Creating a sustainable rural general surgery workforce: what enables fellows to return as rural general surgeons?

INTRODUCTION: In the context of shortfalls in rural general surgeon supply, this research aims to explore why rural general surgical Fellows returned and remained after fellowship at a single rural centre in Victoria, Australia. Fellowship positions post achievement of Fellowship of the Australasian College of Surgeons are traditionally not funded by government because they currently fall outside the accredited rural training post funding provided by the federal government. This article aims to explore if fellowship positions can be an important part in sustaining the rural general surgery workforce. METHODS: Semi-structured interviews were conducted with nine former general surgery Fellows from a single rural Australian institution. Interviews were recorded, transcribed, coded and themed to undertake analysis according to thematic analysis. RESULTS: This research demonstrates that consultant rural general surgeons can be recruited from a fellowship year when emphasis is placed on: (1) creating a positive workplace culture with safe working hours, (2) ensuring diversification of the general surgical case mix, (3) facilitating opportunities for schooling and work for the surgeon's family, and (4) preferentially selecting for those who identify as rural general surgeons. Rural towns can effectively recruit general surgeons when families are supported with career and school opportunities, and the newly qualified surgeon can initially commit to a 12-month position so that opportunities can be assessed by the entire family unit. Fellowship positions (post completion of general surgical training) allow young surgeons to 'try before they buy' prior to moving to a rural area. CONCLUSION: Ensuring a sustainable general surgical workforce in a rural community requires employee and surgical leadership to ensure a collaborative and progressive culture, which offers work diversity, supports the family lifestyle and petitions for selecting those who embody the rural general surgeon identity. Post-fellowship positions can enable young general surgeons to have exposure to the realities of a rural lifestyle, which is likely to have a positive effect on recruitment. Due to the return investment of the fellowship program, we propose that the federal government should look at funding post-fellowship positions to improve rural recruitment.

A Review of Small-Molecule Inhibitors of One-Carbon Enzymes: SHMT2 and MTHFD2 in the Spotlight.

Metabolic reprogramming is a key hallmark of cancer and shifts cellular metabolism to meet the demands of biomass production necessary for abnormal cell reproduction. One-carbon metabolism (1CM) contributes to many biosynthetic pathways that fuel growth and is comprised of a complex network of enzymes. Methotrexate and 5-fluorouracil were pioneering drugs in this field and are still widely used today as anticancer agents as well as for other diseases such as arthritis. Besides dihydrofolate reductase and thymidylate synthase, two other enzymes of the folate cycle arm of 1CM have not been targeted clinically: serine hydroxymethyltransferase (SHMT) and methylenetetrahydrofolate dehydrogenase (MTHFD). An increasing body of literature suggests that the mitochondrial isoforms of these enzymes (SHMT2 and MTHFD2) are clinically relevant in the context of cancer. In this review, we focused on the 1CM pathway as a target for cancer therapy and, in particular, SHMT2 and MTHFD2. The function, regulation, and clinical relevance of SHMT2 and MTHFD2 are all discussed. We expand on previous clinical studies and evaluate the prognostic significance of these critical enzymes by performing a pan-cancer analysis of patient data from the The Cancer Genome Atlas and a transcriptional coexpression network enrichment analysis. We also provide an overview of preclinical and clinical inhibitors targeting the folate pathway, the methionine cycle, and folate-dependent purine biosynthesis enzymes.

The Dihydroorotate Dehydrogenase Inhibitor Brequinar Is Synergistic with ENT1/2 Inhibitors.

The dihydroorotate dehydrogenase (DHODH) inhibitor brequinar failed all clinical trials for solid tumors. To investigate mechanisms to increase brequinar's efficacy, we employed a combination strategy to simultaneously inhibit the nucleotide salvage pathways. Brequinar is synergistic with the equilibrative nucleoside transporter (ENT) inhibitor dipyridamole, but not the concentrative nucleoside transporter inhibitor phlorizin. This synergy carries over to ENT1/2 inhibition, but not ENT4. Our previously described brequinar analogue 41 was also synergistic with dipyridamole as were the FDA-approved DHODH inhibitors leflunomide and teriflunomide but the latter required much higher concentrations than brequinar. Therefore, a combination of brequinar and ENT inhibitors presents a potential anti-cancer strategy in select tumors.

Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer.

Identified as a hallmark of cancer, metabolic reprogramming allows cancer cells to rapidly proliferate, resist chemotherapies, invade, metastasize, and survive a nutrient-deprived microenvironment. Rapidly growing cells depend on sufficient concentrations of nucleotides to sustain proliferation. One enzyme essential for the de novo biosynthesis of pyrimidine-based nucleotides is dihydroorotate dehydrogenase (DHODH), a known therapeutic target for multiple diseases. Brequinar, leflunomide, and teriflunomide, all of which are potent DHODH inhibitors, have been clinically evaluated but failed to receive FDA approval for the treatment of cancer. Inhibition of DHODH depletes intracellular pyrimidine nucleotide pools and results in cell cycle arrest in S-phase, sensitization to current chemotherapies, and differentiation in neural crest cells and acute myeloid leukemia (AML). Furthermore, DHODH is a synthetic lethal susceptibility in several oncogenic backgrounds. Therefore, DHODH-targeted therapy has potential value as part of a combination therapy for the treatment of cancer. In this review, we focus on the de novo pyrimidine biosynthesis pathway as a target for cancer therapy, and in particular, DHODH. In the first part, we provide a comprehensive overview of this pathway and its regulation in cancer. We further describe the relevance of DHODH as a target for cancer therapy using bioinformatic analyses. We then explore the preclinical and clinical results of pharmacological strategies to target the de novo pyrimidine biosynthesis pathway, with an emphasis on DHODH. Finally, we discuss potential strategies to harness DHODH as a target for the treatment of cancer.

Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase.

We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC50 = 9.71 ± 1.4 nM) and 43 (DHODH IC50 = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC50 = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability ( F = 56%) and an elimination t1/2 = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.

Design, Synthesis, and Characterization of Brequinar Conjugates as Probes to Study DHODH Inhibition.

Brequinar, a potent dihydroorotate dehydrogenase (DHODH) inhibitor, has been evaluated in multiple clinical trials as a potential treatment for cancer. To further understand brequinar-based DHODH inhibition and DHODH's therapeutic relevance in cancer, we have developed novel brequinar-based probes. We disclose a 16-step convergent synthesis of the first brequinar-PROTAC and a four-step approach towards the first mitochondrial-directed brequinar probe. A PROTAC and mitochondria-directed probe of brequinar both possess cytotoxicity that is superior to brequinar in a colony formation assay.

Hyperbaric oxygen improves capillary morphology in severe acute pancreatitis.

OBJECTIVES: This article aims to determine the effect of acute pancreatitis on microvascular morphology and the impact of treatment with hyperbaric oxygen (HBO). METHODS: Sixty-seven male Wistar rats were induced with acute pancreatitis by retrograde bile duct injection. Rats were randomized to 12-hourly HBO or control treatment. Two rats in each group were killed at baseline and 24, 48, and 72 hours postinduction, and a cast of the pancreatic microvasculature was examined using scanning electron microscopy. RESULTS: Normal pancreatic vasculature is a dense network with a consistent capillary diameter. In acute pancreatitis, mean capillary diameter is increased at 24 hours (P < 0.001) and further increased at 48 hours (P = 0.007). From 24 hours, diameter heterogeneity is increased (P < 0.001) and capillary density is reduced (P < 0.001). Hyperbaric oxygen has a significant effect on vascular morphology changes from 48 hours after induction. Capillary diameter and heterogeneity of diameter are decreased by HBO (both P < 0.001). Capillary density is increased by HBO at 48 and 72 hours (P < 0.001). CONCLUSIONS: In acute pancreatitis, structural capillary diameter and heterogeneity of diameter increase and capillary density decreases. These parameters are all improved by HBO treatment. Hyperbaric oxygen treatment normalizes the pancreatic microvasculature after acute pancreatitis and may be a potentially effective treatment of this disease.

