BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression.

The molecular processes by which some human ductal carcinoma in situ (DCIS) lesions advance to the more aggressive form, while others remain indolent, are largely unknown. Experiments utilizing a patient-derived (PDX) DCIS Mouse INtraDuctal (MIND) animal model combined with ChIP-exo and RNA sequencing revealed that the formation of protein complexes between B Cell Lymphoma-9 (BCL9), phosphoserine 727 STAT3 (PS-727-STAT3) and non-STAT3 transcription factors on chromatin enhancers lead to subsequent transcription of key drivers of DCIS malignancy. Downregulation of two such targets, integrin ß3 and its associated metalloproteinase, MMP16, resulted in a significant inhibition of DCIS invasive progression. Finally, in vivo targeting of BCL9, using rosemary extract, resulted in significant inhibition of DCIS malignancy in both cell line and PDX DCIS MIND animal models. As such, our studies provide compelling evidence for future testing of rosemary extract as a chemopreventive agent in breast cancer.

How Trainees Finance Their Medical Education: Implications of Higher Education Act Reform.

CONTEXT: The Public Service Loan Forgiveness (PSLF) program is among several repayment programs currently available for recipients of federal student loans. Medical education debt has continued to expand at a rapid pace in the decade since PSLF was created. Proposed changes to the Higher Education Act would substantially transform how future medical trainees finance and repay medical education debt. OBJECTIVE: To better understand relationships between debt and personal stress, as well as between repayment- and forgiveness-program use, in the context of competing legislation. METHODS: Surveys were sent to all Accreditation Council for Graduate Medical Education-accredited internal medicine residency programs (osteopathic and allopathic). RESULTS: From a potential pool of 579 residents, data were obtained from 403 unique respondents (response rate, 69.6%) at 12 residency programs, for a program response rate of 2.2%. Of these respondents, 290 (71.9%) completed the demographic portion of the survey. Median education debt was $225,000. Residents with the top quartile of debt burden were more likely to use PSLF (odds ratio [OR], 3.27; P=.02), more likely to enter loan forbearance (OR, 2.14; P=.03), and indicated a higher level of stress (OR, 5.94; P<.001) compared with those in the second and third quartiles. CONCLUSION: Proposed legislative changes to the Higher Education Act would scale back loan repayment options and also eliminate PSLF for future borrowers. Our data suggest that higher debt burdens are associated with increased debt-related stress. Given program popularity and growing use, along with growing concerns of physician burnout, policy makers should weigh the potential downstream effects of policy change on prospective future physicians.

Role of Debt and Loan Forgiveness/Repayment Programs in Osteopathic Medical Graduates' Plans to Enter Primary Care.

CONTEXT: Osteopathic medicine emphasizes partnering with patients to help them attain or maintain health. This philosophy encourages physicians to practice primary care and a mission of improving community health. However, there is currently a shortage of primary care physicians in many areas of the United States. OBJECTIVE: To determine whether intended practice patterns of recent graduates of colleges of osteopathic medicine favor primary care and whether practice patterns correlate with medical education debt. METHODS: Responses were analyzed from the American Association of Colleges of Osteopathic Medicine survey of pending medical school graduates from 2007 through 2016 regarding indebtedness and specialty selection. RESULTS: The percentage of graduating osteopathic medical students who chose a primary care specialty increased from 28.1% (676 students) in 2007 to 33.2% (1377 students) in 2016. Among graduates, those above the 75th percentile of debt had a general move toward more non-primary care positions, with a value of 74.4% in 2007 and 79.9% in 2016. Graduates below the 25th percentile had a gradual increase in primary care representation, moving from 24.6% in 2007 to 29.4% in 2016. In 2007, graduates with a loan forgiveness/repayment program were more likely to choose primary care over graduates without such a program (OR, 0.681 [95% CI, 0.505-0.920]; P=.02). Analysis of subsequent years showed a declining OR with increasing significance. CONCLUSIONS: Results of this analysis indicated that increased educational debt loan directly influenced physician practice choice. Graduates with high debt burden were more likely to enter primary care fields and use loan forgiveness/repayment programs. Graduates with high debt burden who did not use loan forgiveness/repayment programs were more likely to enter non-primary care specialty fields, with this trend increasing as mean medical school debt increased. This association has implications for policies that could affect choice of primary care. However, further research is needed to fully understand the primary care choice by graduates of colleges of osteopathic medicine.

RalA is overactivated in medulloblastoma.

Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies. We have studied an important effector down-stream of Ras, namely RalA (Ras-Like), for the first time and revealed overactivation of RalA in MDB. Affinity precipitation analysis of active RalA (RalA-GTP) in eight MDB cell lines (DAOY, RES256, RES262, UW228-1, UW426, UW473, D283 and D425) revealed that the majority contained elevated levels of active RalA (RalA-GTP) as compared with fetal cerebellar tissue as a normal control. Additionally, total RalA levels were shown to be elevated in 20 MDB patient samples as compared to normal brain tissue. The overall expression of RalA, however, was comparable in cancerous and normal samples. Other important effectors of RalA pathway including RalA binding protein-1 (RalBP1) and protein phosphatase A (PP2A) down-stream of Ral and Aurora kinase A (AKA) as an upstream RalA activator were also investigated in MDB. Considering the lack of specific inhibitors for RalA, we used gene specific silencing in order to inhibit RalA expression. Using a lentivirus expressing anti-RalA shRNA we successfully inhibited RalA expression in MDB and observed a significant reduction in proliferation and invasiveness. Similar results were observed using inhibitors of AKA and geranyl-geranyl transferase (non-specific inhibitors of RalA signaling) in terms of loss of in vivo tumorigenicity in heterotopic nude mouse model. Finally, once tested in cells expressing CD133 (a marker for MDB cancer stem cells), higher levels of RalA activation was observed. These data not only bring RalA to light as an important contributor to the malignant phenotype of MDB but introduces this pathway as a novel target in the treatment of this malignancy.