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Purpose: We investigated the contribution of Sonic hedgehog (SHH) to pancreatic cancer progression.Experimental Design: We expressed SHH in a transformed primary ductal-derived epithelial cell line from the human pancreas, transformed hTert-HPNE (T-HPNE), and evaluated the effects on tumor growth. We also directly inhibited the activity of SHH in vivo by administering a blocking antibody to mice challenged orthotopically with the Capan-2 pancreatic cancer cell line, which is known to express SHH and form moderately differentiated tumors in nude mice.Results: Our data provide evidence that expression of SHH influences tumor growth by contributing to the formation of desmoplasia in pancreatic cancer. We further show that SHH affects the differentiation and motility of human pancreatic stellate cells and fibroblasts.Conclusions: These data suggest that SHH contributes to the formation of desmoplasia in pancreatic cancer, an important component of the tumor microenvironment.

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Perineural invasion in pancreatic adenocarcinoma, a common pathologic phenomenon whereby cancer cells invade and intimately contact the endoneurium of pancreatic nerves, is thought to contribute to both pain and local disease recurrence. MUC1, a type I transmembrane mucin that can affect the adhesive properties of cells, contains a large extracellular tandem repeat domain, which is heavily glycosylated in normal epithelia, but is overexpressed and differentially glycosylated in pancreatic cancer. This altered glycosylation includes the shortened core I O-glycans for monosialyl and disialyl T antigens. Myelin-associated glycoprotein (MAG), a membrane-bound protein expressed on oligodendrocytes and Schwann cells, binds myelin to neurons. MAG's preferred ligands are derivatives of the monosialyl and disialyl T antigen. We investigated whether MUC1 is a counter-receptor for MAG and if their interaction contributed to pancreatic perineural invasion. Results showed that MAG binds pancreatic cells expressing MUC1, that this binding is sialidase-sensitive, and that MAG physically associates with MUC1. Heterotypic adhesion assays between pancreatic cancer cells and Schwann cells revealed that increased expression of MUC1 or MAG enhanced adhesion. Conversely, specific inhibition of MAG or sialyl-T MUC1 partially blocked adhesion. Immunohistochemical analysis of pancreatic perineural invasion showed the expression of both MUC1 and MAG. These results support the hypothesis that the adhesive interactions between MUC1 and MAG are of biological significance in pancreatic cancer perineural invasion. [Cancer Res 2007;67(21):10222–9]

Supplementary Figures 1-2 from MUC1 Is a Counter-Receptor for Myelin-Associated Glycoprotein (Siglec-4a) and Their Interaction Contributes to Adhesion in Pancreatic Cancer Perineural Invasion

Surgical helmet systems (SHSs) have been used to decrease iatrogenic contamination to prevent periprosthetic joint infections. However, the use of SHSs has been controversial. Therefore, the purpose of this study was to investigate iatrogenic contamination of traditional surgical attire (TSA), SHSs, and SHSs with delayed ventilation (SHS-DV) (helmet fan not turned on until surgeon gowned and gloved). A total of 180 orthopedic surgical procedures were prospectively enrolled and randomized into one of three cohorts. The TSA cohort included any orthopedic procedures, while the SHS and SHS-DV cohorts included arthroplasty procedures. Cultures were obtained from bilateral forearms, axillae, the sternum, and face shields for SHS groups. There were 60 surgeries in each group. The rate of positive cultures was calculated for each cohort and stratified by location and type of microorganism. The positive culture rates were 15% in the TSA, 25% in the SHS, 18% in the SHS-DV cohorts. The positive swab culture rates were 6% in the TSA, 7% in the SHS, and 4% in the SHS-DV cohorts. The positive culture rate was highest from the forearms in the TSA cohort (10%), the face shield in the SHS cohort (20%), and the chest in the SHS-DV cohort (7%). Coagulase-negative Staphylococcus was the most common bacteria cultured. The overall bacterial contamination rates were similar between the TSA and the SHS cohorts, with a lower rate in the SHS-DV cohort. Waiting to initiate airflow in SHSs and treating the shields as contaminated may reduce iatrogenic contamination. [ Orthopedics . 2021;44(6):e753–e756.]

