Anna Weiss

Regulation of Vascular Smooth Muscle Cell Turnover by Endothelial Cell-secreted MicroRNA-126: Role of Shear Stress

Rationale: Endothelial microRNA-126 (miR-126) modulates vascular development and angiogenesis. However, its role in the regulation of smooth muscle cell (SMC) function is unknown. Objective: To elucidate the role of miR-126 secreted by endothelial cells (ECs) in regulating SMC turnover in vitro and in vivo, as well as the effects of shear stress on the regulation. Methods and Results: Coculture of SMCs with ECs or treatment of SMCs with conditioned media from static EC monoculture (EC-CM) increased SMC miR-126 level and SMC turnover; these effects were abolished by inhibition of endothelial miR-126 and by the application of laminar shear stress to ECs. SMC miR-126 did not increase when treated with EC-CM from ECs subjected to inhibition of miR biogenesis, or with CM from sheared ECs. Depletion of extracellular/secreted vesicles in EC-CM did not affect the increase of SMC miR-126 by EC-CM. Biotinylated miR-126 or FLAG (DYKDDDDK epitope)-tagged Argonaute2 transfected into ECs was detected in the cocultured or EC-CM–treated SMCs, indicating a direct EC-to-SMC transmission of miR-126 and Argonaute2. Endothelial miR-126 represses forkhead box O3, B-cell lymphoma 2, and insulin receptor substrate 1 mRNAs in the cocultured SMCs, suggesting the functional roles of the transmitted miR-126. Systemic depletion of miR-126 in mice inhibited neointimal lesion formation of carotid arteries induced by cessation of blood flow. Administration of EC-CM or miR-126 mitigated the inhibitory effect. Conclusions: Endothelial miR-126 acts as a key intercellular mediator to increase SMC turnover, and its release is reduced by atheroprotective laminar shear stress.

MicroRNA-23b Regulates Cyclin-Dependent Kinase–Activating Kinase Complex Through Cyclin H Repression to Modulate Endothelial Transcription and Growth Under Flow

Objective—The site-specificity of endothelial phenotype is attributable to the local hemodynamic forces. The flow regulation of microRNAs in endothelial cells (ECs) plays a significant role in vascular homeostasis and diseases. The objective of this study was to elucidate the molecular mechanism by which the pulsatile shear flow–induced microRNA-23b (miR-23b) exerts antiproliferative effects on ECs. Approach and Results—We used a combination of a cell perfusion system and experimental animals to examine the flow regulation of miR-23b in modulating EC proliferation. Our results demonstrated that pulsatile shear flow induces the transcription factor Krüppel-like factor 2 to promote miR-23b biosynthesis; the increase in miR-23b then represses cyclin H to impair the activity and integrity of cyclin-dependent kinase–activating kinase (CAK) complex. The inhibitory effect of miR-23b on CAK exerts dual actions to suppress cell cycle progression, and reduce basal transcription by deactivating RNA polymerase II. Whereas pulsatile shear flow regulates the miR-23b/CAK pathway to exert antiproliferative effects on ECs, oscillatory shear flow has little effect on the miR-23b/CAK pathway and hence does not cause EC growth arrest. Such flow pattern–dependent phenomena are validated with an in vivo model on rat carotid artery: the flow disturbance induced by partial carotid ligation led to a lower expression of miR-23b and a higher EC proliferation in comparison with the pulsatile flow regions of the unligated vessels. Local delivery of miR-23b mitigated the proliferative EC phenotype in partially ligated vessels. Conclusions—Our findings unveil a novel mechanism by which hemodynamic forces modulate EC proliferative phenotype through the miR-23b/CAK pathway.

Comparing the National Surgical Quality Improvement Program With the Nationwide Inpatient Sample Database

PACIFIC COAST SURGICAL ASSOCIATION Comparing the National Surgical Quality Improvement Program With the Nationwide Inpatient Sample Database Bothrawandrisk-adjustedoutcomesareincreasinglybeingmade publicly available.1-3 The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) is heralded as the most robust database to examine surgical outcomes. However, enrollment in the NSQIP is expensive, and the use of administrative databases may be more cost-effective.2-4 In our study, we compare the receiver operating characteristic curves of the Nationwide Inpatient Sample (NIS) with those of the NSQIP to determine which is superior at performing analyses of risk-adjusted outcomes for several operations.

