Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin – integrin α3/α6 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness — a hallmark of pancreatic cancer — was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo . This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro .
ObjectiveFor patients to engage with the long-term management of liver cirrhosis, sufficient understanding of their condition is essential. The aim of this study was to assess baseline patient knowledge and to test whether a condition-specific multimedia screencast could improve this.DesignService quality improvement study.SettingA UK tertiary liver centre. Patients were recruited during 12 general hepatology outpatient clinics.PatientsFifty-two patients with liver cirrhosis were included. Sixty-two per cent were male; their median age was 56 years and their median clinic attendance period was 3 years.InterventionsParticipants completed a baseline questionnaire assessing their knowledge of the management and complications of cirrhosis. They then watched a tailored screencast discussing this condition, which had been developed by expert hepatologists in collaboration with patient representatives. Knowledge was reassessed using a new copy of the original questionnaire after an interval of at least one month.Main outcome measuresPatient scores on knowledge questionnaires at baseline and follow-up.ResultsFifty-two patients achieved a median score of 25.0% before viewing the screencast. Thirty-five patients then completed a follow-up questionnaire after an interval period. The median questionnaire score in this group improved from 25.0% to 66.7%; an increase of 41.7% compared with baseline (p<0.001).ConclusionsDespite regular review at a specialist clinic, participants had poor baseline knowledge of liver cirrhosis. Delivering information by screencast led to a significant improvement. We therefore present an effective way to empower patients with accurate, up-to-date and retainable information that can easily be translated to many other conditions.
A 4-month-old female kitten presented with chronic lower urinary tract signs and Escherichia coli cystitis, and was diagnosed with urinary bladder malakoplakia based upon histopathology. The kitten was treated with a prolonged antibiotic course and the malakoplakia resolved. Malakoplakia is a chronic granulomatous reaction characterized by the formation of Michaelis-Gutman bodies within von Hansemann macrophages. It is well described in humans, but has never been documented in a living veterinary patient. This case report describes the first successful treatment of malakoplakia in veterinary medicine.
◥Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic reaction, warranting intense cancer-stroma communication. In this study, we interrogated the contribution of the BET family of chromatin adaptors to the cross-talk between PDAC cells and the tumor stroma. Short-term treatment of orthotopic xenograft tumors with CPI203, a small-molecule inhibitor of BET proteins, resulted in broad changes in the expression of genes encoding components of the extracellular matrix (matrisome) in both cancer and stromal cells. Remarkably, more than half of matrisome genes were expressed by cancer cells. In vitro cocultures of PDAC cells and cancer-associated fibroblasts (CAF) demonstrated that matrisome expression was regulated by BET-dependent cancer-CAF cross-talk. Disrupting this cross-talk in vivo resulted in diminished growth of orthotopic patient-derived xenograft tumors, reduced proliferation of cancer cells, and changes in collagen structure consistent with that of patients who experienced better survival. Examination of matrisome gene expression in publicly available data sets of 573 PDAC tumors identified a 65-gene signature that was able to distinguish long-and short-term PDAC survivors. Importantly, the expression of genes predictive of shortterm survival was diminished in the cancer cells of orthotopic xenograft tumors of mice treated with CPI203. Taken together, these results demonstrate that inhibiting the activity BET proteins results in transcriptional and structural differences in the matrisome are associated with better patient survival.Implications: These studies highlight the biological relevance of the matrisome program in PDAC and suggest targeting of epigenetically driven tumor-stroma cross-talk as a potential therapeutic avenue.
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