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Binod Dhakal Anita DSouza Arjun Lakshman Mehdi Hamadani Saurabh Chhabra Robert Thompson Nirav Shah Marcelo Pasquini Paramweswaran Hari 《Biology of blood and marrow transplantation》2018,24(8):1610-1614
High-dose melphalan followed by autologous stem cell transplant (ASCT) is standard of care for eligible patients with multiple myeloma (MM). Evomela (propylene glycol–free melphalan HCl [PG-Free Mel]; Spectrum Pharmaceuticals, Irvine, CA) was approved by the US Food and Drug Administration as conditioning therapy for ASCT in MM in 2 daily 100-mg/m2 doses for a total dose of 200?mg/m2. In this phase II, open-label study PG-Free Mel (Evomela) conditioning was given at single dose of 200?mg/m2 on day ?2 pre-ASCT to establish pharmacokinetic (PK) parameters and safety. Twenty-four patients (median age, 64 years) were enrolled between August 2016 and February 2017. Myeloablation followed by successful neutrophil engraftment occurred at a median of 10 days in all patients. Peak melphalan concentration was observed at 10 minutes after infusion, whereas there was considerable variation in the maximum plasma concentration (Cmax) and area under concentration time curve (AUC). Median Cmax was 7380?ng/mL (interquartile range [IQR], 6522 to 8027). Similarly, median AUC was 533,552?ng/mL?min (IQR, 450,850 to 662,936). PG-Free Mel had an acceptable safety profile regardless of the exposure, with no mortality and an overall response rate of 96% and a very good partial response rate of 75%. In conclusion, although PG-Free Mel at a single dose of 200?mg/m2 was safe, considerable PK variability was observed with the highest quartile having an ~3-fold higher AUC than the first quartile, suggesting that strategies for higher targeted exposure could be explored in future trials to optimize clinical benefit. 相似文献
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Janet Stavnezer Erin K. Linehan Mikayla R. Thompson Ghaith Habboub Anna J. Ucher Tatenda Kadungure Daisuke Tsuchimoto Yusaku Nakabeppu Carol E. Schrader 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(25):9217-9222
Somatic hypermutation (SHM) of antibody variable region genes is initiated in germinal center B cells during an immune response by activation-induced cytidine deaminase (AID), which converts cytosines to uracils. During accurate repair in nonmutating cells, uracil is excised by uracil DNA glycosylase (UNG), leaving abasic sites that are incised by AP endonuclease (APE) to create single-strand breaks, and the correct nucleotide is reinserted by DNA polymerase β. During SHM, for unknown reasons, repair is error prone. There are two APE homologs in mammals and, surprisingly, APE1, in contrast to its high expression in both resting and in vitro-activated splenic B cells, is expressed at very low levels in mouse germinal center B cells where SHM occurs, and APE1 haploinsufficiency has very little effect on SHM. In contrast, the less efficient homolog, APE2, is highly expressed and contributes not only to the frequency of mutations, but also to the generation of mutations at A:T base pair (bp), insertions, and deletions. In the absence of both UNG and APE2, mutations at A:T bp are dramatically reduced. Single-strand breaks generated by APE2 could provide entry points for exonuclease recruited by the mismatch repair proteins Msh2–Msh6, and the known association of APE2 with proliferating cell nuclear antigen could recruit translesion polymerases to create mutations at AID-induced lesions and also at A:T bp. Our data provide new insight into error-prone repair of AID-induced lesions, which we propose is facilitated by down-regulation of APE1 and up-regulation of APE2 expression in germinal center B cells.During humoral immune responses, the recombined antibody variable [V(D)J] region genes undergo somatic hypermutation (SHM), which, after selection, greatly increases the affinity of antibodies for the activating antigen. This process occurs in germinal centers (GCs) in the spleen, lymph nodes, and Peyer’s patches (PPs) and entirely depends on activation-induced cytidine deaminase (AID) (1, 2). AID initiates SHM by deamination of cytidine nucleotides in the variable region of antibody genes, converting the cytosine (dC) to uracil (dU) (1, 3, 4). Some AID-induced dUs are excised by the ubiquitous enzyme uracil DNA glycosylase (UNG), resulting in abasic (AP) sites that can be recognized by apurinic/apyrimidinic endonuclease (APE) (4, 5). APE cleaves the DNA backbone at AP sites to form a single-strand break (SSB) with a 3′ OH that can be extended by DNA polymerase (Pol) to replace the excised nucleotide (6). In most cells, DNA Pol β performs this extension with high fidelity, reinserting dC across from the template dG. In contrast, GC B cells undergoing SHM are rapidly proliferating, and some of the dUs are replicated over before they can be excised and are read as dT by replicative polymerases, resulting in dC to dT transition mutations. Unrepaired AP sites encountering replication lead to