Equity in surgical leadership for women: more work to do

BACKGROUND Sex disparity in the Program Director role has not been studied. The goal of this study is to evaluate the percentage of women in Chair and Program Director positions. We hypothesize that there is a higher percentage of women in the Program Director role than Chair role. METHODS An Internet search identified Chairs, Program Directors, Associate Program Directors, and Division Chiefs. Statistical analysis compared percentages of women in these roles at all institutions, academic/community programs, and regions. RESULTS There is higher female representation in the Program Director position than Chair position (P = .002) in General Surgery, Otolaryngology, and Orthopedics. More women are Associate Program Directors than Division Chiefs (23.6% vs 9.8%, P ≤ .001). Academic and community programs are no different. In the West, a greater percentage of women are Chairs as compared with the other regions (P ≤ .002). CONCLUSIONS There are higher rates of women in Program Director position than Department Chair position. This discrepancy warrants further investigation.

Outcomes of thyroidectomy from a large California state database.

BACKGROUND Thyroidectomy is an operation with infrequent but potentially significant complications. This study aimed to determine risk factors for complication after thyroidectomy in California. METHODS The California Office of Statewide Health Planning and Development database was retrospectively analyzed from 1995 to 2010. Main outcome measures were complications including death. Logistic regression identified risk factors for complications. RESULTS There were 106,773 patients; 61% were women and 44% Caucasian; 16,287 (15%) thyroidectomies were performed at high-volume centers. Complication rates included voice change (.5%), vocal cord dysfunction (1.1%), hypocalcemia (4.5%), tracheostomy (1.62%), hematoma (1.75%), and death (.3%). There was significantly increased risk of complications for patients older than 65 compared with those younger than 40 years (odds ratio, 2.0; 95% confidence interval, 1.8 to 2.3; P < .01). High-volume hospitals were protective against complication (odds ratio, .8; 95% confidence interval, .6 to .97; P = .026). CONCLUSIONS Older age was a significant risk factor for complication after thyroidectomy. High-volume hospitals had lower risk. This information is useful in counseling patients about the risks of thyroid surgery.

Quality and safety in obesity surgery-15 years of Roux-en-Y gastric bypass outcomes from a longitudinal database.

BACKGROUND Most population-based studies lack long-term data, making the reporting of true mortality and outcome rates difficult. An accurate estimate of these rates in a high-risk population is critical for obtaining informed consent, especially for an elective procedure such as Roux-en-Y gastric bypass (RYGB). OBJECTIVES To examine the longitudinal outcomes of RYGB. SETTING The California Office of Statewide Health Planning and Development (OSHPD) longitudinal database. METHODS The OSHPD longitudinal database was queried for patients who underwent RYGB between 1995 and 2009. The primary outcome was mortality rates at 1, 5, and 10 years. Secondary outcomes were marginal ulcer and reoperation. The Cox hazard proportional analysis was used to determine adjusted survival and long-term outcomes for laparoscopic RYGB compared with open RYGB. RESULTS The study included 129,432 RYGB patients. Rates of laparoscopy increased from 3% to 35% from 1995 to 2004 and then steeply increased to 80% in 2005 and to 93% in 2009. Overall mortality rate at 1, 5, and 10 years was 2.2%, 4.4%, and 8.1%, respectively; the rates of marginal ulcer were .3%, .7%, and 1%, respectively; and the reoperation rates were .3%, .8%, and 1.2%, respectively. Predictors of poor outcomes were male gender, age, smoking, alcohol, Medicare, Medi-Cal insurance, and Asian or Native American race. The laparoscopic approach was protective against death (hazard ratio [HR] 95% confidence interval [95%CI]: .63[.58-.69]) and long-term complications (HR .78[.72-.85]). CONCLUSIONS This longitudinal population study showed high rates of mortality following RYGB, with improved long-term outcomes when the laparoscopic approach was used.

Environmentalism in surgical practice

Most surgeons equate environmentalism with the softer sciences related more to personal philosophy than with anything connected to the harder science and business of healing patients. Only after we can get beyond the jokes about “saving whales” and “hugging trees” and “going green,” canwe truly appreciate environmentalism in surgery for what it is: a smart, efficient, and cost effective way to do business in 2016. In the past decade, and especially in the wake of the Affordable Care Act, there has been national emphasis on improving the quality of health care delivery and increasing transparency while decreasing cost. Ironically, this is happening at a time when rapidly evolving technology is making health care more and more expensive. By evaluating the current system and eliminating waste and unnecessary expense, providers and health care systems can achieve that balance between quality and affordability. When waste accounts for at least 20% of health care costs, the current system of tight operating margins and hypersensitive awareness to expense is bound to fail. Medicare and Medicaid estimates that health care spending is growing at a rate of 1.1% per year (faster than Gross Domestic Product [GDP] itself). By 2024, it would account for 19.6% of GDP. Overall, 60% of all hospital costs are accrued in the operating room (OR). Surgeons are stewards of the medical profession and leaders, not just in the OR, but in their communities as well. As such, it is the surgeon’s obligation to proactively address the issues of quality and cost at the same time as environmental concerns such as global warming, landfill burden, toxic waste disposal, and limited and dwindling precious resources. Luckily for surgeons, these issues are

