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Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal assessment of the matrisome of the highly metastatic KPC ( Pdx1-Cre , LSL-Kras G12D/+ , LSL-Trp53 R172H/+ ) and poorly metastatic KP fl C ( Pdx1-Cre , LSL-Kras G12D/+ , Trp53 fl/+ ) genetically engineered mouse models of pancreatic cancer using mass spectrometry proteomics. Our assessment at early-, mid-, and late-stage disease reveals an increased abundance of nidogen-2 (NID2) in the KPC model compared to KP fl C, with further validation showing that NID2 is primarily expressed by cancer-associated fibroblasts (CAFs). Using biomechanical assessments, second harmonic generation imaging, and birefringence analysis, we show that NID2 reduction by CRISPR interference (CRISPRi) in CAFs reduces stiffness and matrix remodeling in three-dimensional models, leading to impaired cancer cell invasion. Intravital imaging revealed improved vascular patency in live NID2-depleted tumors, with enhanced response to gemcitabine/Abraxane. In orthotopic models, NID2 CRISPRi tumors had less liver metastasis and increased survival, highlighting NID2 as a potential PDAC cotarget.

This study aimed to identify work-related and personal factors associated with occupational stress in submariners. Work and well-being questionnaires were distributed to 219 male submariners (mean age 34 years), as part of a larger cohort study involving a stratified sample of 4951 Royal Navy (RN) personnel. The stress rate in submariners was 40%; significantly higher than the stress rate in the general RN, although once demographic factors were controlled for in a matched control sample, this difference was no longer significant. A summary model accounted for 49% of the variance in submariner stress, with key differences emerging between the occupational factors associated with stress in submariners and in the general RN. The longitudinal nature of this study permits stress in submariners to be monitored over 5 years, which will provide valuable insights into the chronicity of stress in this specialised occupational group. STATEMENT OF RELEVANCE: This paper contributes to the current literature on the negative impact of working in isolated conditions. It is demonstrated that occupational stress in submarines can be partially explained using current theories of stress in the workplace. However, the constraints of a restricted environment introduce additional factors which can also be associated with occupational stress.

Fifty consecutive patients presenting in a general practice with dyspepsia were studied. Each patient was referred for a combined barium-meal examination and cholecystogram, followed by fibreoptic endoscopy of the oesophagus, stomach, and duodenum. Thirty patients had a specific lesion of the upper digestive tract and a further four had gall-bladder disease; of these, 16 required surgical treatment. Endoscopy in the remaining 16 patients showed nine with mucosal abnormalities, leaving only seven patients to be classified as normal.The advantage of having an endoscopy service to supplement radiological investigation of dyspepsia is shown.