Endovascular covered stent graft repair by through-and-through snaring of an acute traumatic femoral-femoral arteriovenous fistula following a gunshot wound.

Arteriovenous fistula (AVF) formation after penetrating injury underscores a rare and challenging complication of vascular trauma. Traumatic AVFs have various clinical presentations and reported methods of repair. Although open surgical repair is the most frequently used method of repair, the advancement of endovascular techniques has been increasingly used during the past 3 decades. We report a case of an acute traumatic AVF of the superficial femoral artery and superficial femoral vein from a gunshot wound repaired with a unique endovascular technique involving snaring to establish through-and-through access to allow deployment of a covered stent graft.

Pseudoaneurysms of the Peripheral Arteries.

Peripheral arterial pseudoaneurysm, while relatively rare, are encountered by most vascular specialists. This review evaluates the epidemiology, diagnosis, natural history, and treatment of pseudoaneurysm in the peripheral arteries. Most of this review concentrates on iatrogenic peripheral pseudoaneurysms, but pseudoaneurysms of other etiologies will also be discussed.

Peroneal bypass versus endovascular peroneal intervention for critical limb ischemia.

OBJECTIVE: The peroneal artery is a well-established target for bypass in patients with critical limb ischemia (CLI). The objective of this study was to evaluate the outcomes of peroneal artery revascularization in terms of wound healing and limb salvage in patients with CLI. METHODS: Patients presenting between 2006 and 2013 with CLI (Rutherford 4-6) and isolated peroneal runoff were included in the study. They were divided into patients who underwent bypass to the peroneal artery and those who underwent endovascular peroneal artery intervention. Demographics, comorbidities, and follow-up data were recorded. Wounds were classified by Wound, Ischemia, foot Infection (WIfI) score. The primary outcome was wound healing; secondary outcomes included mortality, major amputation, and patency. RESULTS: There were 200 limbs with peroneal bypass and 138 limbs with endovascular peroneal intervention included, with mean follow-up of 24.0 ± 26.3 and 14.5 ± 19.1 months, respectively (P = .0001). The two groups were comparable in comorbidities, with the exception of the endovascular group's having more patients with cardiac and renal disease and diabetes mellitus but fewer patients with smoking history. Based on WIfI criteria, ischemia scores were worse in bypass patients, but wound and foot infection scores were worse in endovascular patients. Perioperatively, bypass patients had higher rates of myocardial infarction (4.5% vs 0%; P = .012) and incisional complications (13.0% vs 4.4%; P = .008). At 12 months, the bypass group compared with the endovascular group had better primary patency (47.9% vs 23.4%; P = .002) and primary assisted patency (63.6% vs 42.2%; P = .003) and a trend toward better secondary patency (74.2% vs 63.5%; P = .11). There were no differences in the rate of wound healing (52.6% vs 37.7% at 1 year; P = .09) or freedom from major amputation (81.5% vs 74.7% at 1 year; P = .37). In a multivariate analysis, neuropathy was associated with improved wound healing, whereas WIfI wound score, cancer, chronic renal insufficiency, and smoking were associated with decreased wound healing. Treatment modality was not a significant predictor (P = .15). CONCLUSIONS: Endovascular peroneal artery intervention results in poorer primary and primary assisted patency rates than surgical bypass to the peroneal artery but provides similar wound healing and limb salvage rates with a lower rate of complications. In appropriately selected patients, endovascular intervention to treat the peroneal artery is a low-risk intervention that may be sufficient to heal ischemic foot wounds.

Heel Wounds Predict Mortality but Not Amputation after Infrapopliteal Revascularization.