Purpose: To evaluate the nature of cyclin-dependent kinase 5 (CDK5) hyperactivity in pancreatic cancer progression. Experimental Design: We used genetic, biochemical, and molecular biology methods to investigate the nature and function of overexpression of CDK5 and its activators p35 and p39 during the progression of pancreatic cancer. Results: Amplification of the CDK5 gene or either of its main activators, p35 and p39, was observed in 67% of human pancreatic ductal adenocarcinoma (PDAC). CDK5, p35, and p39 were rarely expressed in pancreatic ducts whereas more than 90% of PDACs had increased levels of CDK5 and p35. Increased levels of CDK5, p35, and p39 protein were observed in several pancreatic cancer cell lines. Inhibition of CDK5 kinase activity using a CDK5 dominant-negative mutant or the drug roscovitine significantly decreased the migration and invasion of pancreatic cancer cells in vitro. Increased CDK5 kinase activity was also observed in immortalized human pancreatic nestin-expressing (HPNE) cells expressing a mutant form of K-Ras (G12D) compared with HPNE cells expressing native K-Ras. G12D K-Ras increased cleavage of p35 to p25, a stable and greater activator of CDK5, thus implicating a role for CDK5 in early progression of PDAC. Inhibition of the signaling cascade downstream of mutant K-Ras (G12D) that involves mitogen-activated protein/extracellular signal–regulated kinase, phosphoinositide 3-kinase, or CDK5 decreased p25 protein levels. Conclusion: These results suggest that mutant K-Ras acts in concert with CDK5 and its activators to increase malignant progression, migration, and invasion of pancreatic cancer cells. Clin Cancer Res; 17(19); 6140–50. ©2011 AACR.

MUC1, a transmembrane mucin, is a key modulator of several signaling pathways that affect oncogenesis, motility, and cell morphology. The interaction of MUC1 cytoplasmic tail (MUC1CT) with signal transducers and its nuclear translocation and subsequent biological responses are believed to be regulated by phosphorylation status, but the precise mechanisms by which this occurs remain poorly defined. We detected a novel association between the Met receptor tyrosine kinase and the MUC1CT. Met catalyzed phosphorylation of tyrosine at YHPM in the MUC1CT. Stimulation of S2-013.MUC1F pancreatic cancer cells with hepatocyte growth factor facilitated nuclear localization of MUC1CT, as determined by real time confocal imaging analysis. MUC1 overexpression also facilitated faster turnover of Met. Phosphorylation of MUC1CT by Met enhanced its interaction with p53, which led to suppression of AP1 transcription factor activity through interactions at the MMP1 promoter, ultimately leading to reduced transcription of MMP1. This correlated with a decrease in hepatocyte growth factor-induced invasiveness when MUC1 was overexpressed. The results demonstrate that MUC1 modulates Met-mediated oncogenic signaling in cancer.

