Career Trajectory After General Surgery Residency: Do Academic Program Graduates Pursue Academic Surgery?

OBJECTIVE: Determine the proportion of contemporary US academic general surgery residency program graduates who pursue academic careers and identify factors associated with pursuing academic careers. SUMMARY BACKGROUND DATA: Many academic residency programs aim to cultivate academic surgeons, yet the proportion of contemporary graduates who choose academic careers is unclear. The potential determinants that affect graduates' decisions to pursue academic careers remain underexplored. METHODS: We collected program and individual-level data on 2015 and 2018 graduates across 96 US academic general surgery residency programs using public resources. We defined those pursuing academic careers as faculty within US allopathic medical school-affiliated surgery departments who published two or more peer-reviewed publications as the first or senior author between 2020-2021. After variable selection using sample splitting LASSO regression, multivariable regression evaluated association with pursuing academic careers among all graduates, and graduates of top-20 residency programs. Secondary analysis using multivariable ordinal regression explored factors associated with high research productivity during early faculty years. RESULTS: Among 992 graduates, 166 (17%) were pursuing academic careers according to our definition. Graduating from a top-20 ranked residency program (OR[95%CI]: 2.34[1.40-3.88]), working with a longitudinal research mentor during residency (OR[95%CI]: 2.21[1.24-3.95]), holding an advanced degree (OR[95%CI]: 2.20[1.19-3.99]), and the number of peer-reviewed publications during residency as first or senior author (OR[95%CI]: 1.13[1.07-1.20]) were associated with pursuing an academic surgery career, while the number of peer-reviewed publications before residency was not (OR[95%CI]: 1.08[0.99-1.20]). Among top 20 program graduates, working with a longitudinal research mentor during residency (OR[95%CI]: 0.95[0.43-2.09]) was not associated with pursuing an academic surgery career. The number of peer-reviewed publications during residency as first or senior author was the only variable associated with higher productivity during early faculty years (OR[95%CI]: 1.12[1.07-1.18]). CONCLUSIONS: Our findings suggest programs that aim to graduate academic surgeons may benefit from ensuring trainees receive infrastructural support and demonstrate sustained commitment to research throughout residency. Our results should be interpreted cautiously as the impact of unmeasured confounders is unclear.

De novo design of highly selective miniprotein inhibitors of integrins αvß6 and αvß8.

The RGD (Arg-Gly-Asp)-binding integrins αvß6 and αvß8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvß6 and αvß8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvß6 and αvß8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvß6 and the αvß8 integrins. In a lung fibrosis mouse model, the αvß6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.

De novo design of highly selective miniprotein inhibitors of integrins αvß6 and αvß8.

The RGD (Arg-Gly-Asp)-binding integrins αvß6 and αvß8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between the two closely related integrin proteins and other RGD integrins, stabilize specific conformational states, and have sufficient stability enabling tissue restricted administration could have considerable therapeutic utility. Existing small molecules and antibody inhibitors do not have all of these properties, and hence there is a need for new approaches. Here we describe a method for computationally designing hyperstable RGD-containing miniproteins that are highly selective for a single RGD integrin heterodimer and conformational state, and use this strategy to design inhibitors of αvß6 and αvß8 with high selectivity. The αvß6 and αvß8 inhibitors have picomolar affinities for their targets, and >1000-fold selectivity over other RGD integrins. CryoEM structures are within 0.6-0.7Å root-mean-square deviation (RMSD) to the computational design models; the designed αvß6 inhibitor and native ligand stabilize the open conformation in contrast to the therapeutic anti-αvß6 antibody BG00011 that stabilizes the bent-closed conformation and caused on-target toxicity in patients with lung fibrosis, and the αvß8 inhibitor maintains the constitutively fixed extended-closed αvß8 conformation. In a mouse model of bleomycin-induced lung fibrosis, the αvß6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics when delivered via oropharyngeal administration mimicking inhalation, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.

Computational design of constitutively active cGAS.

Cyclic GMP-AMP synthase (cGAS) is a pattern recognition receptor critical for the innate immune response to intracellular pathogens, DNA damage, tumorigenesis and senescence. Binding to double-stranded DNA (dsDNA) induces conformational changes in cGAS that activate the enzyme to produce 2'-3' cyclic GMP-AMP (cGAMP), a second messenger that initiates a potent interferon (IFN) response through its receptor, STING. Here, we combined two-state computational design with informatics-guided design to create constitutively active, dsDNA ligand-independent cGAS (CA-cGAS). We identified CA-cGAS mutants with IFN-stimulating activity approaching that of dsDNA-stimulated wild-type cGAS. DNA-independent adoption of the active conformation was directly confirmed by X-ray crystallography. In vivo expression of CA-cGAS in tumor cells resulted in STING-dependent tumor regression, demonstrating that the designed proteins have therapeutically relevant biological activity. Our work provides a general framework for stabilizing active conformations of enzymes and provides CA-cGAS variants that could be useful as genetically encoded adjuvants and tools for understanding inflammatory diseases.

Salinomycin Suppresses PDGFRß, MYC, and Notch Signaling in Human Medulloblastoma.

Medulloblastoma (MB) is the most common childhood brain tumor. Despite improved therapy and management, approximately 30% of patients die of the disease. To search for a more effective therapeutic strategy, the effects of salinomycin were tested on cell proliferation, cell death, and cell cycle progression in human MB cell lines. The results demonstrated that salinomycin inhibits cell proliferation, induces cell death , and disrupts cell cycle progression in MB cells. Salinomycin was also tested on the expression levels of key genes involved in proliferation and survival signaling and revealed that salinomycin down-regulates the expression of PDGFRß, MYC, p21 and Bcl-2 as well as up-regulates the expression of cyclin A. In addition, the results reveal that salinomycin suppresses the expression of Hes1 and Hes5 in MB cells. Our data shed light on the potential of using salinomycin as a novel therapeutic agent for patients with MB.

Combined positron emission tomography/computed tomography for evaluation of presumed choroidal metastases.

BACKGROUND: Choroidal metastases are the most common intraocular malignancy and are the first sign of systemic malignancy in approximately one-third of patients. Of patients with no previous diagnosis of cancer, oncological evaluation fails to find the primary lesion in approximately 50% of cases. Newer imaging modalities such as combined positron emission tomography/computed tomography (PET/CT) may improve the yield of the systemic work-up. METHODS: Consecutive patients presenting with presumed choroidal metastases were evaluated with whole body combined PET/CT scanning. RESULTS: Four patients presenting to a tertiary referral hospital with choroidal metastases as the first sign of systemic malignancy were evaluated. In all four cases, PET/CT demonstrated the ocular lesion, and the primary malignancy which was confirmed by tissue biopsy. False-negative results were seen in two cases of cerebral metastases. PET/CT demonstrated lesions not visible on CT or magnetic resonance imaging in two cases. CONCLUSIONS: Combined PET/CT is a useful addition to the work-up of patients with choroidal metastases. It provides the opportunity to detect lesions not visible with other imaging modalities and the ability to image patients with contraindications to magnetic resonance imaging. It is essential to correlate PET images with clinical information and the results of other imaging modalities and tissue biopsy remains the gold standard in the diagnosis of malignancy. False positives and negatives can occur with PET/CT, and further research is needed before this promising technology becomes a routine part of the evaluation of patients with choroidal metastases.