BACKGROUND: Ischemic heel ulcerations are generally thought to carry a poor prognosis for limb salvage. We hypothesized that patients undergoing infrapopliteal revascularization for heel wounds, either bypass or endovascular intervention, would have lower wound healing rates and amputation-free survival (AFS) than patients with forefoot wounds. METHODS: A retrospective chart review was performed on patients who presented between 2006 and 2013 to our institution with ischemic foot wounds and infrapopliteal arterial disease and underwent either pedal bypass or endovascular tibial artery intervention. Data were collected on patient demographics, comorbidities, wound characteristics, procedural details, and postoperative outcomes then analyzed by initial wound classification. The primary outcome was major amputation or death. RESULTS: Three hundred ninety-eight limbs underwent treatment for foot wounds; accurate wound data were available in 380 cases. There were 101 bypasses and 279 endovascular interventions, with mean follow-up of 24.6 and 19.9 months, respectively (P = 0.02). Heel wounds comprised 12.1% of the total with the remainder being forefoot wounds; there was no difference in treatment modality by wound type (P = 0.94). Of 46 heel wounds, 5 (10.9%) had clinical or radiographic evidence of calcaneal osteomyelitis. Patients with heel wounds were more likely to have diabetes mellitus (DM) (P = 0.03) and renal insufficiency (P = 0.004). 43.1% of wounds healed within 1 year, with no difference by wound location (P = 0.30). Major amputation rate at 1 year was 17.8%, with no difference by wound location (P = 0.81) or treatment type (P = 0.33). One- and 3-year AFS was 66.2% and 44.0% for forefoot wounds and 45.7% and 17.6% for heel wounds, respectively (P = 0.001). In a multivariate analysis, heel wounds and endovascular intervention were both predictors of death; however, there was significant interaction such that endovascular intervention was associated with higher mortality in patients with forefoot wounds (hazard ratio 2.25, P < 0.001) but not those with heel wounds (hazard ratio 0.67, P = 0.31). CONCLUSIONS: Patients presenting with heel ulceration who undergo infrapopliteal revascularization are prone to higher mortality despite equivalent rates of amputation and wound healing and regardless of treatment modality. These patients may benefit from an endovascular-first strategy.

Prior Endovascular Intervention Is Not Detrimental to Pedal Bypasses for Ischemic Wounds.

BACKGROUND: Endovascular strategies are often preferred for revascularization of ischemic foot wounds secondary to infrapopliteal disease because of the less invasive technique and faster recovery. Bypass is typically reserved for failures or lesions not amenable to balloon angioplasty. However, the effects of an endovascular-first approach on subsequent bypass grafts are largely unknown. This study evaluates the effects of prior endovascular tibial interventions (PTIs) on successive bypasses to pedal targets. METHODS: Patients who presented with ischemic tissue loss and tibial arterial occlusive disease to University of Pittsburgh Medical Center between 2006 and 2013 and underwent a surgical bypass to pedal arteries were included in this study. A retrospective chart review was conducted to obtain patient demographics, past medical history, extent of disease, prior tibial endovascular interventions, the treatment intervention, subsequent interventions, wound healing status, limb salvage, and patient survival. The primary outcome was primary patency of the pedal bypass graft. RESULTS: From 122 eligible patients, 27 had a PTI, whereas 95 had no prior endovascular tibial intervention (nPTI) in the treatment of ischemic pedal wounds with mean follow-up of 24.5 and 20.5 months, respectively (P = 0.36). The 2 groups were largely similar in terms of demographics, comorbidities, wound size, and degree of ischemia. Runoff scores between the 2 groups were also comparable (5.0 ± 1.6 for PTI and 4.8 ± 1.9 for nPTI, P = 0.59). The plantar artery was a more common target vessel in the PTI group, whereas the posterior tibial artery was targeted more often in the nPTI group (P = 0.04). At 12 months, those with a PTI exhibited a shorter primary patency (34.8% vs. 60.2%, P = 0.04). In a multivariate model, PTI was a significant risk factor for primary patency loss (hazard ratio 2.51, P = 0.004). Primary assisted patency and secondary patency were similar between the 2 groups. Wound healing was improved in those patients who had a prior endovascular intervention with 63.8% healed at 1 year compared with only 34.8% of those without intervention (P = 0.01). Amputation-free survival was similar (P = 0.68), as was survival alone (P = 0.50). CONCLUSIONS: Despite a decrease in primary patency, pedal bypass was not otherwise negatively affected by a PTI. Similar primary assisted patency, secondary patency, wound healing, and survival between the 2 patient populations indicate that an endovascular-first approach is a feasible treatment strategy to achieve similar clinical outcomes in the management of ischemic foot wounds.

Bypass versus endovascular intervention for healing ischemic foot wounds secondary to tibial arterial disease.

