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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a formidable challenge for patients and clinicians. OBJECTIVE: To analyze the distribution of 31 different markers in tumor and stromal portions of the tumor microenvironment (TME) and identify immune cell populations to better understand how neoplastic, non-malignant structural, and immune cells, diversify the TME and influence PDAC progression. METHODS: Whole slide imaging (WSI) and cyclic multiplexed-immunofluorescence (MxIF) was used to collect 31 different markers over the course of nine distinctive imaging series of human PDAC samples. Image registration and machine learning algorithms were developed to largely automate an imaging analysis pipeline identifying distinct cell types in the TME. RESULTS: A random forest algorithm accurately predicted tumor and stromal-rich areas with 87% accuracy using 31 markers and 77% accuracy using only five markers. Top tumor-predictive markers guided downstream analyses to identify immune populations effectively invading into the tumor, including dendritic cells, CD4+ T cells, and multiple immunoregulatory subtypes. CONCLUSIONS: Immunoprofiling of PDAC to identify differential distribution of immune cells in the TME is critical for understanding disease progression, response and/or resistance to treatment, and the development of new treatment strategies.

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

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a formidable challenge for patients and clinicians. OBJECTIVE: To analyze the distribution of 31 different markers in tumor and stromal portions of the tumor microenvironment (TME) and identify immune cell populations to better understand how neoplastic, non-malignant structural, and immune cells, diversify the TME and influence PDAC progression. METHODS: Whole slide imaging (WSI) and cyclic multiplexed-immunofluorescence (MxIF) was used to collect 31 different markers over the course of nine distinctive imaging series of human PDAC samples. Image registration and machine learning algorithms were developed to largely automate an imaging analysis pipeline identifying distinct cell types in the TME. RESULTS: A random forest algorithm accurately predicted tumor and stromal-rich areas with 87% accuracy using 31 markers and 77% accuracy using only five markers. Top tumor-predictive markers guided downstream analyses to identify immune populations effectively invading into the tumor, including dendritic cells, CD4+ T cells, and multiple immunoregulatory subtypes. CONCLUSIONS: Immunoprofiling of PDAC to identify differential distribution of immune cells in the TME is critical for understanding disease progression, response and/or resistance to treatment, and the development of new treatment strategies.

Aberrant expression of CA125/MUC16 is associated with pancreatic ductal adenocarcinoma (PDAC) progression and metastasis. However, knowledge of the contribution of MUC16 to pancreatic tumorigenesis is limited. Here, we show that MUC16 expression is associated with disease progression, basal-like and squamous tumor subtypes, increased tumor metastasis, and short-term survival of PDAC patients. MUC16 enhanced tumor malignancy through the activation of AKT and GSK3β oncogenic signaling pathways. Activation of these oncogenic signaling pathways resulted in part from increased interactions between MUC16 and epidermal growth factor (EGF)-type receptors, which were enhanced for aberrant glycoforms of MUC16. Treatment of PDAC cells with monoclonal antibody (mAb) AR9.6 significantly reduced MUC16-induced oncogenic signaling. mAb AR9.6 binds to a unique conformational epitope on MUC16, which is influenced by O-glycosylation. Additionally, treatment of PDAC tumor-bearing mice with either mAb AR9.6 alone or in combination with gemcitabine significantly reduced tumor growth and metastasis. We conclude that the aberrant expression of MUC16 enhances PDAC progression to an aggressive phenotype by modulating oncogenic signaling through ErbB receptors. Anti-MUC16 mAb AR9.6 blocks oncogenic activities and tumor growth and could be a novel immunotherapeutic agent against MUC16-mediated PDAC tumor malignancy.

Pancreatic ductal adenocarcinoma (PDAC) is a formidable challenge for patients and clinicians.To analyze the distribution of 31 different markers in tumor and stromal portions of the tumor microenvironment (TME) and identify immune cell populations to better understand how neoplastic, non-malignant structural, and immune cells, diversify the TME and influence PDAC progression.Whole slide imaging (WSI) and cyclic multiplexed-immunofluorescence (MxIF) was used to collect 31 different markers over the course of nine distinctive imaging series of human PDAC samples. Image registration and machine learning algorithms were developed to largely automate an imaging analysis pipeline identifying distinct cell types in the TME.A random forest algorithm accurately predicted tumor and stromal-rich areas with 87% accuracy using 31 markers and 77% accuracy using only five markers. Top tumor-predictive markers guided downstream analyses to identify immune populations effectively invading into the tumor, including dendritic cells, CD4+ T cells, and multiple immunoregulatory subtypes.Immunoprofiling of PDAC to identify differential distribution of immune cells in the TME is critical for understanding disease progression, response and/or resistance to treatment, and the development of new treatment strategies.

