Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Investigation of PIN1 as a Genetic Modifier in Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a heterogeneous cancer predisposition syndrome caused by germline mutations in TP53. Some of this phenotypic variability can be explained by presence of oncogenic mutant p53 proteins in patients with missense TP53 mutations. Recent data suggest that the prolyl-isomerase, PIN1, serves a fundamental role in mutant TP53 oncogenic gain-of-function (GOF). We hypothesized that alterations in expression of PIN1, mediated by the promoter SNP(-)842G>C (rs2233678), modify the cancer phenotype of LFS patients. We demonstrate that the PIN1(-)842 GG genotype is associated with increased PIN1 expression at the transcript and protein level. Overexpression of PIN1 selectively enhances the clonogenicity and chemotherapy resistance of LFS fibroblasts harbouring R248Q mutant p53. Concordantly, LFS patients with the PIN1(-)842 GG genotype develop cancer earlier than those with GC/CC genotypes, with a prominent effect in pediatric patients. The GG genotype may also be associated with some predilection for the development of carcinomas.M.Sc.2016-12-21 00:00:0

A new simple procedure for discriminating between deracemization and an induced CD effect in chiral recognition experiments on atropoisomers

A CD band in chiral recognition experiments on racemic stereolabile compounds can be ascribed either to deracemization or to a solely induced CD effect. A procedure is presented that allows one to discriminate positively between the two phenomena. The procedure, based on CD spectroscopy, was used in experiments on racemic biphenylic derivatives in aggregates formed by enantiopure surfactants. In addition to demonstrating a deracemization event, the procedure allowed us to measure the enantiomeric excess

Important hypercalcemia due to subcutaneous fat necrosis treated with pamidronate in an infant with severe hypoxic-ischemic encephalopathy

Subcutaneous fat necrosis (SCFN) of the newborn is an uncommon form of panniculitis that occurs after fetal distress and involves fatty areas during the first weeks of life. This rare disorder is generally self-limiting and undergoes complete regression. However, it can be complicated with a potentially life-threatening hypercalcemia. We report a case of severe hypercalcemia due to SCFN occurring after serious perinatal hypoxic injury, which resolved by intravenous administration of pamidronate. This treatment was rapidly effective and well tolerated. We suggest that pamidronate could be the first-line therapy for severe hypercalcemia in SCFN.<br /