OBJECTIVE: Pedal (inframalleolar) bypass is a long-standing therapy for tibial arterial disease in patients with ischemic tissue loss. Endovascular tibial intervention is an appealing alternative with lower risks of perioperative mortality or complications. Our objective was to compare the effectiveness of these two treatment modalities with respect to patency and limb-related clinical outcomes. METHODS: We performed a retrospective chart review of patients presenting between 2006 and 2013 with ischemic foot wounds and infrapopliteal arterial disease who underwent a revascularization procedure (either open surgical bypass to an inframalleolar target or endovascular tibial intervention). Data were collected on baseline demographics and comorbidities, procedural details, and postprocedure outcomes. The primary outcome was successful healing of the index wound, with mortality, major amputation, and patency assessed as secondary outcomes. RESULTS: We identified 417 patients who met our eligibility criteria; 105 underwent surgical bypass and 312 underwent endovascular intervention, with mean follow-up of 25.0 and 20.2 months, respectively (P = .08). The endovascular patients were older at baseline (P = .009), with higher rates of hyperlipidemia (P = .02), prior cerebrovascular accidents (P = .04), and smoking history (P = .04). Within 30 days postoperatively, there was no difference in mortality (P = .31), but bypass patients had longer hospital length of stay (P < .0001), higher rate of discharge to nursing facility (P < .001), and higher rates of myocardial infarctions (P = .03) and wound complications (P < .001). At 6 months, the rate of wound healing was 22.4% in the bypass group compared with 29.0% in the endovascular group (P = .02). At 1 year, survival was higher after bypass (86.2% vs 70.4%; P < .0001), but freedom from major amputation was similar (84.9% vs 82.8%; P = .42). Primary patency (53.1% vs 38.2%; P = .002) and primary assisted patency (76.6% vs 51.7%; P < .0001) were higher in the bypass group, but there was no difference in secondary patency (77.3% vs 73.8%; P = .13). CONCLUSIONS: Endovascular tibial intervention is associated with poorer primary patency but similar secondary patency and wound healing rates compared with the "gold standard" of surgical bypass to a pedal target. In patients with tibial arterial disease, endovascular intervention should be considered a lower risk alternative to pedal bypass that provides similar clinical outcomes.

Cephalic vein transposition is a durable approach to managing cephalic arch stenosis.

INTRODUCTION: The proximal cephalic vein that enters the axillary vein (cephalic arch) is a common site of stenosis in patients with upper extremity arteriovenous fistulas for hemodialysis (HD). In this study, we present the outcomes of a series of cephalic vein transposition, to determine its utility in the setting of refractory arch stenosis. METHODS: We conducted a retrospective review of patients undergoing cephalic vein transposition to manage refractory cephalic arch stenosis from January 1, 2008 to August 31, 2015. Demographics, past medical history, access history of the patients as well as procedural details of the surgery to the stenotic segment, patency of the access, and the need for subsequent interventions were recorded. RESULTS: Twenty-three patients underwent a cephalic vein transposition during the study period. The patients undergoing cephalic transposition had their current access for an average of 3.0 ± 2.6 years and had an average of 2.3 ± 0.9 interventions on the access prior to the surgery. Complications from the surgery were uncommon (8.7%) and no patient required a temporary tunneled dialysis catheter. The re-intervention rate was 0.2 ± 0.2 interventions per patient per year. At two years, primary patency was 70.9% and cumulative patency was 94.7% for the patients with cephalic transposition. CONCLUSIONS: Cephalic vein transposition is safe and effective treatment for cephalic arch stenosis without interrupting utilization of the access. The surgical approach to stenosis of the proximal cephalic vein is effective, requires minimal re-interventions, and should be considered for isolated, refractory cephalic arch stenosis in mature arteriovenous fistulas.

Preoperative antiplatelet use does not increase incidence of bleeding after major operations.

BACKGROUND: This study examined the outcomes of patients holding or continuing clopidogrel during the preoperative period. METHODS: We reviewed all patients taking clopidogrel who underwent one of 72 different Current Procedural Terminology code procedures, representing major emergency and elective general thoracic and vascular operations from 2009-2012 at a single institution. Demographics, comorbidities, aspirin use, details of coronary stents, and perioperative events were collected. RESULTS: A total of 2,154 major operative procedures were performed on 1,851 patients during the study period. A total of 213 patients (11.5%) were taking clopidogrel at the time of their last office visit or hospital admission and were then instructed to hold or continue the drug prior to an operation. A total of 205 procedures in 200 patients comprised the final study population. Clopidogrel was held in 116 procedures for ≥5 days prior to operative intervention (56.6%, Group A), and clopidogrel was administered within 5 days of an operation in 89 procedures (43.4%, Group B). There were no differences between the 2 groups regarding estimated blood loss, units transfused, myocardial infarction, stroke, acute visceral or peripheral ischemia, or death within 30 days. CONCLUSION: We did not identify significantly increased adverse patient outcomes in those patients who received preoperative clopidogrel within this population. We assert that it appears to be reasonable and safe to continue antiplatelet therapy with clopidogrel in this population in elective situations and that preoperative clopidogrel use does not increase the risk of bleeding in emergency circumstances.

