Lipoprotein remnants and dense LDL are associated with features of unstable carotid plaque: A flag for non-HDL-C

OBJECTIVE: We investigated the association between cholesterol across the LDL density range and in the VLDL and IDL particles with the prevalence of inflammatory cells in plaques of patients with severe carotid artery stenosis. METHODS: Forty-five patients undergoing carotid endarterectomy were studied. Plaque specimens were analyzed for cellular composition by immunocytochemistry using monoclonal antibodies. Lipoprotein subclasses were separated by gradient ultracentrifugation. RESULTS: We found no correlations between LDL-C, HDL-C and plasma triglyceride levels with plaque cellular composition. On the other hand, macrophage content was significantly related to cholesterol in the dense LDL subclasses (r = 0.30, p < 0.01) and in the triglyceride-rich lipoprotein remnants, namely dense VLDL and IDL particles (r = 0.46, p < 0.01). HDL subclasses were not correlated with plaque cellular composition. In a mirror manner, smooth muscle cells were inversely associated with cholesterol levels of the dense LDL subclasses (r = -0.32, p < 0.01 fraction 10; r = -0.26, p < 0.05 fraction 11) while only a non-significant trend was observed with the cholesterol in the VLDL-IDL fractions. These results provide the pathophysiological background to account for the relevance of non-HDL-C as the only lipid parameter, aside LDL density, significantly associated (\u3b2 = 0.351, p = 0.021) with carotid plaque macrophage content. CONCLUSIONS: We provide evidence that lipoprotein subclasses, specifically cholesterol in the dense LDL fractions and in the triglyceride-rich lipoprotein remnants, significantly affect carotid plaque cellular composition, in particular macrophages content

The development of PARP as a successful target for cancer therapy

PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer. Finally, an insight is provided into the key data of PARPi in these distinctive clinical settings. Expert commentary: PARP inhibition could be a new therapeutic option for a number of tumors in the near future. However, several aspects will be of paramount interest for future investigations, including the molecular bases for PARPi synthetic lethality, the DNA repair independent functions of PARP and BRCA genes, the resistance and biomarkers of response to PARP inhibition, and the mechanisms of interaction between PARPi and antiangiogenic or immunotherapeutic agents

Atorvastatin Reduces Macrophage Accumulation in Atherosclerotic Plaques. A Comparison of a Nonstatin-Based Regimen in Patients Undergoing Carotid Endarterectomy.

BACKGROUND AND PURPOSE: The object of our study was to compare the effect of high-dose vs low-dose atorvastatin vs nonstatin-based treatment (cholestyramine plus sitosterol) on cell composition of carotid plaque. METHODS: We recruited 60 hypercholesterolemic patients (total cholesterol, 5.83-7.64 mmol/L) eligible for carotid endarterectomy. Three months before surgery, patients were randomized into 3 groups (n=20) receiving atorvastatin 10 mg/day (AT-10) or atorvastatin 80 mg/day (AT-80) or cholestyramine 8 g/day plus sitosterol 2.5 g/day. Analysis of cell composition was performed on endarterectomy specimens. RESULTS: The 3 treatments resulted in a significant reduction of total cholesterol and low-density lipoprotein cholesterol (LDL-C), although the decrease in total cholesterol and LDL-C was of smaller magnitude in the cholestyramine plus sitosterol group. The 3 regimens did not influence the levels of inflammatory markers (including high-sensitivity C-reactive protein). Macrophage content was significantly lower in the AT-10 group plaques compared to the cholestyramine plus sitosterol group. It was further reduced in the AT-80 group plaques. These differences were no longer significant after adjustment for changes in LDL-C. No difference in lymphocyte number was observed among treatments, whereas the content of smooth muscle cells was higher in the AT- 80 group. An inverse association was observed between LDL-C changes in the 3 groups and macrophage content in the plaques. CONCLUSIONS: Short-term treatment with high-dose statin is superior to a nonstatin lipid-lowering regimen in reducing the macrophage cell content within atherosclerotic lesions, but this effect was determined by the degree of LDL-C-lowering

Acquired hemophagocytic syndrome in a patient with synovial sarcoma: a case report

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by severe hyperinflammation due to an overwhelming ineffective immune response to different triggers. Most important symptoms are fever, hepatosplenomegaly and cytopenias. Biochemical signs include elevated ferritin, hypertriglyceridemia and low fibrinogen. Hemophagocytosis in the bone marrow is a hallmark of this syndrome. Based on the pathogenetic mechanism, it can be classified into primary (inherited) or secondary (acquired) HLH. We report, to our knowledge, the first case of acquired hemophagocytic syndrome that arose in a 20-year-old man affected by synovial sarcoma as a complication during chemotherapy

Perfusion CT Changes in Liver Metastases from Pancreatic Neuroendocrine Tumors During Everolimus Treatment

Aim: To evaluate modifications of perfusional parameters assessed by perfusion computed tomography (P-CT) of liver metastases (LM) from pancreatic neuroendocrine tumors (PanNETs) during everolimus treatment. Patients and Methods: All patients with LMs from G1-2 PanNETs undergoing everolimus treatment between January 2013 and January 2015 were prospectively evaluated with P-CT at baseline, and after 2 and 4 months of therapy. Size, perfusion, blood volume (BV), peak enhancement intensity (PEI) and time to peak for each lesion were calculated. Results: A total of 33 LMs in nine patients with G1-2 PanNETs were prospectively evaluated: 23/33 (69.7%) were responders, 10/33 (30.3%) were non-responders. Among perfusional parameters, only numerical peak enhancement intensity values significantly differed between the two groups at baseline (p=0.043). BV increase was the most significant perfusional modification identifying responding lesions, even at an early stage of treatment, with a high positive predictive value (89.47%). Conclusion: P-CT seems to be useful for prediction of response to everolimus of LMs from PanNETs