COVID-19, the syndrome caused by the novel coronavirus SARS-CoV-2, has spread throughout the world, causing the death of at least three million people. For the over 81 million who have recovered, however, the long-term effects are only beginning to manifest. We performed a bilateral lung transplant on a 31-year-old male patient for chronic hypoxic respiratory failure, severe pulmonary hypertension and radiographically identified pulmonary fibrosis five months after an acute COVID-19 infection. The explant demonstrated moderate pulmonary vascular remodeling with intimal thickening and medial hypertrophy throughout, consistent with pulmonary hypertension. The parenchyma demonstrated an organizing lung injury in the proliferative phase, with severe fibrosis, histiocytic proliferation, type II pneumocyte hyperplasia, and alveolar loss consistent with known COVID-19 pneumonia complications. This report highlights a novel histologic finding in severe, chronic COVID-19. Although the findings in acute COVID-19 pneumonia have been well-examined at autopsy, the chronic course of this complex disease is not yet understood. The case presented herein suggests that COVID-induced pulmonary hypertension may become more common as more patients survive severe SARS-CoV-2-related pneumonia. Pulmonologists and pulmonary pathologists should be aware of this possible association and look for the clinical, radiographic, and histologic criteria in the appropriate clinical setting.

Identifying individuals with hereditary syndromes allows for timely cancer surveillance, opportunities for risk reduction, and syndrome-specific management. Establishing criteria for hereditary cancer risk assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provides recommendations for the assessment and management of patients at risk for or diagnosed with high-risk colorectal cancer syndromes. The NCCN Genetic/Familial High-Risk Assessment: Colorectal panel meets annually to evaluate and update their recommendations based on their clinical expertise and new scientific data. These NCCN Guidelines Insights focus on familial adenomatous polyposis (FAP)/attenuated familial adenomatous polyposis (AFAP) syndrome and considerations for management of duodenal neoplasia.

Intestinal transplant recipients experience a high rate of renal complications secondary to dehydration due to increased ostomy output. It is hypothesized that inclusion of donor colon in the intestinal allograft may improve renal function in patients without functional native colon by improving fluid absorption. A single-center retrospective study of intestinal transplant recipients compared outcomes of patients receiving en bloc colon as part an intestinal allograft (ICTx), and those not receiving colon (CCNTx), as well as a control group of intestinal transplant recipients with functional native colon (ITx). Forty-seven patients (ICTx n = 17, CCNTx n = 15, ITx n = 15) were studied. One-year post-transplant renal function, as measured by change in glomerular filtration rate (GFR) and blood urea nitrogen (BUN) from baseline, was superior in ICTx (mean delta-GFR of -1.31 and delta-BUN of -1.46) compared to CCNTx (-6.54 and 17.54, P = 0.05 and P = 0.17, respectively) and similar to the ITx controls (0.55 and 2.09). Recipients of donor colon experienced a higher rate of ileostomy reversal when compared to CCNTx (62.5% vs. 20%, P = 0.0008), which was similar to the ITx controls (60%). These findings support the inclusion of en bloc donor colon in the intestinal allograft for recipients without functional native colon.

Keratan sulfate (KS) is a sulfated linear polymer of N-acetyllactosamine. Proteoglycans carrying keratan sulfate epitopes were majorly observed in cornea, cartilage and brain; and mainly involved in embryonic development, cornea transparency, and wound healing process. Recently, expression of KS in cancer has been shown to be highly associated with advanced tumor grade and poor prognosis. Therefore, we aimed to identify the expression of KS epitope in human pancreatic cancer primary and metastatic tumor lesions. Immunohistochemical analysis of KS expression was performed on primary pancreatic tumors and metastatic tissues. We observed an increased expression of KS epitope on primary tumor tissues compared to uninvolved normal and tumor stroma; and is associated with worse overall survival. Moreover, lung metastatic tumors show a higher-level expression of KS compared to primary tumors. Interestingly, KS biosynthesis specific glycosyltransferases expression was differentially regulated in metastatic pancreatic tumors. Taken together, these results indicate that aberrant expression of KS is predictive of pancreatic cancer progression and metastasis and may serve as a novel prognostic biomarker for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal. MUC4 (mucin4) is a heavily glycosylated protein aberrantly expressed in PDAC and promotes tumorigenesis via an unknown mechanism. To assess this, we genetically knocked out (KO) MUC4 in PDAC cells that did not express and did express truncated O-glycans (Tn/STn) using CRISPR/Cas9 technology. We found that MUC4 knockout cells possess less tumorigenicity in vitro and in vivo, which was further reduced in PDAC cells that express aberrant overexpression of truncated O-glycans. Also, MUC4(KO) cells showed a further reduction of epidermal growth factor receptors (ErbB) and their downstream signaling pathways in truncated O-glycan expressing PDAC cells. Tn-MUC4 specific 3B11 antibody inhibited MUC4-induced ErbB receptor and its downstream signaling cascades. MUC4 knockout differentially regulates apoptosis and cell cycle arrest in branched and truncated O-glycan expressing PDAC cells. Additionally, MUC4(KO) cells were found to be more sensitive to gemcitabine treatment. They possessed the upregulated expression of hENT1 and hCNT3 compared to parental cells, which were further affected in cells with aberrant O-glycosylation. Taken together, our results indicate that MUC4 enhances the malignant properties and gemcitabine resistance in PDAC tumors that aberrantly overexpress truncated O-glycans via altering ErbB/AKT signaling cascades and expression of nucleoside transporters, respectively.

