM1 negative melanoma line, UACC930. Additionally we assessed the efficacy of these inhibitors to inhibit the growth of fresh melanoma tumor samples cultured on a 74μm nylon mesh. Both Riluzole and BAY36-7620 significantly inhibited tumor cell growth into the interstitial spaces of the mesh. When repeated with normal mole samples both inhibitors were much less effective in preventing the outgrowth of cells. These experiments show that a specific antagonist of GRM1 (BAY36-7620) or an inhibitor of glutamate release (Riluzole) can significantly suppress melanoma migration, invasion and colony formation as well as inhibit the proliferation of fresh melanoma cells. These findings added to our previous work, strengthen the case that GRM1 is a valid therapeutic target in patients with melanoma.

Objective To examine the association between linguistic acculturation (assessed using the Language Use and Linguistic Preference subscales from the Bidimensional Acculturation Scale for Hispanics) and skin cancer-related behaviors among U.S. Hispanic adults. We hypothesized that, compared to Hispanics denoted as Spanish acculturated, English acculturated Hispanics would report less frequent shade seeking and use of sun protective clothing and higher rates of sunscreen use, sunbathing, and indoor tanning. Design Online survey study conducted in September, 2011. Setting Survey of Hispanic adults residing in five southern and western U.S. states. Participants A population-based sample of 788 Hispanic adults drawn from a nationally representative web panel. Main Outcome Measures Self-reported sunscreen use, shade seeking, use of sun protective clothing, sunbathing, and indoor tanning. Results Multivariable regression analyses were conducted to examine predictors of the skin cancer-related behaviors. As hypothesized, English acculturated Hispanics had lower rates of shade seeking and use of sun protective clothing and reported higher rates of sunbathing and indoor tanning than Spanish acculturated Hispanics. English acculturated Hispanics and bicultural Hispanics (i.e., those with high Spanish and high English acculturation) reported comparably high rates of sunbathing and indoor tanning. Results suggested that bicultural Hispanics seek shade and wear sun protective clothing less often than Spanish acculturated Hispanics but more often than English acculturated Hispanics. Acculturation was not associated with sunscreen use. Conclusions Hispanic adults do not routinely engage in behaviors that reduce their risk of skin cancer. Bicultural and English acculturated Hispanics are particularly in need of skin cancer prevention interventions.