Browse Articles

The AMR Accelerator: from individual organizations to efficient antibiotic development partnerships

One-for-all gene inactivation via PAM-independent base editing in bacteria

The steroid hormone 20-hydroxyecdysone inhibits RAPTOR expression by repressing Hox gene transcription to induce autophagy

Redirecting E3 ubiquitin ligases for targeted protein degradation with heterologous recognition domains

Spatial chromosome organization and adaptation of the radiation-resistant extremophile Deinococcus radiodurans

The signaling landscape of insulin-like growth factor 1

Dynamic O-GlcNAcylation coordinates etoposide-triggered tumor cell pyroptosis by regulating p53 stability

Thrombin confers chemotherapeutic resistance by promoting transcriptional induction and post-translational stabilization of pro-survival MCL1 in TNBC

Structural basis for the pathogenicity of parkin catalytic domain mutants

A conserved acidic residue drives thyroxine synthesis within thyroglobulin and other protein precursors

Inhibition of the neddylation E2 enzyme UBE2M in macrophages protects against E. coli-induced sepsis

Purification of micrococcal nuclease for use in ribosomal profiling of high-salinity extremophiles

On the Nose: Reducing Nasopharyngeal Cancer–Related Mortality Using Risk-Based Epstein-Barr Virus Serology Screening

mRNA vaccine sequence and structure design and optimization: Advances and challenges

Surveillance Systemic Imaging After Curative Intent for Breast Cancer: A Double Standard?

Iron regulatory protein 1-deficient mice exhibit hypospermatogenesis

Single or Double Induction With 7 + 3 Containing Standard or High-Dose Daunorubicin for Newly Diagnosed AML: The Randomized DaunoDouble Trial by the Study Alliance Leukemia

PURPOSE To determine the optimal daunorubicin dose and number of 7 + 3 induction cycles in newly diagnosed AML, this randomized controlled trial compared a once daily dose of 60 mg/m 2 with 90 mg/m 2 daunorubicin in the first 7 + 3 induction and one versus two cycles of 7 + 3 induction. PATIENTS AND METHODS Patients age 18-65 years with newly diagnosed AML were randomly assigned to 60 versus 90 mg/m 2 daunorubicin once daily plus cytarabine. Patients with marrow blasts below 5% on day 15 after first induction were randomly assigned to receive a second induction cycle or no second induction cycle. RESULTS Eight hundred and sixty-four patients with a median age of 52 years were randomly assigned. After a preplanned interim analysis showing no significant difference in response between 60 and 90 mg/m 2 , all consecutive patients received 60 mg/m 2 daunorubicin once daily. The proportion of good early responders was 44% versus 48% ( P = .983) with a composite complete remission (CRc) rate of 90% versus 89% after induction ( P = .691); the 3-year relapse-free survival (RFS) after 60 versus 90 mg/m 2 once daily was 54% versus 50% ( P = .561), and the 3-year overall survival (OS) was 65% versus 58% ( P = .242). Among 389 good responders, CRc rates at the end of induction were 87% after single induction and 85% after double induction. The 3-year RFS was 51% versus 60% (hazard ratio [HR], 1.3; P = .091), and the 3-year OS was 76% versus 75% after single versus double induction (HR, 1.0; P = .937). CONCLUSION The use of 90 mg/m 2 daunorubicin once daily in the context of classical 7 + 3 induction does not significantly improve early response and does not lead to higher remission rates or longer survival than 60 mg/m 2 once daily. In patients with a good early response after first induction, a second induction has only a limited impact on RFS and does not result in an OS benefit.

Dual-ligand fluorescence microscopy enables chronological and spatial histological assignment of distinct amyloid-β deposits

Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported . CheckMate 274 is a phase III, randomized, double-blind trial of adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence after radical resection. The primary end points of disease-free survival (DFS) in intent-to-treat (ITT) and tumor PD-L1 expression ≥1% populations were met. We report results at an extended median follow-up of 36.1 months in the ITT population. In addition, we report interim overall survival (OS) data for the first time and an exploratory analysis among patients with bladder primary tumors (muscle-invasive bladder cancer [MIBC]). Consistent DFS benefit with nivolumab versus placebo was observed in both the ITT (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and PD-L1 ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]) patients. The HR for OS with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the ITT population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. Continuous benefit in nonurothelial tract recurrence-free survival and distant metastasis-free survival was also observed in both patient populations. The exploratory analysis of patients with MIBC also showed continued efficacy benefits, irrespective of PD-L1 status. No new safety signals were reported. Overall, these results further support adjuvant nivolumab as a standard of care for high-risk MIUC after radical resection.

The structural basis for high-affinity c-di-GMP binding to the GSPII-B domain of the traffic ATPase PilF from Thermus thermophilus