A complex mixture of dissolved organic contaminants, emanating from a many decades-old, residual, dense non-aqueous phase liquid (DNAPL) source, migrates through unconfined, moderately heterogeneous, glacial-derived sediments and sedimentary rock in a residential area of Dane County, Wisconsin, USA. A portion of this contaminant plume intersects a large man-made pond, roughly 400 m downgradient of the source zone. Depth-discrete, multilevel groundwater sampling, detailed sedimentological logs, and hydraulic head profiles were used to delineate the spatial distribution of hydraulic, geologic, organic contaminant, and redox hydrochemical conditions within the established plume along two transects immediately upgradient of the pond. Twenty-one contaminants were detected and classified into four major contaminant groups: chlorinated ethenes, chlorinated ethanes, aromatics (BTEX: benzene, toluene, ethylbenzene, xylene), and aliphatic ketones. Within the glacial sediments and shallow bedrock, zones of reductive dechlorination of chlorinated ethenes and ethanes were juxtaposed with zones of BTEX and ketone degradation. Spatial heterogeneity in the concentration and distribution of contaminant groups and redox conditions was observed over lateral distances of tens of meters and vertical distances of tens of centimeters along the two transects. Although the site was situated in a complex glacial depositional environment, lithologic and hydraulic heterogeneity surprisingly only had a modest influence on the spatial distribution of plume contaminants. Depth-discrete sampling along paired, closely spaced transects (~20 m apart) was essential to assess internal plume composition/concentration evolution along flow paths with strong attenuation over short migration distances. This study shows how paired, highly resolved transects can enhance understanding of transverse and longitudinal variability in areas where contaminant-induced redox conditions control reaction zones and strong plume attenuation.

Skeletal health consequences associated with inflammatory diseases of the airways significantly contribute to morbidity. Sex differences have been described independently for lung and bone diseases. Repetitive inhalant exposure to lipopolysaccharide (LPS) induces bone loss and deterioration in male mice, but comparison effects in females are unknown. Using an intranasal inhalation exposure model, 8-week-old C57BL/6 male and female mice were treated daily with LPS (100 ng) or saline for 3 weeks. Bronchoalveolar lavage fluids, lung tissues, tibias, bone marrow cells, and blood were collected. LPS-induced airway neutrophil influx, interleukin (IL)-6 and neutrophil chemoattractant levels, and bronchiolar inflammation were exaggerated in male animals as compared to female mice. Trabecular bone micro-CT imaging and analysis of the proximal tibia were conducted. Inhalant LPS exposures lead to deterioration of bone quality only in male mice (not females) marked by decreased bone mineral density, bone volume/tissue volume ratio, trabecular thickness and number, and increased bone surface-to-bone volume ratio. Serum pentraxin-2 levels were modulated by sex differences and LPS exposure. In proof-of-concept studies, ovarectomized female mice demonstrated LPS-induced bone deterioration, and estradiol supplementation of ovarectomized female mice and control male mice protected against LPS-induced bone deterioration findings. Collectively, sex-specific differences exist in LPS-induced airway inflammatory consequences with significant differences found in bone quantity and quality parameters. Male mice demonstrated susceptibility to bone loss and female animals were protected, which was modulated by estrogen. Therefore, sex differences influence the biologic response in the lung-bone inflammatory axis in response to inhalant LPS exposures.

