Neuropeptides are implicated in many tumors, breast cancer (BC) included. Preprotachykinin-I (PPT-I) encodes multiple neuropeptides with pleiotropic functions such as neurotransmission, immune͞hematopoietic modulation, angiogenesis, and mitogenesis. PPT-I is constitutively expressed in some tumors. In this study, we investigated a role for PPT-I and its receptors, neurokinin-1 (NK-1) and NK-2, in BC by using quantitative reverse transcription-PCR, ELISA, and in situ hybridization. Compared with normal mammary epithelial cells (n ‫؍‬ 2) and benign breast biopsies (n ‫؍‬ 21), BC cell lines (n ‫؍‬ 7) and malignant breast biopsies (n ‫؍‬ 25) showed increased expression of PPT-I and NK-1. NK-2 levels were high in normal and malignant cells. Specific NK-1 and NK-2 antagonists inhibited BC cell proliferation, suggesting autocrine and͞or intercrine stimulation of BC cells by PPT-I peptides. NK-2 showed no effect on the proliferation of normal cells but mediated the proliferation of BC cells. Cytosolic extracts from malignant BC cells enhanced PPT-I translation whereas extracts from normal mammary epithelial cells caused no change. These enhancing effects may be protein-specific because a similar increase was observed for IL-6 translation and no effect was observed for IL-1␣ and stem cell factor. The data suggest that PPT-I peptides and their receptors may be important in BC development. Considering that PPT-I peptides are hematopoietic modulators, these results could be extended to understand early integration of BC cells in the bone marrow, a preferred site of metastasis. Molecular signaling transduced by PPT-I peptides and the mechanism that enhances translation of PPT-I mRNA could lead to innovative strategies for BC treatments and metastasis.

ABSTRACT

Background More than 1000 candidates applied for orthopaedic residency positions in 2014, and the competition is intense; approximately one-third of the candidates failed to secure a position in the match. However, the criteria used in the selection process often are subjective and studies have differed in terms of which criteria predict either objective measures or subjective ratings of resident performance by faculty. Questions/purposes Do preresidency selection factors serve as predictors of success in residency? Specifically, we asked which preresidency selection factors are associated or correlated with (1) objective measures of resident knowledge and performance; and (2) subjective ratings by faculty. Methods Charts of 60 orthopaedic residents from our institution were reviewed. Preresidency selection criteria examined included United States Medical Licensing Examination (USMLE) Step 1 and Step 2 scores, Medical College Admission Test (MCAT) scores, number of clinical clerkship honors, number of letters of recommendation, number of away rotations, Alpha Omega Alpha (AOA) honor medical society membership, fourthyear subinternship at our institution, and number of publications. Resident performance was assessed using objective measures including American Board of Orthopaedic Surgery (ABOS) Part I scores and Orthopaedics InTraining Exam (OITE) scores and subjective ratings by faculty including global evaluation scores and faculty rankings of residents. We tested associations between preresidency criteria and the subsequent objective and subjective metrics using linear correlation analysis and Mann-Whitney tests when appropriate. Results Objective measures of resident performance namely, ABOS Part I scores, had a moderate linear correlation with the USMLE Step 2 scores (r = 0.55, p \ 0.001) and number of clinical honors received in medical school (r = 0.45, p \ 0.001). OITE scores had a weak linear correlation with the number of clinical honors (r = 0.35, p = 0.009) and USMLE Step 2 scores (r = 0.29, p = 0.02). With regards to subjective outcomes, AOA membership was associated with higher scores on the global evaluation (p = 0.005). AOA membership also correlated with higher global evaluation scores (r = 0.60, p = 0.005) with the strongest correlation existing between AOA membership and the ''interpersonal and communication skills

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