15 research outputs found
Mechanisms for Survival and Drug Resistance in Cancer Cells
PART I
Prostate cells are hormonally driven to grow and divide. Typical treatments for prostate cancer involve blocking the hormone androgen from activating the androgen receptor (AR) and thus inhibit growth and proliferation of the cancer. Androgen deprivation therapy (ADT) can lead to the selection of cancer cells that grow and divide independently of androgen receptor activation. Prostate cancer cells that are insensitive to androgens commonly display metastatic phenotypes and reduced long-term survival of patients. In this study, we provide evidence that androgen-insensitive prostate cancer cells have elevated phospholipase D (PLD) activity relative to the androgen-sensitive prostate cancer cells. PLD activity has been linked with promoting survival in many human cancer cell lines; and consistent with the previous studies, suppression of PLD activity in the prostate cancer cells resulted in apoptotic cell death. Of significance, suppressing the elevated PLD activity in the androgen-insensitive prostate cancer lines also blocked the ability of these cells to migrate and invade MatrigelTM. Since survival signals are generally an early event in tumorigenesis, the apparent coupling of survival and metastatic phenotypes implies that metastasis could be an earlier event in malignant prostate cancer than generally thought. Resistance to ADT appears to involve an elevation in PLD activity providing a survival program that is coupled to migration and invasion. Interruption of this pathway could provide a therapeutic strategy for treating androgen-insensitive prostate cancer.
PART II
Inhibiting the mammalian Target of Rapamycin Complex 1 (mTORC1) with rapamycin while suppressing Transforming Growth Factor-β (TGF-β) signaling induces apoptosis in many cancer cells. Some cancer cells, though, are resistant to the apoptotic effects of rapamycin treatment in the absence of TGF-β signaling. Both mTORC1 and TGF-β are upstream effectors of Retinoblastoma protein (Rb), a key regulatory protein involved in cell cycle progression from G1 to S-phase. We found that rapamycin-resistant cell lines had a nonfunctional Rb protein and a deleted CDKN2A gene. When Rb function was restored in the rapamycin resistant cells, apoptosis was induced upon rapamycin treatment. When Rb was knocked down in cells with deleted CDKN2A, the cells gained the rapamycin resistant phenotype. The common downstream target of Rb and CDKN2A is E2F1 and inhibition of E2F1 sensitizes the cell to the apoptotic effects of rapamycin. The data suggest that Rb and CDKN2A may be part of compensatory pathways and that the interruption of both pathways is necessary to confer resistance to mTORC1 inhibition. Resistance to mTORC1 inhibition by rapamycin, a downstream target of PLD, appears to involve E2F1 and implicates the involvement of CDKN2A and Rb at the G1-S phase boundary of the cell cycle as a point of therapeutic intervention
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Expanding the scope of quality measurement in surgery to include nonoperative care
Patients managed non-operatively have been excluded from risk-adjusted benchmarking programs, including the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP). Consequently, optimal performance evaluation is not possible for specialties like emergency general surgery (EGS) where non-operative management is common. We developed a multi-institutional EGS clinical data registry within ACS NSQIP that includes patients managed non-operatively to evaluate variability in non-operative care across hospitals and identify gaps in performance assessment that occur when only operative cases are considered.Using ACS NSQIP infrastructure and methodology, surgical consultations for acute appendicitis, acute cholecystitis, and small bowel obstruction (SBO) were sampled at 13 hospitals that volunteered to participate in the EGS clinical data registry. Standard NSQIP variables and 16 EGS-specific variables were abstracted with 30-day follow-up. To determine the influence of complications in non-operative patients, rates of adverse outcomes were identified and hospitals were ranked by performance with and then without including non-operative cases.2,091 patients with EGS diagnoses were included, 46.6% with appendicitis, 24.3% with cholecystitis, and 29.1% with SBO. The overall rate of non-operative management was 27.4%, 6.6% for appendicitis, 16.5% for cholecystitis, and 69.9% for SBO. Despite comprising only 27.4% of patients in the EGS Pilot, non-operative management accounted for 67.7% of deaths, 34.3% of serious morbidities, and 41.8% of hospital readmissions. After adjusting for patient characteristics and hospital diagnosis mix, addition of non-operative management to hospital performance assessment resulted in 12 of 13 hospitals changing performance rank, with 4 hospitals changing by 3 or more positions.This study identifies a gap in performance evaluation when non-operative patients are excluded from surgical quality assessment and demonstrates the feasibility of incorporating non-operative care into existing surgical quality initiatives. Broadening the scope of hospital performance assessment to include non-operative management creates an opportunity to improve the care of all surgical patients, not just those who have an operation.III, Prognostic and Epidemiological