The rotator interval is important in shoulder stability and movement. The rotator interval is enclosed in the triangular area bordered by the subscapularis anteroinferiorly, supraspinatus posterosuperiorly, and the coracoid process medially. The rotator interval contains the long head of the biceps tendon, coracohumeral ligament, superior glenohumeral ligament (SGHL), and the middle glenohumeral ligament (MGHL). The rotator interval contains multiple static stabilizers of the shoulder, and its integrity is important for anterior and inferior stability of the shoulder, especially when the shoulder is adducted. Furthermore, external rotation of the shoulder is altered with rotator interval pathology. For surgical intervention to have success, an intimate understanding of the rotator interval structures is necessary. Rotator Interval Anatomy The rotator interval of the shoulder is the area defined by the subscapularis anteroinferiorly, the supraspinatus posterosuperiorly, and the coracoid process medially. The long head of the biceps tendon traversing in the bicipital groove exits the joint just lateral to the insertion of the subscapularis tendon on the lesser tuberosity (Fig. 1a). The coracohumeral ligament originates from the proximal third of the dorsolateral aspect of the base of the coracoid process and runs on the bursal side of the SGHL, inserting mostly on the greater tuberosity and to a lesser extent on the lesser tuberosity (Ferrari 1990; Burkhart et al. 1993; Jost et al. 2000; Fig. 1a). The superior glenohumeral ligament (SGHL) originates from the glenoid labrum, frequently with the long head of the biceps tendon (Jost et al. 2000; Fig. 1b). The SGHL fibers insert mainly into the lesser tuberosity and also form a band around the biceps tendon and insert into the greater tuberosity contributing to the roof of biceps sling (Ferrari 1990; Burkhart et al. 1993; Jost et al. 2000; Werner et al. 2000; Kask et al. 2010; Fig. 2). During its course, the SGHL borders the biceps anteriorly (Figs. 1b, 2, 3a–d). The MGHL commonly originates in the anterosuperior aspect of the labrum or the supraglenoid tubercle (SGT). The MGHL then inserts onto the inferior aspect of the lesser tuberosity (Ferrari 1990; Jost et al. 2000; Pouliart and Gagey 2005; Kask et al. 2010; Felli et al. 2012). As it enters the shoulder joint in the bicipital groove, the long head of the biceps tendon has a sling formed around it consisting of the supraspinatus, subscapularis, SGHL, and coracohumeral ligament (Fig. 3). The medial aspect of the sling consists of from deep to superficial the SGHL, coracohumeral ligament, and subscapularis tendon, respectively. The lateral aspect of the sling from deep to superficial consists of the SGHL, deep coracohumeral ligament, supraspinatus tendon, and superficial *Email: johnpeggers@gmail.com Sports Injuries DOI 10.1007/978-3-642-36801-1_10-1 # Springer-Verlag Berlin Heidelberg 2013

Purpose: We investigated the contribution of Sonic hedgehog (SHH) to pancreatic cancer progression. Experimental Design: We expressed SHH in a transformed primary ductal-derived epithelial cell line from the human pancreas, transformed hTert-HPNE (T-HPNE), and evaluated the effects on tumor growth. We also directly inhibited the activity of SHH in vivo by administering a blocking antibody to mice challenged orthotopically with the Capan-2 pancreatic cancer cell line, which is known to express SHH and form moderately differentiated tumors in nude mice. Results: Our data provide evidence that expression of SHH influences tumor growth by contributing to the formation of desmoplasia in pancreatic cancer. We further show that SHH affects the differentiation and motility of human pancreatic stellate cells and fibroblasts. Conclusions: These data suggest that SHH contributes to the formation of desmoplasia in pancreatic cancer, an important component of the tumor microenvironment.

Perineural invasion in pancreatic adenocarcinoma, a common pathologic phenomenon whereby cancer cells invade and intimately contact the endoneurium of pancreatic nerves, is thought to contribute to both pain and local disease recurrence. MUC1, a type I transmembrane mucin that can affect the adhesive properties of cells, contains a large extracellular tandem repeat domain, which is heavily glycosylated in normal epithelia, but is overexpressed and differentially glycosylated in pancreatic cancer. This altered glycosylation includes the shortened core I O-glycans for monosialyl and disialyl T antigens. Myelin-associated glycoprotein (MAG), a membrane-bound protein expressed on oligodendrocytes and Schwann cells, binds myelin to neurons. MAG's preferred ligands are derivatives of the monosialyl and disialyl T antigen. We investigated whether MUC1 is a counter-receptor for MAG and if their interaction contributed to pancreatic perineural invasion. Results showed that MAG binds pancreatic cells expressing MUC1, that this binding is sialidase-sensitive, and that MAG physically associates with MUC1. Heterotypic adhesion assays between pancreatic cancer cells and Schwann cells revealed that increased expression of MUC1 or MAG enhanced adhesion. Conversely, specific inhibition of MAG or sialyl-T MUC1 partially blocked adhesion. Immunohistochemical analysis of pancreatic perineural invasion showed the expression of both MUC1 and MAG. These results support the hypothesis that the adhesive interactions between MUC1 and MAG are of biological significance in pancreatic cancer perineural invasion. [Cancer Res 2007;67(21):10222–9]