SMAD4 is a critical cofactor in signal transduction pathways activated in response to transforming growth factor-beta (TGF-b)-related ligands, regulating cell growth and differentiation. The roles played by SMAD4 inactivation in tumours highlighted it as a tumoursuppressor gene. However, restoration of the TGF-b antiproliferative pathway following SMAD4 gene transfer in null-tumour cell lines is controversial. Herein, we report the inhibitory effects of SMAD4 on pancreatic tumour invasion and angiogenesis. Adenoviral transfer of this gene in a panel of SMAD4 homozygous-deleted human pancreatic tumour cell lines restored SMAD4 protein expression and function. Although it did not affect proliferation significantly in vitro, SMAD4 inhibited in vivo tumour growth in immunodeficient mice. In this xenograft setting, differential suppression of tumour growth in vivo was mediated, at least in part, through downregulation of vascular endothelial growth factor and expression of gelatinases. We documented the reduced invasion and angiogenesis histologically and by intravital microscopy, and gained mechanistic insight at the messenger and protein level. Finally, we found a negative reciprocal regulation between SMAD4 and ETS-1. ETS-1 is considered a marker for tumour invasion. Upon SMAD4 deletion, we detected high expression levels of ETS-1 in pancreatic tumour cells, suggesting the shift of the pancreatic tumour toward an invasive phenotype.

This audit suggests that handwritten surgical notes generate several errors that could lead to confusion when notes are reviewed for further follow up or are produced as evidence in medico-legal disputes.

A number of lines of evidence have suggested that the long arm of chromosome 18 apart from SMAD4 may carry a tumor-suppressor gene(s) that plays a role in the early stage of pancreatic ductal carcinogenesis. Thus, adenovirus-mediated introduction of SMAD4 does not suppress in vitro growth in cells with completely inactivated SMAD4, and frequent loss of 18q at the SMAD4 locus is observed in pancreatic cancers but no abnormalities of the normal SMAD4 homolog have been detected. In this study, we introduced a normal copy of chromosome 18 into some pancreatic ductal carcinoma cells with and without a complete inactivation of SMAD4. Both anchorage-dependent and -independent proliferation as well as invasiveness were significantly suppressed in the hybrid clones compared with that of their parental cells. Moreover, significant suppression of tumorigenesis was observed after inoculation in nude mice, irrespective of the SMAD4 status. Our present study provides the first functional evidence of the existence of an additional tumor-suppressor gene(s), other than SMAD4 and DCC, that is responsible for the pathogenesis in the early stage of pancreatic ductal carcinogenesis.

Background The ongoing "coronavirus disease 19" (COVID-19) pandemic has had a strong effect on the delivery of surgical care worldwide. Elective surgeries have been canceled or delayed in order to reallocate resources to the treatment of COVID-19 patients. Currently, the impact of the COVID-19 pandemic on bariatric and metabolic surgical practice remains unclear. Methods An internet-based online survey was performed among bariatric surgeons worldwide. The survey was sent to bariatric surgeons via the International Bariatric Club Facebook group and by electronic mail via the International Federation for the Surgery of Obesity and metabolic disorders (IFSO) secretariat to members of the associated national IFSO societies. Results One hundred sixty-nine (n = 169) bariatric surgeons participated in the survey. The majority of the respondents postponed preoperative upper gastrointestinal tract endoscopies, appointments in the outpatient clinic and bariatric operations. Most surgeons performed video calls for follow-up appointments instead of meeting the patients in the outpatient clinics. Laparoscopy was still the preferred treatment for surgical emergencies, but a trend towards conservative treatment of acute appendicitis and acute cholecystitis was shown. Rapid preoperative COVID-19 testing availability was poor; therefore, routine screening of emergency bariatric cases was not widely provided. A wide variance occurred regarding precautions and personal protection equipment among the participants. Conclusion The COVID-19 pandemic showed a strong impact on bariatric surgical practice regarding surgical and outpatient planning as well as personnel management. Coordinated effort from the national bariatric societies should focus on strict implementation of the current recommendations regarding precaution measures and personal protection equipment. Further studies should evaluate how this impact will evolve in the near future.

In this study, we addressed the hypothesis that transcriptional suppression of erythroblastosis virus E26 oncogene homolog 1 (ETS-1) is an efficient therapeutic approach to pancreatic adenocarcinoma by investigating the effect of ETS-1 suppression in human pancreatic cancer cells. We accomplished this by using an adenoviral vector encoding only the DNA-binding domain of wild-type ETS-1 (ETS-1 dominant negative, ETS-1-DN). ETS-1-DN decreases ETS-1-binding by competing for its binding to DNA. Adenoviralmediated transfer of ETS-1-DN (adenoviral ETS-1-DN construct, AdETS-1-DN) into pancreatic tumor cell lines did not affect their proliferation rate in vitro but did significantly inhibit their in vivo growth in nude mice. Furthermore, to test the efficacy of ETS-1-DN in vivo, we injected the AdETS-1-DN into established human pancreatic adenocarcinomas grown in nude mice. This treatment significantly reduced tumor size as compared to saline injection, without any detectable side effects. Microvessel density in mouse xenografts displayed significantly lower values in tumors in which ETS-1 was downregulated. In addition, expression of the ETS-1-DN in the pancreatic cancer cells resulted in downregulation of urokinase-type plasminogen activator (u-PA) and metalloproteinase-1 (MMP-1) expression. Taken together, these data suggest that transcriptional inactivation of ETS-1 is able to significantly affect angiogenesis and growth of pancreatic cancer. This effect may be due in part to downregulation of MMP-1 and u-PA expression. Our results suggest that ETS-1-DN is a promising candidate for antiangiogenic gene therapy in pancreatic cancer.