Tibial osteochondroma inducing popliteal artery compression.

Compression of the neurovascular contents of the popliteal fossa is a rare condition that leads to exercise-induced pain and paresthesias in young athletes. Most frequently, it is caused by musculotendinous abnormalities resulting in popliteal entrapment syndrome. Bony abnormalities rarely are implicated but can produce symptoms that mimic popliteal entrapment syndrome. We present a patient with a tibial metaphysis osteochondroma inducing popliteal artery compression that was relieved after resection.

Calf muscle venous thrombosis: a review of the clinical implications and therapy.

Calf muscle veins have been demonstrated to be one of the most frequent areas that develop deep venous thrombosis (DVT), both as an isolated finding and in combination with proximal DVT. Calf muscle venous thrombosis (CMVT) has been shown to be more frequently associated with localized calf tenderness, and when left untreated, a proportion tend to propagate proximally and may lead to pulmonary embolism. Imaging with duplex venous scanning is fairly sensitive in the diagnosis of CMVT. Treatment recommendations for CMVT are variable with some studies showing clear clinical benefit of anticoagulation therapy and others showing no benefit.

MicroRNA from pancreatic duct aspirate differentiates cystic lesions of the pancreas.

INTRODUCTION: Prognostication for cystic neoplasms of the pancreas continues to evolve. Beyond simple size and cystic fluid CEA determination, microRNA (miRNA) detection holds great promise as molecular diagnostics for cancer risk. In this study, we sought to identify miRNAs that could predict malignant potential of pancreatic cystic lesions. METHODS: RNA was harvested from the pancreatic duct aspirate of 72 cystic neoplasms of the pancreas. Samples with adequate RNA concentration (≥ 3 ng/µL) were selected for qRTPCR profiling using assays to 379 of the most common miRNAs. miRNA profiles were correlated with histopathology from resected specimens and grouped by benign (serous cystadenomas), premalignant (intraductal papillary mucinous neoplasms and mucinous cystadenomas), or malignant lesions (adenocarcinoma). RESULTS: Adequate RNA for analysis was obtained from 42 (58.3 %) of the samples. Malignant lesions were more likely to have adequate RNA (n = 17, 81 %) than either benign (n = 6, 33 %) or premalignant lesions (n = 19, 59 %; p = 0.011). Nine miRNA were identified as differentially expressed between benign and premalignant/malignant lesions (p < 0.05). A significant correlation was found between the number of differentially expressed miRNA and the likelihood of a premalignant/malignant lesion. All premalignant or malignant lesions expressed at least one miRNA surpassing the threshold of mean miRNA expression, whereas no benign lesions had more than one miRNA surpassing the threshold. CONCLUSIONS: The presence of RNA in the duct aspirate from patients with pancreatic cystic neoplasms may be a predictor of premalignancy or malignancy. miRNA may be utilized to further differentiate between benign, premalignant, and malignant cystic lesions of the pancreas.

Concomitant dysregulation of microRNAs miR-151-3p and miR-126 correlates with improved survival in resected cholangiocarcinoma.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding genes which become dysregulated in cancer and may predict survival. The role of miRNAs in outcomes in cholangiocarcinoma (CC) has not been reported. METHODS: RNA was extracted from 32 resected CCs along with adjacent uninvolved bile duct epithelium. A total of 43 miRNAs were quantified using NanoString™. Clinicopathologic characteristics and outcomes were captured and compared. Overall survival curves were created using the Kaplan-Meier method; factors, including miRNA expression, were compared by log-rank, chi-squared or Cox regression analyses. RESULTS: Absolute expression of each miRNA was compared with overall survival after excluding perioperative deaths (n= 3). One upregulated (miR-151-3p; P= 0.003) and one downregulated (miR-126; P= 0.023) miRNA in resected CC relative to adjacent normal bile duct epithelium correlated with survival on univariate analysis. Clinical factors and these miRNAs were compared. Dysregulated miR-151-3p and miR-126, respectively, were the only factors that correlated with improved overall survival [41.5 months vs. 12.3 months (P= 0.002) and 21.9 months vs. 15.1 months (P= 0.02), respectively]. In eight patients, both miRNAs were dysregulated. In the remainder, only one or neither showed dysregulation. Concomitant dysregulation correlated with the best overall survival (58.7 months vs. 15.1 months; P < 0.000; n= 8); clinicopathologic factors in these groups were otherwise similar. CONCLUSIONS: In resected CC, the concomitant dysregulation of both miR-151-3p and miR-126 was the factor related to the greatest improvement in overall survival. Further analysis of the targets of these miRNAs may yield potential therapeutic targets or prognostic biomarkers.

