Tumor growth inhibition through targeting liposomally bound curcumin to tumor vasculature

Increasing number of Phase I/II clinical studies have demonstrated clinical potential of curcumin for treatment of various types of human cancers. Despite significant anti-tumor efficacies and bio-safety profiles of curcumin, poor systemic bioavailability is retarding its clinical success. Efforts are now being directed toward developing stable formulations of curcumin using various drug delivery systems. To this end, herein we report on the development of a new tumor vasculature targeting liposomal formulation of curcumin containing a lipopeptide with RGDK-head group and two stearyl tails, di-oleyolphosphatidylcholine (DOPC) and cholesterol. We show that essentially water insoluble curcumin can be solubilized in fairly high concentrations (~ 500 μg/mL) in such formulation. Findings in the Annexin V/Propidium iodide (PI) binding based flow cytometric assays showed significant apoptosis inducing properties of the present curcumin formulation in both endothelial (HUVEC) and tumor (B16F10) cells. Using syngeneic mouse tumor model, we show that growth of solid melanoma tumor can be inhibited by targeting such liposomal formulation of curcumin to tumor vasculature. Results in immunohistochemical staining of the tumor cryosections are consistent with tumor growth inhibition being mediated by apoptosis of tumor endothelial cells. Findings in both in vitro and in vivo mechanistic studies are consistent with the supposition that the presently described liposomal formulation of curcumin inhibits tumor growth by blocking VEGF-induced STAT3 phosphorylation in tumor endothelium. To the best of our knowledge, this is the first report on inhibiting tumor growth through targeting liposomal formulation of curcumin to tumor vasculatures.     

New Strategies for Colorectal Cancer Prevention and Treatment

Colorectal cancer (CRC) is the second most common fatal malignancy in the Western world, with more than 150,000 new cases accounting for 55,000 deaths in the United States every year. Surgical resection is an effective treatment for localized disease, achieving a 5-year survival rate of 90%; but chemotherapy and other novel treatments for metastatic disease remain ineffective. There have been significant efforts to identify risk factors associated with the development of CRC and to explore potential preventive therapies. Both genetic and epigenetic factors contribute to the development of colorectal cancer. Specific genetic changes in proto-oncogenes, tumor suppressor genes, and DNA mismatch repair genes have led to a genetic model of CRC. Cooperative genetic aberrations involving APC (adenomatous polyposis coli), beta-catenine, K-ras, and p53 are involved in the multistep adenoma-carcinoma sequence of CRC. Emerging data have implicated cyclooxygenase-2 (COX-2) and prostanoid production in the pathogenesis of colorectal carcinoma. Several reports indicate a close relation between the intake of nonsteroidal antiinflammatory drugs (NSAIDs) and a decreased risk for developing colorectal cancer. Epidemiologic studies indicate a 40% to 50% reduction in mortality due to colorectal cancer in individuals taking NSAIDs (e.g., aspirin). Epigenetic factors including age, diet, angiogenesis, and immune responses also appear to contribute to the development of CRC. Combining knowledge of the genetic and epigenetic events implicated in this disease may allow a broader understanding of the pathogenesis of CRC. These developments may yield benefits in earlier detection and in the design of better antitumor interventions.     

Primary squamous cell carcinoma of breast with ipsilateral axillary lymph node metastasis: An unusual case

Introduction

Pure squamous cell carcinoma of the breast [SCCB] is rare.

Presentation of Case

We report a case of primary squamous cell carcinoma of breast with ipsilateral axillary lymph node metastasis in a 58year old woman.

Discussion

It is a breast carcinoma entirely composed of metaplastic squamous cells that may be keratinized, non-keratinized or spindled. The pure squamous cell carcinoma usually present with central cystic cavity, which we found in our case, also supported by immunohistochemical evidence.

Conclusion

Although a rare breast cancer subtype, SCCB is of considerable interest due to its pathological heterogeneity and differences in clinical behavior and less reported occurrence of nodal metastasis.     

