A Leadership Perspective on the Plastic and Reconstructive Surgery Residency Application Cycle During the COVID-19 Pandemic.

Introduction: The purpose of this study was to identify leadership perspective on the impact of COVID-19 Plastic and Reconstructive Surgery (PRS) residency application cycle in 2020 and its future implications. Methods: A survey was sent to residency program leaders (RPL), consisting of program directors and division chiefs/chairs. The survey was sent weekly for 4 weeks and remained open for 28 days. Results: A total of 156 PRS RPL were emailed. Response rate was 24% (38/156). A total of 68% were division chiefs/chairs, and 42% were program directors. Ten percent were both division chiefs/chairs and program directors. Among them, 78% were male. Eighty-seven percent of RPLs reported changes in the number of away rotations, of which 91% reported less away rotations. Only 27% of programs provided virtual away rotations (VAR), and 88% of RPLs were not comfortable writing letters of recommendation after VARs. Hundred percent of cases reported that VARs influenced whether an applicant received an interview. A total of 24 RPLs (63%) reported no changes in how they viewed applications due to the pandemic. However, 5 (13%) reported USMLE scores were more important, 4 (11%) reported research was more important, and 4 (11%) reported LORs were more important. Sixty-six percent did not feel they relied heavily on home institution candidates. Seventy-six percent found virtual interviews to be effective in evaluating applicants, and 71% reported they would add virtual interviews in future interviews. Conclusions: During the 2020-2021 PRS residency application cycle, fewer away rotations were offered, and formerly in-person activities were moved to virtual platforms. Virtual activities caused difficulty assessing candidates for many residency programs.

In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme.

The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs. The three-dimensional (3D) structure of the full-length native human CYP3A4 has been solved, but the respective structure of the main vitamin D hydroxylating CYP24A1 enzyme is unknown. The structures of recombinant CYP24A1 enzymes have been solved; however, from studies of the vitamin D receptor, the use of a truncated protein for docking studies of ligands led to incorrect results. As the structure of the native CYP3A4 protein is known, we performed rigid docking supported by molecular dynamic simulation using CYP3A4 to predict the metabolic conversion of analogs of 1,25-dihydroxyvitamin D2 (1,25D2). This is highly important to the design of novel vitamin D-based drug candidates of reasonable metabolic stability as CYP3A4 metabolizes ca. 50% of the drug substances. The use of the 3D structure data of human CYP3A4 has allowed us to explain the substantial differences in the metabolic conversion of the side-chain geometric analogs of 1,25D2. The calculated free enthalpy of the binding of an analog of 1,25D2 to CYP3A4 agreed with the experimentally observed conversion of the analog by CYP24A1. The metabolic conversion of an analog of 1,25D2 to the main vitamin D hydroxylating enzyme CYP24A1, of unknown 3D structure, can be explained by the binding strength of the analog to the known 3D structure of the CYP3A4 enzyme.

Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift.

Infection or vaccination leads to the development of germinal centers (GC) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. Here we follow the migratory pathways of B cells emerging from germinal centers (BEM) and find that many BEM cells migrate into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From the SCS, BEM cells may exit the lymph node to enter distant tissues, while some BEM cells interact with and take up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibits the recycling of BEM cells and results in less efficient adaption to antigenic variation. Our findings thus suggest that the recycling of antigen variant-specific BEM cells and transport of antigen back to GC may support affinity maturation to antigenic drift.

The RARγ Oncogene: An Achilles Heel for Some Cancers.

Cancer "stem cells" (CSCs) sustain the hierarchies of dividing cells that characterize cancer. The main causes of cancer-related mortality are metastatic disease and relapse, both of which originate primarily from CSCs, so their eradication may provide a bona fide curative strategy, though there maybe also the need to kill the bulk cancer cells. While classic anti-cancer chemotherapy is effective against the dividing progeny of CSCs, non-dividing or quiescent CSCs are often spared. Improved anti-cancer therapies therefore require approaches that target non-dividing CSCs, which must be underpinned by a better understanding of factors that permit these cells to maintain a stem cell-like state. During hematopoiesis, retinoic acid receptor (RAR) γ is selectively expressed by stem cells and their immediate progeny. It is overexpressed in, and is an oncogene for, many cancers including colorectal, renal and hepatocellular carcinoma, cholangiocarcinomas and some cases of acute myeloid leukemia that harbor RARγ fusion proteins. In vitro studies suggest that RARγ-selective and pan-RAR antagonists provoke the death of CSCs by necroptosis and point to antagonism of RARγ as a potential strategy to treat metastatic disease and relapse, and perhaps provide a cure for some cancers.