Background Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. Methods We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. Results At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Conclusions Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann–La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.)
Designed oligonucleotides can self-assemble into DNA nanostructures with well-defined structures and uniform sizes, which provide unprecedented opportunities for biosensing, molecular imaging, and drug delivery. In this work, we have developed functional, multivalent DNA nanostructures by appending unmethylated CpG motifs to three-dimensional DNA tetrahedra. These small-sized functional nanostructures are compact, mechanically stable, and noncytotoxic. We have demonstrated that DNA nanostructures are resistant to nuclease degradation and remain substantially intact in fetal bovine serum and in cells for at least several hours. Significantly, these functional nanostructures can noninvasively and efficiently enter macrophage-like RAW264.7 cells without the aid of transfection agents. After they are uptaken by cells, CpG motifs are recognized by the Toll-like receptor 9 (TLR9) that activates downstream pathways to induce immunostimulatory effects, producing high-level secretion of various pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-12. We also show that multivalent CpG motifs greatly enhance the immunostimulatory effect of the nanostructures. Given the high efficacy of these functional nanostructures and their noncytotoxic nature, we expect that DNA nanostructures will become a promising tool for targeted drug delivery.
A new fluorinated nonfullerene acceptor, ITIC-Th1, has been designed and synthesized by introducing fluorine (F) atoms onto the end-capping group 1,1-dicyanomethylene-3-indanone (IC). On the one hand, incorporation of F would improve intramolecular interaction, enhance the push-pull effect between the donor unit indacenodithieno[3,2-b]thiophene and the acceptor unit IC due to electron-withdrawing effect of F, and finally adjust energy levels and reduce bandgap, which is beneficial to light harvesting and enhancing short-circuit current density (J ). On the other hand, incorporation of F would improve intermolecular interactions through CF···S, CF···H, and CF···π noncovalent interactions and enhance electron mobility, which is beneficial to enhancing J and fill factor. Indeed, the results show that fluorinated ITIC-Th1 exhibits redshifted absorption, smaller optical bandgap, and higher electron mobility than the nonfluorinated ITIC-Th. Furthermore, nonfullerene organic solar cells (OSCs) based on fluorinated ITIC-Th1 electron acceptor and a wide-bandgap polymer donor FTAZ based on benzodithiophene and benzotriazole exhibit power conversion efficiency (PCE) as high as 12.1%, significantly higher than that of nonfluorinated ITIC-Th (8.88%). The PCE of 12.1% is the highest in fullerene and nonfullerene-based single-junction binary-blend OSCs. Moreover, the OSCs based on FTAZ:ITIC-Th1 show much better efficiency and better stability than the control devices based on FTAZ:PC BM (PCE = 5.22%).
DNA is typically impermeable to the plasma membrane due to its polyanionic nature. Interestingly, several different DNA nanostructures can be readily taken up by cells in the absence of transfection agents, which suggests new opportunities for constructing intelligent cargo delivery systems from these biocompatible, nonviral DNA nanocarriers. However, the underlying mechanism of entry of the DNA nanostructures into the cells remains unknown. Herein, we investigated the endocytotic internalization and subsequent transport of tetrahedral DNA nanostructures (TDNs) by mammalian cells through single-particle tracking. We found that the TDNs were rapidly internalized by a caveolin-dependent pathway. After endocytosis, the TDNs were transported to the lysosomes in a highly ordered, microtubule-dependent manner. Although the TDNs retained their structural integrity within cells over long time periods, their localization in the lysosomes precludes their use as effective delivery agents. To modulate the cellular fate of the TDNs, we functionalized them with nuclear localization signals that directed their escape from the lysosomes and entry into the cellular nuclei. This study improves our understanding of the entry into cells and transport pathways of DNA nanostructures, and the results can be used as a basis for designing DNA-nanostructure-based drug delivery nanocarriers for targeted therapy.
One of the detrimental effects of UV radiation on DNA is the formation of the (6-4) photoproduct (6-4PP) between two adjacent pyrimidines1. This lesion interferes with replication and transcription and may result in mutation and cell death2. In many organisms a flavoenzyme called photolyase uses blue light energy to repair the 6-4PP3. The molecular mechanism of the repair reaction is poorly understood. Here, we use ultrafast spectroscopy to show that the key step in the repair photocycle is a cyclic proton transfer between the enzyme and the substrate. By femtosecond synchronization of the enzymatic dynamics with the repair function, we followed the function evolution and observed direct electron transfer from the excited flavin cofactor to the 6-4PP in 225 ps but surprisingly fast back electron transfer in 50 ps without repair. Strikingly, we found that the catalytic proton transfer between a histidine residue in the active site and the 6-4PP, induced by the initial photoinduced electron transfer from the excited flavin cofactor to 6-4PP, occurs in 425 ps and leads to 6-4PP repair in tens of nanoseconds. These key dynamics define the repair photocycle and explain the underlying molecular mechanism of the enzyme’s modest efficiency.
NF-E2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that binds to the promoter sequence "antioxidant responsive element (ARE)" leading to coordinated up-regulation of ARE-driven detoxification and antioxidant genes. Since the expression of a wide array of antioxidant and detoxification genes are positively regulated by the ARE sequence, Nrf2 may serve as a master regulator of the ARE-driven cellular defense system against oxidative stress. In support of this, numerous studies have shown that Nrf2 protects many cell types and organ systems from a broad spectrum of toxic insults and disease pathogenesis. This Nrf2-conferred, multi-organ protection phenomenon raises an interesting question about how a single protein can protect many different organs from various toxic insults. A possible molecular mechanism explaining this phenomenon is that Nrf2 protects many different cell types by coordinately up-regulating classic ARE-driven genes as well as cell type-specific target genes that are required for the defense system of each cell type in its unique environment. This hypothesis is supported by microarray data indicating the protective role of Nrf2 is conveyed through both known ARE-driven genes and novel cell type-specific genes. The widespread nature of Nrf2 may have an important therapeutic potential, allowing prevention of carcinogenesis and neurodegenerative diseases.
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