Best radiological response to trans-arterial chemoembolization for hepatocellular carcinoma does not imply better outcomes.

INTRODUCTION: Regional therapy with trans-arterial chemoembolization (TACE) is a common treatment for unresectable hepatocellular carcinoma (HCC). Outcomes were examined in patients with the best radiological response (BR) after the initial TACE. METHODS: This was a retrospective cohort study of patients who underwent TACE as the initial treatment for HCC between the years 2000 and 2010. BR was defined as complete disappearance of the tumour or no enhancement with contrast on the first cross-sectional imaging study after the initial TACE. RESULTS: Seventy-eight out of 104 total consecutive patients were identified with the potential for a BR to TACE therapy for unresectable HCC, and 24 met the criteria for BR. Patients with BR had a median survival of 12.8 months (2.2-54.9) compared with 18.9 months(1.3-56.7) for the entire cohort (P= 0.313). The median time to progression was 10.6 months (1.2-24.3) in the BR group and 3.2 months (0.7-49.2) in the patients without a BR (P= 0.003). DISCUSSION: BR to initial TACE for unresectable HCC is associated with comparable survival to those without BR in spite of a longer time to cancer progression. It may be reasonable to consider further therapy such as repeat TACE or biological/systemic therapy in patients with HCC even when the radiological response to the initial TACE is favourable.

A scoring system for the prognosis and treatment of malignant bowel obstruction.

BACKGROUND: Malignant bowel obstruction is a common result of end-stage abdominal cancer that is a treatment dilemma for many physicians. Little has been reported predicting outcomes or determining the role of surgical intervention. We sought to review our experience with surgical and nonsurgical management of malignant bowel obstruction to identify predictors of 30-day mortality and of who would most likely benefit from surgical intervention. METHODS: A chart review of 523 patients treated between 2000 and 2007 with malignant bowel obstruction were evaluated for factors present at admission to determine return to oral intake, 30-day mortality, and overall survival. Propensity score matching was used to homogenize patients treated with and without surgery to identify those who would benefit most from operative intervention. RESULTS: Radiographic evidence of large bowel obstruction was predictive of return to oral intake. Hypoalbuminemia and radiographic evidence of ascites or carcinomatosis were all predictive of increased 30-day mortality and overall survival. A nomogram of 5 identified risk factors correlated with increased 30-day mortality independent of therapy. Patients with large bowel or partial small bowel obstruction benefited most from surgery. A second nomogram was created from 4 identified risk factors that revealed which patients with complete small bowel obstruction might benefit from surgery. CONCLUSION: Two nomograms were created that may guide decisions in the care of patients with malignant bowel obstruction. These nomograms are able to predict 30-day mortality and who may benefit from surgery for small bowel obstruction.

A survey of US dental practices' use of social media.

AIM: Social media is becoming the way for businesses, including health care professionals, to communicate with consumers. The study examines the use of social media by dental practices in the US. MATERIALS AND METHODS: An electronic survey was sent to 22,682 dentists in the United States. The survey consisted of questions related to the use of social media in the dental practice. Data was analyzed using descriptive statistics and comparisons were made using a Fisher's exact test. RESULTS: A total of 573 responses were received. Social media was used in 52% of dental practices, the most common being Facebook. The use of social media was most commonly for marketing purposes (91%). Dentists younger than 45 years old were more likely to use social media in their practice than dentists 45 years or older (p > 0.001). CONCLUSION: Dental practices actively use social media for marketing and communication. Many dentists are unsure how to measure the success of social media in their practice. Additional research is needed to measure the success of social media in a dental practice. CLINICAL SIGNIFICANCE: Social media is a common way practices market and interact with their patients. There are some difficulties in determining what appropriate content for social media is and how to evaluate the success.

The role of microRNAs in human liver cancers.