Solitary fibrous tumor of the pleura

Solitary fibrous tumor of the pleura is a rare clinical entity. Approximately 600 such cases have been reported in the literature. The purpose of this study was to review the surgical outcome of this disease. This is a retrospective review of seven cases of solitary fibrous tumor of the pleura. There were five women and two men. Their ages ranged from 24 to 65 years. Symptoms included cough, shortness of breath, and chest pain. Diagnostic studies included chest X-ray, computed tomography (CT) scan, bronchoscopy, and CT-guided needle biopsy. All the tumors were pedunculated. The sizes ranged from 5.0 to 11.0 cm. All were resected by thoracotomy. The largest of these tumors weighed 68 g. All patients remain disease free. Follow-up ranged from 2 to 20 years. This is a rare disease. Complete resection offers the best chance for long-term care.     

Aortic aneurysm presenting as Budd Chiari syndrome.

Budd Chiari Syndrome is the eponymic designation of symptomatic post sinusoidal venous obstruction, whether or not this is associated with hepatic vein occlusion or vena caval obstruction. Dutta and associates (1) classified the syndrome into two distinct types. Type I involves obstruction to the hepatic veins while Type II pertains to an obstruction in the inferior vena cava above the entry of hepatic veins. We report a case of thoraco-abdominal aortic aneurysm presenting as Type II Budd Chiari Syndrome.     

The effect HBOC-201 and sodium nitrite resuscitation after uncontrolled haemorrhagic shock in swine

BackgroundDevelopment of Haemoglobin-based oxygen carriers (HBOCs) as blood substitutes has reached an impasse due to clinically adverse outcomes attributed to vasoconstriction secondary to nitric oxide (NO) scavenging. Studies suggest haemoglobin exhibits nitrite reductase activity that generates NO and N₂O₃; harnessing this property may offset NO scavenging. Therefore, the effects of concomitantly infusing sodium nitrite (NaNO₂) with HBOC-201 were investigated.MethodsSwine underwent uncontrolled liver haemorrhage before receiving up to three 10 min 10 ml/kg infusions of HBOC-201 (HBOC) with or without concurrent NaNO₂ (5.4 μmol/kg [LD NaNO₂] or 10.8 μmol/kg [HD NaNO₂]) or 6% Hetastarch (HEX) with or without HD NaNO₂ during “prehospital” resuscitation (15, 30 and 45 min after injury). Definitive surgical care occurred at 75 min; anaesthetic recovery at 120 min. Animals were euthanised at 72 h.ResultsNaNO₂ temporarily reduced systemic and pulmonary blood pressure increases from HBOC in a dose-dependent fashion. There was no significant effect between groups in indices of tissue oxygenation or survival. Adverse clinical signs requiring humane euthanasia occurred with highest frequency after HBOC + HD NaNO₂ (3 of 4 pigs) and HBOC + LD NaNO₂ (2 of 4 pigs). Gross evidence of pulmonary congestion was observed in 5 of 8 swine receiving a HBOC and NaNO₂ combination compared to 1 of 16 swine receiving HBOC alone, HEX alone, or HEX + NaNO₂. Gross lesions correlated with histological evidence of pulmonary oedema and congestion, and in 2 of 4 HBOC + HD NaNO₂ pigs, pulmonary fibrin thrombi also were found. No other pig had similar evidence of thrombi. Asymmetric pre-resuscitation cardiac index was a potential confounder.ConclusionsA significant interaction between NaNO₂ and HBOC-201 ameliorated HBOC-201 vasoconstrictive effects, consistent with HBOC possessing a nitrite reductase activity that generates vasodilator NO equivalents. Results were relatively equivalent in survival and markers of tissue oxygenation. The highest dose of NaNO₂ was the most effective in reducing HBOC-associated pulmonary and systemic vasoactivity but also with the highest incidence of adverse events. In this model, the transient nature of NaNO₂ in off-setting HBOC-201 vasoconstriction makes it less clinically promising than anticipated and the combination of NaNO₂ and HBOC appear to increase the risk of pulmonary complications in a dose-dependent fashion independently of haemodilutional effects on haemostatic components.     