Li et al. show that OGT-mediated STAT3 O-GlcNAcylation, which is modulated by CUL3-Nrf2 signaling, negatively regulates STAT3 phosphorylation and IL-10 production in macrophages and exacerbates experimental colitis and colitis-associated cancer., Signal transducer and activator of transcription 3 (STAT3) is a key mediator of intestinal inflammation and tumorigenesis. However, the molecular mechanism that modulates STAT3 phosphorylation and activation is not fully understood. Here, we demonstrate that modification of STAT3 with O-linked β-N-acetylglucosamine (O-GlcNAc) on threonine 717 (T717) negatively regulates its phosphorylation and targets gene expression in macrophages. We further found that cullin 3 (CUL3), a cullin family E3 ubiquitin ligase, down-regulates the expression of the O-GlcNAc transferase (OGT) and inhibits STAT3 O-GlcNAcylation. The inhibitory effect of CUL3 on OGT expression is dependent on nuclear factor E2–related factor-2 (Nrf2), which binds to the Ogt promoter region and increases gene transcription. Myeloid deletion of Cul3 led to defective STAT3 phosphorylation in colon macrophages, which was accompanied by exacerbated colonic inflammation and inflammation-driven tumorigenesis. Thus, this study identifies a new form of posttranslational modification of STAT3, modulating its phosphorylation, and suggests the importance of immunometabolism on colonic inflammation and tumorigenesis.

INTRODUCTION: SARS-CoV-2 most commonly presents with respiratory symptoms and fever A significant proportion of patients are also experiencing gastrointestinal (GI) symptoms with loss of appetite, nausea, vomiting and diarrhea (variable, up to 10%);however, there is limited data about the associated histologic findings in the GI tract CASE DESCRIPTION/METHODS: A 71 year old male presented with fever for past five days after going on a cruise two days prior Antibiotics were initiated along with self-quarantine Over the next few days, he developed cough, shortness of breath, fever and myalgia SARS-CoV-2 infection was confirmed on nasopharyngeal swab He was intubated for ARDS and started on Remdesivir, which was stopped due to acute kidney injury Over the next month he developed septic shock, arrythmias, spontaneous venous bleeds, acalculous cholecystitis, ventilator associated pneumonia and profuse diarrhea GI pathogen panel and Clostridium difficile testing were negative CT of the abdomen showed colonic and distal small bowel wall thickening with adjacent inflammatory changes EGD and colonoscopy demonstrated ulceration of the duodenum, splenic flexure, sigmoid colon and rectum (Figure 1) Biopsies from the terminal ileum showed increased apoptotic bodies (>10 apoptosis per 10 crypts), mild villous blunting, patchy crypt dropout and crypt abscess (Figure 2) Colon biopsies had similar features along with mucosal erosion and focal crypt abscess formation No significant increase in intra-epithelial lymphocytes was identified Viral stains for CMV and Adenovirus were negative DISCUSSION: Limited data on GI specimens from SARS-CoV-2 positive patients have showed no significant damage with few infiltrating plasma cells and lymphocytes in lamina propria along with interstitial edema In our case, we observed extensive apoptotic injury with acute inflammation Although confirmatory stool testing was not performed, SARS CoV-2 was favored as the etiology due a long gap between the administration of Remdesivir and lack of any other identifiable causes Further studies are needed to characterize SARS-CoV-2 associated gastrointestinal disease (Figure Presented)

Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principal metabolic pathways, we identified the specific metabolites that are altered during pancreatic cancer progression in the spontaneous progression (KPC) mouse model. Genetically engineered mice exhibited metabolic alterations during PanINs formation, even before the tumor development. To account for other cells in the tumor microenvironment and to focus on metabolic adaptations concerning tumorigenic cells only, we compared the metabolic profile of KPC and orthotopic tumors with those obtained from KPC-tumor derived cell lines. We observed significant upregulation of glycolysis and the pentose phosphate pathway metabolites even at the early stages of pathogenesis. Other biosynthetic pathways also demonstrated a few common perturbations. While some of the metabolic changes in tumor cells are not detectable in orthotopic and spontaneous tumors, a significant number of tumor cell-intrinsic metabolic alterations are readily detectable in the animal models. Overall, we identified that metabolic alterations in precancerous lesions are maintained during cancer development and are largely mirrored by cancer cells in culture conditions.

