Quantifying the Financial Value of Clinical Specialty Choice and Its Association With Competitiveness of Admissions.

Background The factors influencing medical student clinical specialty choice have important implications for the future composition of the US physician workforce. The objective of this study was to determine the career net present values (NPVs) of US medical students' clinical specialty choices and identify any relationships between a specialty's NPV and competitiveness of admissions as measured by the US Medical Licensing Examination (USMLE) Step 1 scores. Methodology NPVs were calculated using the results of the 2019 Doximity Physician Compensation report, a survey of 90,000 physicians. Mean USMLE Step 1 scores for matched US allopathic seniors in the 2018 National Resident Matching Program were used as a measure of clinical specialties' competitiveness of admissions. We calculated a composite measure of NPV and annual work-hours by dividing each specialty's NPV by the reported average number of hours worked per year. Results In our analysis, orthopedic surgery had the highest NPV ($10,308,868), whereas family medicine had the lowest NPV ($5,274,546). Dermatology and plastic surgery had the highest mean USMLE Step 1 scores (249 for both), whereas family medicine had the lowest (220). Clinical specialties' NPVs were positively associated with mean USMLE Step 1 scores (Pearson's r = 0.82; p < 0.001). Conclusions In this study, we describe associations suggesting that medical students respond to financial incentives in choosing clinical specialties and that these decisions are mediated by USMLE Step 1 scores. This underscores the importance of titrating and aligning incentives to improve the allocation of medical students into clinical specialties.

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism.

Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PIP2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg2+ -inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP2 closely correlates with 42-residue amyloid beta-peptide (Abeta42) levels. Our data suggest that PIP2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic Abeta42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP2 may offer a therapeutic approach in Alzheimer's disease.

Regulated intramembrane proteolysis of the p75 neurotrophin receptor modulates its association with the TrkA receptor.

The generation of biologically active proteins by regulated intramembrane proteolysis is a highly conserved mechanism in cell signaling. Presenilin-dependent gamma-secretase activity is responsible for the intramembrane proteolysis of selected type I membrane proteins, including beta-amyloid precursor protein (APP) and Notch. A small fraction of intracellular domains derived from both APP and Notch translocates to and appears to function in the nucleus, suggesting a generic role for gamma-secretase cleavage in nuclear signaling. Here we show that the p75 neurotrophin receptor (p75NTR) undergoes presenilin-dependent intramembrane proteolysis to yield the soluble p75-intracellular domain. The p75NTR is a multifunctional type I membrane protein that promotes neurotrophin-induced neuronal survival and differentiation by forming a heteromeric co-receptor complex with the Trk receptors. Mass spectrometric analysis revealed that gamma-secretase-mediated cleavage of p75NTR occurs at a position located in the middle of the transmembrane (TM) domain, which is reminiscent of the amyloid beta-peptide 40 (Abeta40) cleavage of APP and is topologically distinct from the major TM cleavage site of Notch 1. Size exclusion chromatography and co-immunoprecipitation analyses revealed that TrkA forms a molecular complex together with either full-length p75 or membrane-tethered C-terminal fragments. The p75-ICD was not recruited into the TrkA-containing high molecular weight complex, indicating that gamma-secretase-mediated removal of the p75 TM domain may perturb the interaction with TrkA. Independent of the possible nuclear function, our studies suggest that gamma-secretase-mediated p75NTR proteolysis plays a role in the formation/disassembly of the p75-TrkA receptor complex by regulating the availability of the p75 TM domain that is required for this interaction.

Decreased expression of the mannose 6-phosphate/insulin-like growth factor-II receptor promotes growth of human breast cancer cells.

BACKGROUND: Loss or mutation of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) has been found in breast cancer. However, whether or not decreased levels of functional M6P/IGF2R directly contribute to the process of carcinogenesis needs to be further verified by functional studies. METHODS: In this study, using viral and ribozyme strategies we reduced the expression of M6P/IGF2R in human breast cancer cells and then examined the effect on growth and apoptosis of these cells. RESULTS: Our results showed that infection of MCF-7 cells with the adenovirus carrying a ribozyme targeted against the M6P/IGF2R mRNA dramatically reduced the level of transcripts and the functional activity of M6P/IGF2R in these cells. Accordingly, cells treated with a ribozyme exhibited a higher growth rate and a lower apoptotic index than control cells (infected with a control vector). Furthermore, decreased expression of M6P/IGF2R enhanced IGF-II-induced proliferation and reduced cell susceptibility to TNF-induced apoptosis. CONCLUSIONS: These results suggest that M6P/IGF2R functions as a growth suppressor and its loss or mutation may contribute to development and progression of cancer. This study also demonstrates that adenoviral delivery of the ribozyme provides a useful tool for investigating the role of M6P/IGF2R in regulation of cell growth.