Notch and transforming growth factor-beta (TGFbeta) signaling pathways cooperatively regulate vascular smooth muscle cell differentiation.

Notch and transforming growth factor-beta (TGFbeta) 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 TGFbeta1 and Notch signaling on contractile gene expression. Activation of Notch signaling using Notch intracellular domain or Jagged1 ligand induced smooth muscle alpha-actin (SM actin), smooth muscle myosin heavy chain, and calponin1, and the expression of Notch downstream effectors hairy-related transcription factors. Similarly, TGFbeta1 treatment of human aortic smooth muscle cells induced SM actin, calponin1, and smooth muscle protein 22-alpha (SM22alpha) in a dose- and time-dependent manner. Hairy-related transcription factor proteins, which antagonize Notch activity, also suppressed the TGFbeta1-induced increase in SMC markers, suggesting a general mechanism of inhibition. We found that Notch and TGFbeta1 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 TGFbeta1 treatment led to synergistic activation of a TGFbeta-responsive promoter. This increase corresponded to increased levels of phosphoSmad2/3 interaction at Smad consensus binding sites within the SM actin, calponin1, and SM22alpha promoters. Thus, Notch and TGFbeta coordinately induce a molecular and functional contractile phenotype by co-regulation of Smad activity at SMC promoters.

Residents' Views on the Impact of Robotic Surgery on General Surgery Education.

OBJECTIVE: The use of the da Vinci Robot has been fast growing in general surgery in the United States over the past decade. While the financial cost of robot-assisted procedures has been studied, there has been limited research on the educational cost of the robotic approach on general surgery trainees, and their surgical skills. DESIGN: Analysis of anonymous educational survey responses collected from residents, in addition to case logs which were used as a retrospective review for the 5 years preceding the survey. SETTING: One thousand bed, tertiary care hospital general surgery residency program. PARTICIPANTS: Twenty-four enrolled general surgery residents in 2018. RESULTS: There has been a rapid expansion in the use of robotics in general surgery. In 2017 the total number of general surgery cases using the da Vinci robot increased 6 fold over that in 2013 (23 cases in 2013, 136 in 2017), while both open and laparoscopic procedures have witnessed about a 33% drop in the case volume during those years. Almost all residents would prefer a residency program which offers the da Vinci robot for care and training (95%), however, 38% of general surgery residents reported that the presence of robotic-assisted surgery had a "detrimental" effect on their surgical training. Senior residents were more likely to report a "detrimental" effect (56% vs 27%). A third of the residents believe that robotic surgery is impeding their ability to learn open and laparoscopic surgical techniques, and only 25% denied a negative impact. Senior residents are more likely to report this negative impact (67% vs 13%). CONCLUSIONS: Reforms in residency curricula need to be in place to accommodate the expansion of the use of the robotic platform in general surgery. A subjective survey of the residents suggests that robotic surgery can potentially impede the development of residents' open and laparoscopic surgical skills.

Practice patterns, attitudes, and knowledge among physicians regarding cytoreductive surgery and HIPEC for patients with peritoneal metastases.

BACKGROUND: Cytoreductive 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. METHODS: Surveys 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. RESULTS: Surveys 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. CONCLUSIONS: Referral 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.