Rheumatoid arthritis (RA) is characterized by extra-articular involvement including lung disease, yet the mechanisms linking the two conditions are poorly understood. The collagen-induced arthritis (CIA) model was combined with the organic dust extract (ODE) airway inflammatory model to assess bone/joint-lung inflammatory outcomes. DBA/1J mice were intranasally treated with saline or ODE daily for 5 weeks. CIA was induced on days 1 and 21. Treatment groups included sham (saline injection/saline inhalation), CIA (CIA/saline), ODE (saline/ODE), and CIA + ODE (CIA/ODE). Arthritis inflammatory scores, bones, bronchoalveolar lavage fluid, lung tissues, and serum were assessed. In DBA/1J male mice, arthritis was increased in CIA + ODE > CIA > ODE versus sham. Micro-computed tomography (µCT) demonstrated that loss of BMD and volume and deterioration of bone microarchitecture was greatest in CIA + ODE. However, ODE-induced airway neutrophil influx and inflammatory cytokine/chemokine levels in lavage fluids were increased in ODE > CIA + ODE versus sham. Activated lung CD11c+ CD11b+ macrophages were increased in ODE > CIA + ODE > CIA pattern, whereas lung hyaluronan, fibronectin, and amphiregulin levels were greatest in CIA + ODE. Serum autoantibody and inflammatory marker concentrations varied among experimental groups. Compared with male mice, female mice showed less articular and pulmonary disease. The interaction of inhalation-induced airway inflammation and arthritis induction resulted in compartmentalized responses with the greatest degree of arthritis and bone loss in male mice with combined exposures. Data also support suppression of the lung inflammatory response, but increases in extracellular matrix protein deposition/interstitial disease in the setting of arthritis. This coexposure model could be exploited to better understand and treat RA-lung disease. © 2019 American Society for Bone and Mineral Research.

Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5′-ATN-3′ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1, and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon (IFN) and nuclear factor kappa B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCCs, in contrast to their gains in HPV-negative OSCCs. High-ranking variant allele fractions implicated ZNF750, PIK3CA, and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

Objective The aim of this study is to determine the diagnostic accuracy of preoperative evaluation to detect main pancreatic duct involvement in pancreatic cystic lesions thus differentiating mixed intraductal papillary mucinous neoplasm (IPMN) from branch duct (BD)-IPMN. Methods The pathology database of pancreatic resections from 2000 to 2014 was reviewed. Main pancreatic duct-IPMNs and IPMNs with intracystic mass/nodules were excluded. The preoperative test characteristics were analyzed using surgical histopathology as the "gold standard." Results Sixty BD-IPMNs and 23 mixed-IPMNs were identified. Mixed-IPMNs were larger (mean [standard deviation], 4.14 [2.9] vs 2.74 [1.9] mm; P = 0.03) and demonstrated frequent high-grade dysplasia/adenocarcinoma (43% vs 12%, P = 0.004) than BD-IPMNs. Endoscopic ultrasound (EUS) (sensitivity, 80%; specificity, 78%; accuracy, 79%) had the best diagnostic accuracy, whereas magnetic resonance imaging (MRI) (sensitivity, 83%; specificity, 63%; accuracy, 68%) had the highest sensitivity for the diagnosis of mixed-IPMN. A combination of EUS and MRI reached maximum sensitivity but with decreased accuracy (sensitivity, 100%; specificity, 64%; accuracy, 67%). The area under the curve for receiver operation curve was 0.71 whereas the optimal cyst size to detect main duct involvement was 3 cm. Conclusions For preoperative evaluation of pancreatic cystic lesions without evidence of intracystic nodules, a combination of MRI and EUS should be considered for improved detection of main duct involvement.

OBJECTIVES Our objective was to delineate predictive factors differentiating groove pancreatitis (GP) from other lesions involving the head of the pancreas (HOP). METHODS A case-control study of patients older than 10 years was performed comparing patients with GP to those with other surgically resected HOP lesions. RESULTS Thirteen patients with GP (mean ± SD age, 51.9 ± 10.5 years; 11 males [84.6%]), all with a history of smoking (mean, 37.54 ± 17.8 pack-years), were identified. Twelve patients (92.3%) had a history of heavy alcohol drinking (heavy alcohol [EtOH]). The mean lesion size was 2.6 ± 1.1 cm, and the CA 19-9 was elevated (>37 IU/mL) in 5 patients (45.5%). The most common histopathologic condition was duodenal wall cyst with myofibroblastic proliferation and changes of chronic pancreatitis in the HOP.Univariate analysis revealed decreasing age, male sex, weight loss, nausea/vomiting, heavy EtOH, smoking, and a history of chronic pancreatitis were predictive of GP. A multivariate analysis among smokers demonstrated that weight loss (P = 0.006; odds ratio, 11.96; 95% confidence interval, 2.1-70.2), and heavy EtOH (P < 0.001; odds ratio, 82.2; 95% confidence interval, 9.16-738.1) were most predictive of GP. Compared to pancreatic adenocarcinoma (n = 183), weight loss and heavy EtOH remained predictive of GP. CONCLUSION Groove pancreatitis in the HOP is associated with a history of heavy EtOH and weight loss. In the absence of these symptoms, it is essential to rule out a malignant lesion.

