Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy.

Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G(2)/M cell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

Unfreezing the Flexnerian Model: introducing longitudinal integrated clerkships in rural communities.

INTRODUCTION: Physician shortages in rural areas remain severe but may be ameliorated by recent expansions in medical school class sizes. Expanding student exposure to rural medicine by increasing the amount of prolonged clinical experiences in rural areas may increase the likelihood of students pursuing a career in rural medicine. This research sought to investigate the perspective of rural physicians on the introduction of a rurally based nine-month Longitudinal Integrated Clerkship (LIC). METHODS: In this mixed-methods study, nine physician leaders were interviewed from five Maine, USA, rural hospitals participating in an LIC. Semi-structured interviews were audiotaped and transcribed. Qualitative analysis techniques were used to code the transcripts and develop themes. Forty-seven participating rural LIC preceptors were also surveyed through an online survey. RESULTS: Four major themes related to implementing the LIC model emerged: (1) melting old ways, (2) overcoming fears, (3) synergy of energy, and (4) benefits all-around. The faculty were very positive about the LIC, with increased job satisfaction, practice morale, and ongoing learning, but concerned about the financial impact on productivity. CONCLUSIONS: The importance of these themes and perceptions are discussed within the three-stage model of change by Lewin. These results describe how the innovative LIC model can conceptually unfreeze the traditional Flexnerian construct for rural physicians. Highlighting the many stakeholder benefits and addressing the anxieties and fears of rural faculty may facilitate the implementation of a rural LIC. Given the net favorable perception of rural faculty of the LIC, this educational model has the potential to play a major role in increasing the rural workforce.