Hyperbaric oxygen therapy reduces severity and improves survival in severe acute pancreatitis.

Severe acute pancreatitis is characterized by pancreatic necrosis, resulting in local and systemic inflammation. Hyperbaric oxygen (HBO) therapy modulates inflammation, but has not been extensively studied in pancreatitis. This study investigates the effects of HBO in a rat model of severe acute pancreatitis. Sixty-four rats were induced with severe pancreatitis using 4% sodium taurocholate and randomized to HBO treatment or control. HBO was commenced 6 h after induction (100% oxygen at 2.5 atmospheres for 90 min) and continued every 12 h for a maximum of eight treatment episodes. Surviving animals were killed at 7 days. Severity of pancreatitis was graded macroscopically and microscopically. Lung edema was calculated using wet and dry lung weights. Macroscopic and microscopic severity scores (mean +/- SE) of HBO-treated animals with pancreatitis (8.3 +/- 0.7; 9.6 +/- 0.4) were lower than those of controls (10.5 +/- 0.5; 11.1 +/- 0.4) (p = 0.02 and p = 0.03, respectively). The HBO-treated group had reduced pancreatic necrosis compared to controls (40 +/- 4% vs. 54 +/- 4%; p = 0.003). There was no difference in pulmonary edema between the groups. Median survival in the HBO-treatment group was 51 h, compared to 26 h in controls. Day-7 survival was significantly improved in the HBO-treated animals compared to controls (40% vs. 27%; p = 0.04). HBO therapy reduces overall severity, decreases the extent of necrosis, and improves survival in severe acute pancreatitis.

Potential effects of hyperbaric oxygen therapy in acute pancreatitis.

BACKGROUND: To extract from the biomedical published reports, the effects of hyperbaric oxygen (HBO) on inflammatory disease, in particular acute pancreatitis. METHODS: This review will explain these effects and evaluate potential mechanisms of action of HBO in acute pancreatitis. A Medline/PubMed search (January 1966 to July 2004) with manual cross-referencing was conducted, including all relevant articles investigating the molecular and systemic effects of HBO on inflammatory diseases, particularly focusing on the studies of acute pancreatitis. All publication types, languages and subsets were searched. RESULTS: Original and review articles and short communications were extracted. The selected original articles covered the molecular and systemic effects of HBO and the effects in inflammatory disease states. The major findings are that HBO can act as an anti-inflammatory agent and as an antimicrobial agent. Many of the effects of HBO would be beneficial in the treatment of acute severe pancreatitis. Work carried out to date in animal models of acute pancreatitis shows promising improvements in severity but studies are limited to date. CONCLUSION: Acute pancreatitis impairs the pancreatic and systemic microcirculation and causes acute inflammation. These processes are potentially improved by HBO therapy.

Review of experimental animal models of acute pancreatitis.

The underlying mechanisms involved in the pathogenesis of acute pancreatitis are ill understood. The mortality rate of this disease has not significantly improved over the past few decades. Current treatment options are limited, and predominantly aimed at supportive therapy. A key feature of severe acute pancreatitis is the presence of extensive tissue necrosis with both local and systemic manifestations of inflammatory response syndromes. A better understanding of the underlying pathophysiology of severe acute pancreatitis may lead to more targeted therapeutic options, potentially leading to improved survival. Animal models of acute pancreatitis are therefore an essential investigative tool for these aims to be achieved. This review discusses the suitability of recent non-invasive models of acute pancreatitis such as hormone-induced, alcohol-induced, immune-mediated, diet-induced, gene knockout and L-arginine; and invasive models including closed duodenal loop, antegrade pancreatic duct perfusion, biliopancreatic duct injection, combination of secretory hyperstimulation with minimal intraductal bile acid exposure, vascular-induced, ischaemia/reperfusion and duct ligation.