Maturation of mammalian H/ACA box snoRNAs: PAPD5-dependent adenylation and PARN-dependent trimming.

Small nucleolar and small Cajal body RNAs (snoRNAs and scaRNAs) of the H/ACA box and C/D box type are generated by exonucleolytic shortening of longer precursors. Removal of the last few nucleotides at the 3' end is known to be a distinct step. We report that, in human cells, knock-down of the poly(A) specific ribonuclease (PARN), previously implicated only in mRNA metabolism, causes the accumulation of oligoadenylated processing intermediates of H/ACA box but not C/D box RNAs. In agreement with a role of PARN in snoRNA and scaRNA processing, the enzyme is concentrated in nucleoli and Cajal bodies. Oligo(A) tails are attached to a short stub of intron sequence remaining beyond the mature 3' end of the snoRNAs. The noncanonical poly(A) polymerase PAPD5 is responsible for addition of the oligo(A) tails. We suggest that deadenylation is coupled to clean 3' end trimming, which might serve to enhance snoRNA stability.

Micafungin versus liposomal amphotericin B for pediatric patients with invasive candidiasis: substudy of a randomized double-blind trial.

BACKGROUND: Invasive candidiasis is increasingly prevalent in premature infants and seriously ill children, and pediatric data on available antifungal therapies are lacking. METHODS: We conducted a pediatric substudy as part of a double-blind, randomized, multinational trial to compare micafungin (2 mg/kg) with liposomal amphotericin B (3 mg/kg) as first-line treatment of invasive candidiasis. Treatment success was defined as clinical and mycologic response at the end of therapy. Statistical analyses were descriptive, as the sample size meant that the study was not powered for hypothesis testing. RESULTS: One hundred six patients were included in the intent-to-treat population; and 98 patients-48 patients in the micafungin group and 50 patients in the liposomal amphotericin B group-in the modified intent-to-treat population. Baseline characteristics were balanced between treatment groups. Overall, 57 patients were <2 years old including 19 patients who were premature at birth; and 41 patients were 2 to <16 years old. Most patients (91/98, 92.9%) had candidemia, and 7/98 (7.1%) patients had other forms of invasive candidiasis. Treatment success was observed for 35/48 (72.9%) patients treated with micafungin and 38/50 (76.0%) patients treated with liposomal amphotericin B. The difference in proportions adjusted for neutropenic status was -2.4% [95% CI: (-20.1 to 15.3)]. Efficacy findings were consistent, independent of the neutropenic status, the age of the patient, and whether the patient was premature at birth. Both treatments were well tolerated, but with a lower incidence of adverse events that led to discontinuation in the micafungin group (2/52, 3.8%) compared with the liposomal amphotericin B group (9/54, 16.7%) (P = 0.05, Fisher exact test). CONCLUSIONS: Micafungin seems to be similarly effective and as safe as liposomal amphotericin B for the treatment of invasive candidiasis in pediatric patients. (ClinicalTrials.gov number, NCT00106288).

Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial.

BACKGROUND: Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis. METHODS: We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288. FINDINGS: 264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI -5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events--including those that were serious or led to treatment discontinuation--with micafungin than there were with liposomal amphotericin B. INTERPRETATION: Micafungin was as effective as--and caused fewer adverse events than--liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.