We report the morphologic description of the bile acid sequestrants (BAS) colesevelam and colestipol, as well as the largest series of cholestyramine. Histologically similar medication resins from 4 institutions were prospectively collected over 1 year (26 specimens, 15 patients). Comorbidities included hyperlipidemia (4/15), hypertension (4/15), inflammatory bowel disease (4/15), coronary artery disease (3/15), diarrhea (7/15), hypothyroidism (2/15), and ischemic bowel (1/15). Sites of involvement included the esophagus (1/26), stomach (1/26), small intestine (1/26), ileocecal valve (1/26), and colorectum (22/26). Associated histologic diagnoses included normal (8/26), chronic mucosal injury (11/26), acute inflammation (9/26), erosion/ulceration (6/26), and cytomegalovirus (2/26). The BAS resins were histologically indistinguishable from each other; they were all eosinophilic on hematoxylin and eosin (HE) and lacked internal "fish-scales." To validate these observations, respective medications were submitted for histologic processing; the processed medications were identical to those in the patient specimens. Rare, irregular "fracture" lines presented diagnostic pitfalls by mimicking the true "fish-scales" of Kayexalate and sevelamer. Clues to the correct identification of BAS include recognition that the "fracture" lines were subtle, irregular, and restricted to large fragments or thick sections, likely representing a processing artifact. Moreover, Kayexalate is violet on HE and black on acid fast bacillus, and sevelamer characteristically displays a 2-tone color on HE and is magenta on acid fast bacillus. An association with inflammatory injury was seen (15/26). We believe that the BAS are innocent bystanders in complicated patients, although we cannot exclude their ability to cause mucosal injury in specific settings.

Numerous morphological changes can occur where two channels of distinct sediment and flow regimes meet, including abrupt shifts in channel slope, cross-sectional area, planform style, and bed sediment size along the receiving channel. Along the Rio Chama between El Vado and Abiquiu Dams, northern New Mexico, arroyo tributaries intermittently deliver sediment from erodible sandstone and shale canyon walls to the mainstem channel. Much of the tributary activity occurs in flash floods and debris flows during summer thunderstorms, which often load the channel with sand and deposit coarser material at the mainstem confluence. In contrast, mainstem channel flow is dominated by snowmelt runoff. To examine tributary controls, we systematically collected cross-section elevation and bed sediment data upstream and downstream of 26 tributary confluences along a 17 km reach. Data from 203 cross-sections were used to build a one-dimensional hydraulic model for comparing estimated channel parameters at bankfull and low-flow conditions at these sites As compared to intermediate reaches, confluences primarily impact gradient and bed sediment size, reducing both parameters upstream of confluences and increasing them downstream. Cross-section area is also slightly elevated above tributary confluences and reduced below. Major shifts in slope and bed sediment size at confluences appear to drive variations in sediment entrainment and transport capacity and the relative storage of sand along the channel bed. The data were analyzed and compared to models of channel organization based on lateral inputs, such as the Network Variance Model and the Sediment Link Concept. At a larger scale, hillslope − channel coupling increases in the downstream third of the study reach, where the canyon narrows, resulting in steeper slopes and more continuous coarse bed material along the mainstem, and thus, limiting the contrast with tributary confluences. However, channel form and sediment characteristics are highly variable along the study reach, reflecting variations in the size and volume of sediment inputs related to the surface geology in tributary watersheds, morphology of the Rio Chama at the junction (i.e. bends, confinement), and the relative magnitude and location of past depositional events. Copyright © 2014 John Wiley & Sons, Ltd.

The purpose of this study was to review long-term outcomes of sinonasal adenoid cystic carcinoma (ACC) and to clarify its association with human papillomavirus (HPV).The medical records of 23 patients with sinonasal ACC treated with primary surgical resection between 1998 and 2013 were reviewed. Tissue specimens were available for 17 patients. The p16 testing was performed using immunohistochemistry (IHC), and HPV infection was determined using quantitative polymerase chain reaction (PCR) with primers targeting the E6/E7 region.Two of the 17 samples showed strong and diffuse p16 staining, whereas the remaining 15 cases showed p16-positivity isolated to the luminal cells. Only one of the p16-positive cases was positive for HPV. The 5-year local failure, disease-free survival (DFS), and overall survival (OS) were 51%, 52%, and 62%, respectively.Local failures are common with advanced sinonasal ACC, and the association of HPV with true sinonasal ACC is low.

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.

Skin related diseases comprise a major health challenge to the practicing physician, and constitute a significant psychological, social and financial burden to the society. Further, skin cancer, especially non-melanoma skin cancer is currently the leading type of malignancy in the Western world. Given the huge burden of skin diseases, there is growing emphasis on understanding their pathophysiology, and towards their early detection. Mucins are high molecular weight O- and N-linked glycoproteins that have emerged in recent years as important molecules in maintaining health and in promoting or protecting against inflammation and cancer. They have also begun to emerge as highly specific diagnostic and prognostic markers and novel therapeutic targets in several malignant disorders. However, their role in cutaneous pathologies has remained largely obscured. The present review provides the expression patterns and proposed role of mucins in the healthy skin and various benign and malignant skin diseases. The review has immense clinical significance as the availability of highly specific reagents including monoclonal antibodies against mucins makes them extremely attractive targets for specific diagnosis and/or immunotherapy of benign and malignant cutaneous diseases.

