Notch and transforming growth factor- (TGF) play pivotal roles during vascular development and the pathogenesis of vascular disease. The interaction of these two pathways is not fully understood. The present study utilized primary human smooth muscle cells (SMC) to examine molecular cross-talk between TGF1 and Notch signaling on contractile gene expression. Activation of Notch signaling using Notch intracellular domain or Jagged1 ligand induced smooth muscle ␣-actin (SM actin), smooth muscle myosin heavy chain, and calponin1, and the expression of Notch downstream effectors hairy-related transcription factors. Similarly, TGF1 treatment of human aortic smooth muscle cells induced SM actin, calponin1, and smooth muscle protein 22-␣ (SM22␣) in a dose-and time-dependent manner. Hairy-related transcription factor proteins, which antagonize Notch activity, also suppressed the TGF1-induced increase in SMC markers, suggesting a general mechanism of inhibition. We found that Notch and TGF1 cooperatively activate SMC marker transcripts and protein through parallel signaling axes. Although the intracellular domain of Notch4 interacted with phosphoSmad2/3 in SMC, this interaction was not observed with Notch1 or Notch2. However, we found that CBF1 co-immunoprecipitated with phosphoSmad2/3, suggesting a mechanism to link canonical Notch signaling to phosphoSmad activity. Indeed, the combination of Notch activation and TGF1 treatment led to synergistic activation of a TGF-responsive promoter. This increase corresponded to increased levels of phosphoSmad2/3 interaction at Smad consensus binding sites within the SM actin, calponin1, and SM22␣ promoters. Thus, Notch and TGF coordinately induce a molecular and functional contractile phenotype by co-regulation of Smad activity at SMC promoters.
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BackgroundCytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is a treatment option for patients with peritoneal metastases shown to provide improved overall survival for appropriately selected patients. However, the availability and utilization of this treatment remains limited. The aim of this survey-based study was to evaluate factors influencing physician treatment choices for peritoneal metastases.MethodsSurveys were mailed to medical oncologists and surgeons in Virginia, Maryland, and Washington, D.C. Survey questions evaluated access to HIPEC centers, prior experience with referral to HIPEC centers, opinions regarding efficacy, and knowledge regarding outcomes of CRS and HIPEC.ResultsSurveys were mailed to 2279 physicians; 116 eligible surveys were returned. Seventy-five percent of respondents would consider referral to a HIPEC center for appendiceal peritoneal metastasis, while only 50% would consider it for colon cancer and peritoneal mesothelioma. The most common reason for never referring a patient to a HIPEC center was lack of access to a HIPEC specialist (47%) followed by perceived lack of evidence for the treatment modality (31%). Five-year survival after CRS and HIPEC was underestimated while 30-day mortality was overestimated by more than half of respondents.ConclusionsReferral to HIPEC centers is underutilized among community physicians in practice. Limited access to HIPEC experts is the most common cause for lack of referral, followed by a perception of insufficient evidence for this treatment approach. Lack of familiarity with data regarding outcomes impacts referral patterns and treatment choices. Possible actions to increase awareness and appropriate utilization of CRS and HIPEC are suggested.
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