Adaptations in trabecular bone microarchitecture in Olympic athletes determined by 7T MRI

PURPOSE: To produce in vivo high-resolution images of the knee and to determine the feasibility of using 7T MR to detect changes in trabecular bone microarchitecture in elite athletes (Olympic fencers) who undergo high impact activity. MATERIALS AND METHODS: The dominant knees of four males from the U.S. Olympic Fencing Team and three matched healthy male controls were scanned in a 7T whole-body scanner using a quadrature knee coil with three-dimensional (3D) fast low angle shot (FLASH): 50 axial images at the distal femur (0.156 mm x 0.156 mm) and 80 axial images at the knee joint (0.195 mm x 0.195 mm). Bone volume fraction (BVF) and marrow volume fraction (MVF) images were computed and fuzzy distance transform (FDT) and digital topological analysis (DTA) were applied to determine: trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp); BVF (BV/TV); trabecular and marrow space surface-to-curve ratio (SC, marker of plate to rod ratio); and trabecular and marrow space erosion index (EI, inverse marker for network connectivity). Quadriceps muscle volume (MV) was calculated as well. We calculated group means and performed two-tailed t-tests to determine statistical significance. RESULTS: Compared to controls, fencers had: decreased Tb.Sp (P = 0.0082 at femur, P = 0.051 at joint); increased Tb.N (P < 0.05 at both femur and joint) and BV/TV (P < 0.001 at both femur and joint); increased trabecular SC and decreased marrow space SC (P < 0.01 at both femur and joint); decreased trabecular EI and increased marrow space EI (P < 0.01 at both femur and joint); and increased MV (P = 0.038). There was no difference in Tb.Th at the distal femur (P = 0.92) or joint (P = 0.71) between groups. CONCLUSION: To our knowledge, this is the first study to perform 7T MRI of the knee in vivo. Elite athletes who undergo high impact activity have increased MV and improved trabecular bone structure compared to controls.     

The prevalence of peripheral arterial disease and medial arterial calcification in patients with chronic renal failure: requirements for diagnostics

BACKGROUND: Knowledge of the prevalence of peripheral arterial disease (PAD) in patients with chronic renal failure (CRF) is limited because of a lack of uniformity in disease definition and recognition. Furthermore, little is known of the prevalence of medial arterial calcification (MAC) in patients with CRF. Our goal is to study the prevalence of PAD and MAC defined by ankle brachial index (ABI) or toe brachial index (TBI) measurements in a Finnish population of patients with CRF consisting of predialysis and dialysis patients, as well as renal transplant recipients. METHODS: We examined 136 patients with CRF and 59 control subjects. Fifty-nine of the patients with CRF had moderate to severe predialysis CRF, 36 patients were on dialysis treatment, and 41 were renal transplant recipients. Mean age of patients was 51.9 +/- 11.5 years, and 39 patients (29%) had diabetes. ABI and TBI were measured by means of photoplethysmography. The definition of PAD required an ABI value of 0.90 or less, a TBI value of 0.60 or less, or a previous positive lower-extremity angiogram result. ABI values of 1.3 or greater or incompressible arteries at ankle level indicated MAC. The presence of claudication was determined by an interview. RESULTS: Prevalences of PAD on this study were 22.0% in patients with predialysis CRF, 30.6% in patients on dialysis treatment, 14.6% in renal transplant recipients, and 1.7% in the control group (P = 0.001). Prevalences of MAC were 23.7%, 41.7%, 23.1%, and 3.4% (P < 0.001), respectively. Only 9 patients had claudication, and 6 of those patients had PAD. CONCLUSION: Both asymptomatic PAD and MAC are common in patients with CRF. Therefore, we recommend the use of both ABI and TBI measurements in the evaluation of PAD in patients with CRF.