Over the last century, geomorphic processes along the Middle Rio Grande have been altered by flood control and bank stabilization projects, intensified land and water use, and climate change. In response to potential risks to infrastructure and ecological integrity, recent (1985–2008) adjustment was investigated and historic (1918–1985) changes in Rio Grande channel planform through the Albuquerque, New Mexico, area were reviewed, especially in relation to changes in annual peak discharge and river engineering measures. Using a GIS, channel characteristics were digitized from georeferenced photographs and analyzed with particular attention to quantifying potential measurement error and its propagation. Error associated with average channel widths and channel area ranged between 4 and 13%. For smaller polygons, e.g. islands, error was higher (11 to 40% for width and >200% for area) because width error is large relative to polygon width. Between 1918 and 1963, average channel widths decreased 8 m/yr, from 516 ± 67 m to 176 ± 7 m, mostly due to decreasing peak flows and the implementation of flood control and other engineering measures. From 1985 to 2008, widths decreased 0·7 m/yr, from 176 ± 23 m to 146 ± 5 m, accompanied by an increase in vegetated island area which largely coincided with low flow periods. Narrowing was concentrated at tributary inputs and in the upstream part of the reach, where bedload trapping by Cochiti Dam has caused degradation. Bank protection structures and dense vegetation limit bank erosion in the reach, but erosion is significant where expanding islands, incision, and increased meandering force water against banks. Copyright © 2010 John Wiley & Sons, Ltd.

MUC1 is a heterodimeric transmembrane glycoprotein that is overexpressed and aberrantly glycosylated in ductal adenocarcinomas. Differential phosphorylation of the MUC1 cytoplasmic tail (MUC1CT) has been associated with signaling events that influence the proliferation and metastasis of cancer cells. We identified a novel tyrosine phosphorylation site (HGRYVPP) in the MUC1CT by mass spectrometric analysis of MUC1 from human pancreatic adenocarcinoma cell lines. Analyses in vitro and in vivo showed that platelet-derived growth factor receptor β (PDGFRβ) catalyzed phosphorylation of this site and of tyrosine in the RDTYHPM site. Stimulation of S2-013.MUC1F cells with PDGF-BB increased nuclear colocalization of MUC1CT and β-catenin. PDGF-BB stimulation had no significant effect on cell proliferation rate; however, it enhanced invasion in vitro through Matrigel and in vivo tumor growth and metastases. Invasive properties of the cells were significantly altered on expression of phosphorylation-abrogating or phosphorylation-mimicking mutations at these sites. We propose that interactions of MUC1 and PDGFRβ induce signal transduction events that influence the metastatic properties of pancreatic adenocarcinoma. [Cancer Res 2007;67(11):5201–10]

A modular multilevel system was adapted for high-resolution, depth-discrete monitoring of hydraulic head and ground water quality in rotasonic boreholes or boreholes produced with similar dual-casing drilling methods. The system accommodates up to 15 monitoring intervals within one hole and can be used to monitor overburden and/or bedrock to depths of 100 m (330 feet) or more. It is most effective where static water levels are shallower than 9 m (30 feet) below ground surface. Sand packs around each monitoring port define the monitoring interval, and bentonite seals placed above and below each sand pack isolate the intervals. Each sand and bentonite layer has a practical minimum length of 0.5 m (1.6 feet); therefore, a 15 port system can monitor, with maximum detail, a minimum vertical span of 15 m (50 feet). All system components

MUC1 is a highly glycosylated, type I transmembrane protein expressed by normal ductal epithelial cells of the pancreas, breast, lung, and gastrointestinal tract, and overexpressed in many cases of adenocarcinoma. We down-regulated MUC1 expression by RNA interference and investigated the effects on malignant and metastatic potential of a human pancreatic cancer cell line, S2-013. MUC1-suppressed clones, S2-013.MTII.C1 and S2-013.MTII.C2, were established by targeting a sequence 3,151 bp from the initiation codon and characterized in vitro for proliferation, invasion, and adhesion. We evaluated the effects of MUC1 suppression in vivo on tumor growth and metastatic properties following implantation into the cecum or pancreas of athymic mice. MUC1-suppressed clones showed significantly decreased proliferation in vitro and in vivo. Global gene expression was evaluated by oligonucleotide microarray analysis. Surprisingly, genes predicted to increase doubling times (cyclin B1 and cyclin D3) were overexpressed in MUC1-suppressed clones. There were alterations in expression of several genes that may affect the malignant properties of pancreatic cancer. Adhesion of MUC1-suppressed cells in vitro to type IV collagen and fibronectin was slightly increased, and adhesion was slightly decreased to type I collagen and laminin. Results of implantation to cecum and pancreas showed significant reduction of metastasis to lymph nodes, lung, or peritoneal sites compared with S2-013.gfp-neo control cells. These results support the hypothesis that MUC1 contributes significantly to growth and metastasis, and that down-regulation of MUC1 protein expression decreases the metastatic potential of pancreatic adenocarcinoma.