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver of global importance. Recent studies of the expression and role of microRNA (miRNA) in HCC are providing new insights into disease pathogenesis. In addition, therapeutic efforts targeting specific miRNAs are being evaluated in animal models of HCC. The potential of miRNAs as biomarkers of disease or prognostic markers is being explored. Herein, we review studies of miRNA expression in human HCC, and discuss recent advances in knowledge about the involvement and role of selected miRNAs in disease pathogenesis, as biomarkers, or as therapeutic targets for HCC.

MicroRNA replacement therapy for cancer.

MicroRNA are small noncoding RNAs that translationally repress their target messenger RNAs. Many microRNAs are expressed at reduced levels in tumors. microRNAs with reduced expression in cancer often regulate oncogenes, resulting in enhanced tumor growth. One therapeutic option is to restore microRNA levels in the tumor to that of the non-diseased tissue. This is possible by delivering microRNA to the tumor in the form of an oligonucleotide mimic or by expressing the microRNA in the cancer using a gene vector. This article surveys the field of oligonucleotide mimics and gene vector approaches to restore microRNA levels in tumors and reviews the literature on experimental and pre-clinical studies that have used these approaches to treat cancer.

miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor.

Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR-212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target the retinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR-132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G(2)/M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the ß2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over-expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The ß2 adrenergic pathway may play an important role in this novel mechanism.

miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines.

Previous work by us and others reported decreased expression of miR-199a-3p in hepatocellular carcinoma (HCC) tissues compared to adjacent benign tissue. We report here a significant reduction of miR-199a-3p expression in 7 HCC cell lines. To determine if miR-199a-3p has a tumor suppressive role, pre-miR-199a-3p oligonucleotides were transfected into the HCC cell lines. Pre-miR-199a-3p oligonucleotide reduced cell proliferation by approximately 60% compared to control oligonucleotide in only two cell lines (SNU449 and SNU423); the proliferation of the other 5 treated cell lines was similar to control oligonucleotide. A pre-miR-199a-3p oligonucleotide formulated with chemical modifications to enhance stability while preserving processing, reduced cell proliferation in SNU449 and SNU423 to the same extent as the commercially available pre-miR-199a-3p oligonucleotide. Furthermore, only the duplex miR-199a-3p oligonucleotide, and not the guide strand alone, was effective at reducing cell viability. Since a CD44 variant was essential for c-Met signaling [V. Orian-Rousseau, L. Chen, J.P. Sleeman, P. Herrlich, H. Ponta, CD44 is required for two consecutive steps in HGF/c-Met signaling, Genes Dev. 16 (2002) 3074-3086] and c-Met is a known miR-199a-3p target, we hypothesized that miR-199a-3p may also target CD44. Immunoblotting confirmed that only the two HCC lines that were sensitive to the effects of pre-miR-199a-3p were CD44+. Direct targeting of CD44 by miR-199a-3p was confirmed using luciferase reporter assays and immunoblotting. Transfection of miR-199a-3p into SNU449 cells reduced in vitro invasion and sensitized the cells to doxorubicin; both effects were enhanced when hyaluronic acid (HA) was added to the cell cultures. An inverse correlation between the expression of miR-199a-3p and CD44 protein was noted in primary HCC specimens. The ability of miR-199a-3p to selectively kill CD44+ HCC may be a useful targeted therapy for CD44+ HCC.

Ribonucleotide reductase inhibitors reduce atherosclerosis in a double-injury rabbit model.

Atheroproliferative disorders such as atherosclerosis are an important health problem and one of the leading causes of morbidity and mortality in the United States. Minimally invasive therapeutic procedures, including angioplasty with stent deployment, are used frequently for obstructive coronary artery disease. However, restenosis, a proliferative vascular response, is a common sequela to this procedure. The current study investigated the effect of inhibiting ribonucleotide reductase (RR), an enzyme necessary for cellular proliferation, in an attempt to ameliorate the proliferative response. Two RR inhibitors, didox and hydroxyurea, were chosen for their potent antiproliferative properties. Studies were carried out by using a double-injury rabbit model, in which endothelial denudation was followed by the administration of a high-fat diet. At 4 wk after initial endothelial denudation, the developing atherosclerotic lesion was subjected to transluminal balloon dilation to simulate clinical intervention with percutaneous transluminal angioplasty. The degree of restenosis and atheroproliferation was assessed at 8 wk. Histologic evaluation of the lesion demonstrated that treatment with didox and hydroxyurea significantly decreased lesion area and lumen loss. These results suggest that RR inhibition may be an effective new tool for the treatment of atheroproliferative disorders.