Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet

Atherosclerosis is associated with oxidative stress and inflammation, and upregulation of LOX-1, an endothelial receptor for oxidized LDL (oxLDL). Here, we describe generation of LOX-1 knockout (KO) mice in which binding of oxLDL to aortic endothelium was reduced and endothelium-dependent vasorelaxation preserved after treatment with oxLDL (P<0.01 versus wild-type mice). To address whether endothelial functional preservation might lead to reduction in atherogenesis, we crossed LOX-1 KO mice with LDLR KO mice and fed these mice 4% cholesterol/10% cocoa butter diet for 18 weeks. Atherosclerosis was found to cover 61+/-2% of aorta in the LDLR KO mice, but only 36+/-3% of aorta in the double KO mice. Luminal obstruction and intima thickness were significantly reduced in the double KO mice (versus LDLR KO mice). Expression of redox-sensitive NF-kappaB and the inflammatory marker CD68 in LDLR KO mice was increased (P<0.01 versus wild-type mice), but not in the double KO mice. On the other hand, antiinflammatory cytokine IL-10 expression and superoxide dismutase activity were low in the LDLR KO mice (P<0.01 versus wild-type mice), but not in the double KO mice. Endothelial nitric oxide synthase expression was also preserved in the double KO mice. The proinflammatory signal MAPK P38 was activated in the LDLR KO mice, and LOX-1 deletion reduced this signal. In conclusion, LOX-1 deletion sustains endothelial function leading to a reduction in atherogenesis in association with reduction in proinflammatory and prooxidant signals.     

Distribution of brain metastases in relation to the hippocampus: implications for neurocognitive functional preservation

PURPOSE: With the advent of intensity-modulated radiotherapy, the ability to limit the radiation dose to normal tissue offers an avenue to limit side effects. This study attempted to delineate the distribution of brain metastases with relation to the hippocampus for the purpose of exploring the viability of tomotherapy-guided hippocampal sparing therapy potentially to reduce neurocognitive deficits from radiation. METHODS AND MATERIALS: The pre-radiotherapy T1-weighted, postcontrast axial MR images of 100 patients who received whole brain radiotherapy, stereotactic radiosurgery, or a radiosurgical boost following whole brain radiotherapy between 2002 and 2006 were examined. We contoured brain metastases as well as hippocampi with 5-, 10-, and 15-mm expansion envelopes. RESULTS: Of the 272 identified metastases, 3.3% (n = 9) were within 5 mm of the hippocampus, and 86.4% of metastases were greater than 15 mm from the hippocampus (n = 235). The most common location for metastatic disease was the frontal lobe (31.6%, n = 86). This was followed by the cerebellum (24.3%, n = 66), parietal lobe (16.9%, n = 46), temporal lobe (12.9%, n = 35), occipital lobe (7.7%, n = 21), deep brain nuclei (4.0%, n = 11), and brainstem (2.6%, n = 7). CONCLUSIONS: Of the 100 patients, 8 had metastases within 5 mm of the hippocampus. Hence, a 5-mm margin around the hippocampus for conformal avoidance whole brain radiotherapy represents an acceptable risk, especially because these patients in the absence of any other intracranial disease could be salvaged using stereotactic radiosurgery. Moreover, we developed a hippocampal sparing tomotherapy plan as proof of principle to verify the feasibility of this therapy in the setting of brain metastases.     

Results of the phase I dose-escalating study of motexafin gadolinium with standard radiotherapy in patients with glioblastoma multiforme

PURPOSE: Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. This Phase I trial studied the safety and tolerability of a 2-6-week course (10-22 doses) of MGd with radiotherapy for glioblastoma multiforme. METHODS AND MATERIALS: A total of 33 glioblastoma multiforme patients received one of seven MGd regimens starting at 10 doses of 4 mg/kg/d MGd and escalating to 22 doses of 5.3 mg/kg/d MGd (5 or 10 daily doses then three times per week). The National Cancer Institute Cancer Therapy Evaluation Program toxicity and stopping rules were applied. RESULTS: The maximal tolerated dose was 5.0 mg/kg/d MGd (5 d/wk for 2 weeks, then three times per week) for 22 doses. The dose-limiting toxicity was reversible transaminase elevation. Adverse reactions included rash/pruritus (45%), chills/fever (30%), and self-limiting vesiculobullous rash of the thumb and fingers (42%). The median survival of 17.6 months prompted a case-matched analysis. In the case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31) compared with the matched Radiation Therapy Oncology Group database patients with a median survival of 11.8 months (hazard ratio, 0.43; 95% confidence interval, 0.20-0.94). CONCLUSION: The maximal tolerated dose of MGd with radiotherapy for glioblastoma multiforme in this study was 5 mg/kg/d for 22 doses (daily for 2 weeks, then three times weekly). The baseline survival calculations suggest progression to Phase II trials is appropriate, with the addition of MGd to radiotherapy with concurrent and adjuvant temozolomide.     

Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells

Distant metastasis is frequently observed in patients with breast cancer and is a major cause of cancer-related deaths in these patients. Currently, very little is known about the mechanisms that underlie the development of the metastatic phenotype in breast cancer cells. We previously found that metastatic breast cancer cells express high levels of tissue transglutaminase (TG2), but established no direct link between TG2 and metastasis. In this study, we hypothesized that TG2 plays a role in conferring the metastatic phenotype to breast cancer cells. The results obtained suggested that increased expression of TG2 in breast cancer cells contributes to their increased survival, invasion and motility. We further found that TG2 protein in a metastatic breast cancer MDA-MB231 cells was present on the cell surface in close association with integrins beta1, beta4 and beta5. Downregulation of endogenous TG2 by small interfering RNA inhibited fibronectin (Fn)-mediated cell attachment, survival and invasion. Conversely, ectopic expression of TG2 augmented invasion of breast cancer cells and attachment to Fn-coated surfaces. We conclude that TG2 expression in breast cancer cells plays an important role in the development of the metastatic phenotype.     

IFN-gamma-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: a novel mechanism for IFN-gamma response

MUC4 is a transmembrane mucin, which is aberrantly expressed in pancreatic adenocarcinoma with no detectable expression in the normal pancreas. Here, we present a novel mechanism of IFN-gamma-induced expression of MUC4 in pancreatic cancer cells. Our studies highlight the upregulation of STAT-1 as a basis for MUC4 induction and demonstrate that its activation and upregulation by IFN-gamma are two distinct, albeit temporally integrated, signalling events that drive the selective induction of IRF-1 and MUC4, respectively, within a single cell system. The profile of interferon regulatory factor (IRF)-1 gene induction by IFN-gamma is consistent with its rapid transactivation by phospho-Y701-STAT-1. In contrast, the induction of the MUC4 mucin gene expression is relatively delayed, and occurs only in response to an increase in STAT-1 expression. A progressive binding of STAT-1 to various gamma-interferon-activated sequences (GAS) in the MUC4 promoter is observed in chromatin immunoprecipitation assay, indicating its direct association. Stimulation of STAT-1 expression by double-stranded polynucleotides or ectopic expression is shown to induce MUC4 expression, without Y701 phosphorylation of STAT-1. This effect is abrogated by short interfering RNA (siRNA)-mediated inhibition of STAT-1 expression, supporting further the relevance of STAT-1 in MUC4 regulation. In conclusion, our findings identify a novel mechanism for MUC4 regulation in pancreatic cancer cells and unfold new perspectives on the foundation of IFN-gamma-dependent gene regulation.     

Impact of recipient obesity on living donor kidney transplant outcomes: a single-center experience

The number of overweight and obese patients undergoing renal transplantation has drastically increased in the last two decades. Studies on graft survival and complication rates of these obese patients have had conflicting results, with some reporting a significant risk and others reporting relatively good outcomes. We examined 1-year outcomes in obese and nonobese patients who underwent living donor transplants at our transplant program, a slightly different approach than prior studies of deceased donor transplants into patients with high body mass index (BMI). The mean serum creatinine clearance by the modified MDRD equation at the end of 1 year in the nonobese group was 58.9 mL/min whereas the mean creatinine clearance in the obese group was 48.9 mL/min (P = .09). The length of stay, incidence of delayed graft function, and 1-year graft survival did not differ between the obese and nonobese groups. The results of this single-center experience with living donor transplant into obese subjects suggest no differences in outcomes with regard to surgical or wound complications, delayed graft function, or serum creatinine at 1 year.     

Anterior minimally invasive approaches for the cervical spine

The percutaneous endoscopic discectomy (PECD) with working channel endoscope (WSH) endoscopy set could be a safe and effective minimally invasive surgical option for non-contained cervical disc herniation in selected patients. Judicious use of the end-firing Ho: Yttrium-Aluminium-Garnet (YAG) laser for both decompressive and thermoannuloplasty effect during the percutaneous endoscopic cervical annuloplasty (PECA) is mandatory in order to prevent possible injury to spinal cord or root. Although the percutaneous cervical stabilization (PCS) using the cervical B-Twin may not completely replace the cervical arthrodesis, this minimally invasive procedure can preserve anterior structures and thereby retain segmental stability and prevent the possible kyphotic progression after fusion surgery. To our knowledge, these minimally invasive procedures for cervical spine disease may serve to minimize surgery-induced complications associated with anterior cervical discectomy and fusion (ACDF).     

Dry suction water seal system for management of pericardial fluid during epicardial ablation

Introduction

Epicardial ablation is an important approach in the management of patients with complex ventricular arrhythmias. Irrigated ablation catheters present a challenge in this potential space due to fluid accumulation that can cause hemodynamic compromise, requiring frequent manual fluid aspiration. In this series, we report our initial experience with the use of a dry suction water seal system for pericardial fluid management during epicardial ablation.

Methods

Consecutive patients undergoing epicardial ventricular tachycardia (VT) ablation at a single center were included. All patients underwent epicardial access via a subxiphoid approach with a single operator. A deflectable sheath was advanced into the pericardial space, and the side port was attached to a dry suction water seal system attached to wall suction at −20 mmHg. Procedural information including patient characteristics, outcomes, and adverse events. After a period of initial experience, pericardial fluid infusion and aspiration volumes were recorded.

Results

Eleven patients were included in this series. All patients underwent epicardial ablation with complete success achieved in 8 of the 11 patients and partial success in the remaining patients. Pericardial fluid intake ranging from 485 to 3050 mL with aspiration of 350–3050 mL using the dry suction water seal system. No adverse events occurred.

Conclusion

Dry suction water seal drainage systems can provide a safe strategy for efficient pericardial fluid management during epicardial VT ablation, potentially shortening procedure duration.