Chiral N-acyloxazolidinones derived from conjugated dienoic acids undergo boron-mediated aldol condensation in good yield and with high regio- and diastereoselectivity to provide a convenient method for introducing a 1,3-diene subunit. The condensation of a homologous triene derivative is also described.

BACKGROUND Chronic rejection is a significant barrier to small bowel allograft survival. Although chronic rejection primarily involves vessels of the submucosa, serosa, and mesentery, some mucosal alterations have been suggested to be correlative. METHODS We retrospectively investigated explanted small bowel allografts for clinical characteristics and histological alterations in the mucosa, submucosa, and serosa. RESULTS Crypt epithelial mucin loss, submucosal fibrosis, and length of time to explant were all statistically associated with chronic rejection. Medium-sized and large-sized vessels of the serosa and mesentery preferentially demonstrated histologic changes of chronic rejection. CONCLUSION These results further define chronic vascular rejection and the relationship between the mucosal changes and chronic rejection.

This phase of the study investigated the relation of average and peak flows in the Rio Grande to changes in channel, sand bar, and island widths as measured on historical aerial photographs taken from 1972 to 2006. The study reach lies between Bernalillo Bridge and the Isleta Diversion Dam, with a focus on the river between the North and South Albuquerque Metropolitan Arroyo Flood Control Authority (AMAFCA) Diversion Channels. Digitized and georeferenced photographs were analyzed using a geographic information system (GIS), with particular attention paid to quantifying potential measurement error and its propagation through estimates of channel areas and bank erosion rates. Average active channel widths decreased from 169 +/- 5 m in 1972 to 130 +/- 5 m in 2006. Narrowing concentrated in the upper study reach and in areas where the 1972 channel was relatively wide. Variability in channel width also decreased over the study period. Decreases in channel width and area coincide with periods of low flows, although the area changes are associated with large errors. Island areas have increased since 1972, although islands per se were also lost during the later study period by bank attachment. Bank erosion estimates have large associated errors. Erosion rates appear to be generally decreasing over time, but accelerated during the 2005 high flows.

Aim Mucins comprise a family of high-molecular-weight glycoproteins. MUC4, a large transmembrane mucin, has recently emerged as a novel marker for diagnosis, prognosis and therapy in several malignancies. However, its role in skin pathologies remains unknown. The aim of this study was to analyse the expression of MUC4 in cutaneous pathologies by immunohistochemistry for potential diagnostic, prognostic and therapeutic applications. Methods A total of 330 tissue spots representing the normal skin, and benign and malignant cutaneous diseases, were analysed after staining with the monoclonal antibody to human MUC4 (clone 8G7). Results While the normal epidermis showed a negative to weak-positive expression of MUC4, its expression was significantly upregulated in squamous cell carcinomas (SCCs) where the intensity of staining correlated negatively with tumour grade and positively with age. A moderately strong MUC4 expression was also noted in 2/20 cancer adjacent normal skin and 2/21 chronically inflamed skin tissues, while 10/19 cases of vulval condyloma acuminate, 3/12 of vulval hyperplasia and 2 cases of verruca vulgaris also showed strong MUC4 positivity. Malignant melanoma, basal cell carcinoma and cutaneous cysts were negative. Conclusion The results indicate that MUC4 expression is aberrantly upregulated in cutaneous SCCs, vulval condylomas and verruca vulgaris. Further, it appears that MUC4 expression in the skin may be modulated by chronic inflammation and the presence of an adjacent cutaneous malignancy in certain cases. These observations suggest a novel role for MUC4 mucin in the pathogenesis of cutaneous SCC and a possible application as a diagnostic and/or prognostic marker in cutaneous pathologies.

Chiral N-acyloxazolidinones derived from conjugated dienoic acids undergo boron-mediated aldol condensation in good yield and with high regio- and diastereoselectivity to provide a convenient method for introducing a 1,3-diene subunit. The condensation of a homologous triene derivative is also described.