Pancreatic ductal adenocarcinoma (PDAC) is thought to originate from ductal structures, exhibiting strong desmoplastic reaction with stromal pancreatic myofibroblasts (PMF), which are supposed to drive PDAC tumorigenesis. Previously, we observed high expression of the adhesion molecule L1CAM (CD171) in PDAC cells accounting for chemoresistance. Thus, this study aimed to investigate whether PMFs are involved in the induction of tumoral L1CAM and whether this contributes to malignant transformation of pancreatic ductal cells and PDAC tumorigenesis. Immunohistochemistry of tissues from chronic pancreatitis specimens revealed considerable L1CAM expression in ductal structures surrounded by dense fibrotic tissue, whereas no L1CAM staining was seen in normal pancreatic tissues. Using the human pancreatic duct cell line H6c7, we show that coculture with PMFs led to a transforming growth factor-B1 (TGF-B1)-dependent up-regulation of L1CAM expression. Similarly, L1CAM expression increased in monocultured H6c7 cells after administration of exogenous TGF-B1. Both TGF-B1-and PMF-induced L1CAM expression were independent of Smad proteins but required c-Jun NH 2 -terminal kinase activation leading to the induction of the transcription factor Slug. Moreover, Slug interacted with the L1CAM promoter, and its knockdown abrogated the TGF-B1-and PMF-induced L1CAM expression. As a result of L1CAM expression, H6c7 cells acquired a chemoresistant and migratory phenotype. This mechanism of TGF-B1-induced L1CAM expression and the resulting phenotype could be verified in the TGF-B1-responsive PDAC cell lines Colo357 and Panc1. Our data provide new insights into the mechanisms of tumoral L1CAM induction and how PMFs contribute to malignant transformation of pancreatic duct cells early in PDAC tumorigenesis. [Cancer Res 2009;69(10):4517-26]

The novel coronavirus SARS-CoV-2 causes the infectious disease Covid-19. Newly developed mRNA vaccines can prevent the spread of the virus. Headache is the most common neurological symptom in over 50% of those vaccinated. Detailed information about the clinical characteristics of this form of headache has not yet been described. The aim of the study is to examine in detail the clinical characteristics of headaches occurring after vaccination against Covid-19 with the BNT162b2 mRNA Covid-19 vaccine for the first time. In a multicenter observational cohort study data on the clinical features and corresponding variables were recorded using a standardized online questionnaire. The questionnaire was circulated to 12,000 residential care homes of the elderly as well as tertiary university hospitals in Germany and the United Arab Emirates. The primary outcomes of this study are the clinical features of headache after vaccination. Comorbidities, treatment with medication and sociodemographic variables are also analyzed. A total of 2349 participants reported headaches after vaccination with the BNT162b2 mRNA Covid-19 vaccine. Headaches occur an average of 18.0 ± 27.0 hours after vaccination and last an average duration of 14.2 ± 21.3 hours. Only 9.7% of those affected also report headaches resulting from previous vaccinations. In 66.6% of the participants headache occurs as a single episode. A bilateral location is indicated by 73.1% of the participants. This is most often found on the forehead (38.0%) and temples (32.1%). A pressing pain character is indicated by 49.2% and 40.7% report a dull pain character. The pain intensity is most often moderate (46.2%), severe (32.1%) or very severe (8.2%). The most common accompanying symptoms are fatigue (38.8%), exhaustion (25.7%) and muscle pain (23.4%). Headaches after Covid-19 vaccination show an extensive complex of symptoms. The constellation of accompanying symptoms together with the temporal and spatial headache characteristics delimit a distinctive headache phenotype.

Introduction The most frequently reported neurological adverse event of ChAdOx1 nCoV-19 (AZD1222) vaccine is headache in 57.5%. Several cases of cerebral venous thrombosis (CVT) have developed after vaccination. Headache is the leading symptom of CVT. For the differential diagnosis of headaches attributed to this vaccine and headaches attributed to CVT, it is of central clinical importance whether and, if so, how the phenotypes and course of these headaches can be differentiated. The study aims to examine in detail the phenotype of headache attributed to this vaccine. Methods Data on the clinical features and corresponding variables were recorded using a standardized online questionnaire in this multicenter observational cohort study. The primary outcomes of this study are the clinical features of headaches after vaccination. Findings A total of 2464 participants reported headaches after vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine. On average, headaches occurred 14.5 ± 21.6 h after vaccination and lasted 16.3 ± 30.4 h. A bilateral location was described by 75.8% of participants. This is most often found on the forehead (40.0%) and temples (31.4%); 50.4% reported a pressing and 37.7% a dull pain character. Headache intensity was most often severe (38.7%), moderate (35.2%), or very severe (15.5%). Accompanying symptoms were most commonly fatigue (44.8%), chills (36.1%), exhaustion (34.9%), and fever (30.4%). Conclusion Headaches attributed to COVID-19 vaccination with the ChAdOx1 nCoV-19 (AZD1222) vaccine demonstrate an extensive and characteristic complex of symptoms. The findings have several important clinical implications for the differentiation of post-vaccinal headache and other primary as well as secondary headaches.

<div>Abstract<p>Pancreatic ductal adenocarcinoma (PDAC) is thought to originate from ductal structures, exhibiting strong desmoplastic reaction with stromal pancreatic myofibroblasts (PMF), which are supposed to drive PDAC tumorigenesis. Previously, we observed high expression of the adhesion molecule L1CAM (CD171) in PDAC cells accounting for chemoresistance. Thus, this study aimed to investigate whether PMFs are involved in the induction of tumoral L1CAM and whether this contributes to malignant transformation of pancreatic ductal cells and PDAC tumorigenesis. Immunohistochemistry of tissues from chronic pancreatitis specimens revealed considerable L1CAM expression in ductal structures surrounded by dense fibrotic tissue, whereas no L1CAM staining was seen in normal pancreatic tissues. Using the human pancreatic duct cell line H6c7, we show that coculture with PMFs led to a transforming growth factor-β1 (TGF-β1)–dependent up-regulation of L1CAM expression. Similarly, L1CAM expression increased in monocultured H6c7 cells after administration of exogenous TGF-β1. Both TGF-β1– and PMF-induced L1CAM expression were independent of Smad proteins but required c-Jun NH₂-terminal kinase activation leading to the induction of the transcription factor Slug. Moreover, Slug interacted with the L1CAM promoter, and its knockdown abrogated the TGF-β1– and PMF-induced L1CAM expression. As a result of L1CAM expression, H6c7 cells acquired a chemoresistant and migratory phenotype. This mechanism of TGF-β1–induced L1CAM expression and the resulting phenotype could be verified in the TGF-β1–responsive PDAC cell lines Colo357 and Panc1. Our data provide new insights into the mechanisms of tumoral L1CAM induction and how PMFs contribute to malignant transformation of pancreatic duct cells early in PDAC tumorigenesis. [Cancer Res 2009;69(10):4517–26]</p></div>

Supplementary Figure 1 from Up-regulation of L1CAM in Pancreatic Duct Cells Is Transforming Growth Factor β1– and Slug-Dependent: Role in Malignant Transformation of Pancreatic Cancer