Treatment of Breast Cancer in Women Aged 80 and Older

Background: The elderly population is growing in the United States. Most clinical trials exclude patients over 80, therefore there is a paucity of data regarding the correct treatment of this group. The purpose of this systematic review was to investigate the treatment patterns for women with primary breast cancer aged 80 years old and older - modalities include surgery, chemotherapy, radiation and hormonal treatment, alone or in combination. Methods: A formal systematic review was performed with the support of the medical research librarian at the University of California San Diego Biomedical Library. PubMed and Web of Science were the databases used. A patient population of 2,947 was derived from the 16 papers reviewed. Results: Patients diagnosed over 80 were more likely to be diagnosed by clinical exam. Patients who had standard surgical treatment had an improved disease free survival. Surgical resection and radiation had a low morbidity. Conclusion: Multimodality treatment is safe in elderly women and is associated with better breast cancer specific survival outcomes.

Regulation of Vascular Smooth Muscle Cell Turnover by Endothelial Cell–Secreted MicroRNA-126

Rationale: Endothelial microRNA-126 (miR-126) modulates vascular development and angiogenesis. However, its role in the regulation of smooth muscle cell (SMC) function is unknown. Objective: To elucidate the role of miR-126 secreted by endothelial cells (ECs) in regulating SMC turnover in vitro and in vivo, as well as the effects of shear stress on the regulation. Methods and Results: Coculture of SMCs with ECs or treatment of SMCs with conditioned media from static EC monoculture (EC-CM) increased SMC miR-126 level and SMC turnover; these effects were abolished by inhibition of endothelial miR-126 and by the application of laminar shear stress to ECs. SMC miR-126 did not increase when treated with EC-CM from ECs subjected to inhibition of miR biogenesis, or with CM from sheared ECs. Depletion of extracellular/secreted vesicles in EC-CM did not affect the increase of SMC miR-126 by EC-CM. Biotinylated miR-126 or FLAG (DYKDDDDK epitope)-tagged Argonaute2 transfected into ECs was detected in the cocultured or EC-CM–treated SMCs, indicating a direct EC-to-SMC transmission of miR-126 and Argonaute2. Endothelial miR-126 represses forkhead box O3, B-cell lymphoma 2, and insulin receptor substrate 1 mRNAs in the cocultured SMCs, suggesting the functional roles of the transmitted miR-126. Systemic depletion of miR-126 in mice inhibited neointimal lesion formation of carotid arteries induced by cessation of blood flow. Administration of EC-CM or miR-126 mitigated the inhibitory effect. Conclusions: Endothelial miR-126 acts as a key intercellular mediator to increase SMC turnover, and its release is reduced by atheroprotective laminar shear stress.

Cirrhosis is not a contraindication to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in highly selected patients

BackgroundPatient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is critically important to optimizing outcomes. There is currently no literature regarding the safety of CRS/HIPEC in patients with cirrhosis. The aim of this case series is to report the outcomes of three patients with well-compensated cirrhosis who underwent CRS/HIPEC.MethodsPatients were identified from a prospectively maintained peritoneal surface malignancy database. Patient, tumor, and operative-related details were recorded as short-term postoperative outcomes. Results were analyzed using descriptive statistics.ResultsAll patients had well-compensated (Child-Pugh Class A) cirrhosis and Eastern Cooperative Oncology Group (ECOG) performance status of 0. One patient had preoperative evidence of portal hypertension. All safely underwent CRS/HIPEC with completeness of cytoreduction (CC) scores of 0. The postoperative morbidity profile was unique, but all complications were manageable and resulted in full recovery to preoperative baseline status.ConclusionsPatient selection for CRS/HIPEC is critical for optimization of short- and long-term outcomes. This small series suggests that well-compensated cirrhosis should not be an absolute contraindication to CRS/HIPEC.