the nontemplated addition of any base opposite the site, causing transition and transversion mutations. However, it is not clear why dUs and AP sites escape accurate repair by the highly efficient enzymes UNG and APE1 and lead instead to mutations.Instead of removal by UNG, some U:G mismatches created by AID activity are recognized by the mismatch repair proteins Msh2–Msh6, which recruit exonuclease 1 to initiate excision of one strand surrounding the mismatch (7–9). The excised region (estimated at ∼200 nt; ref. 10) is subsequently filled in by DNA Pols, including error-prone translesion Pols, which spreads mutations beyond the initiating AID-induced lesion. The combined, but noncompeting interaction of the UNG and MMR pathways in generating mutations at A:T base pairs (bp) has been described (10–12). This mismatch repair-dependent process has been termed phase II of SHM (3). Pol η and Msh2–Msh6 have been shown to be essential for nearly all mutations at A:T bp (13–15). During repair of the excision patch, additional C:G bp can be mutated by translesion Pols, but mutations at C:G bp due to AID activity can also be repaired back to the original sequence during this step (16).Mammals express two known homologs of AP endonuclease (APE), APE1 and APE2. APE1 is the major APE; it is ubiquitously expressed and essential for early embryonic development in mice and for viability of human cell lines (17–19). APE1 has strong endonuclease activity and weaker 3′-5′ exonuclease (proofreading) and 3′-phosphodiesterase (end-cleaning) activities (20, 21). Recombinant purified human APE2 has much weaker AP endonuclease activity than APE1, but its 3′-5′ exonuclease activity is strong compared with APE1, although it is not processive (20). However, APE2 has been shown to interact with proliferating cell nuclear antigen (PCNA) (22), which can recruit error-prone translesion polymerases (23, 24), and PCNA also increases the processivity of APE2 exonuclease in vitro (25). Both APE1 and APE2 are expressed in splenic B cells activated in culture (26). APE2 is nonessential, but APE2-deficient mice show a slight growth defect, a twofold reduction of peripheral B and T cells (27), and impaired proliferation of B-cell progenitors in the bone marrow (28).In this study we examine SHM in GC B cells isolated from the PPs of unimmunized apex1+/−, apex2Y/−, and apex1+/−apex2Y/− mice relative to WT mice. [Because the APE2 gene is located on the X chromosome, we used APE2-deficient male mice (apex2Y/−) in all experiments.] We demonstrate that not only is APE2 important for SHM frequency, as reported (29), but APE2 also contributes to the generation of A:T mutations. The proportion of mutations at A:T bp is reduced in apex2Y/− mice to the same extent as it is in ung−/− mice, consistent with APE2 acting as an endonuclease that incises AP sites generated by UNG. Surprisingly, in the absence of both UNG and APE2, mutations at A:T bp are greatly reduced. In addition, we find that expression of APE1 is dramatically reduced in GC B cells, and APE1 haploinsufficiency has very little effect on SHM. We propose a model in which APE2 promotes SHM through inefficient and error-prone repair, whereas APE1, which is known to interact with XRCC1 and Pol β to promote error-free SSB repair (30, 31), is suppressed in GC B cells. 相似文献
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Hussam Milly Frederic Festy Timothy F. Watson Ian Thompson Avijit Banerjee 《Journal of dentistry》2014
Objective
To evaluate the potential of bio-active glass (BAG) powder and BAG containing polyacrylic acid (PAA-BAG) to remineralise enamel white spot lesions (WSL).Methods
32 human enamel samples with artificial WSLs were assigned to 4 experimental groups (n = 8); (a) BAG slurry, (b) PAA-BAG slurry, (c) “standardised” remineralisation solution (positive control) and (d) de-ionised water (negative control). Mechanical properties of enamel were assessed using surface and cross-section Knoop microhardness. Micro-Raman spectroscopy in StreamLine™ scan mode was used to scan lesion cross-sections. The intensity of the Raman phosphate peak at 959 cm−1 was fitted and measured producing depth profiles analysed using a double-step fitting function. A further 20 samples (n = 5) were used to obtain 3D images of surfaces using non-contact white light profilometry permitting measurement of lesion step height in relation to the sound enamel reference level, and to scan the lesion surface using scanning electron microscopy (SEM). Data were analysed statistically using one-way ANOVA with Tukey's HSD post-hoc tests.Results
BAG, PAA-BAG and the remineralisation solution exhibited statistically significantly higher surface and cross-section Knoop microhardness compared to the negative control. Micro-Raman spectroscopy detected significantly higher phosphate content within the treated groups compared to the negative control group. Lesions’ depth was not significantly reduced. SEM images revealed mineral depositions, with different sizes and shapes, within BAG, PAA-BAG and the positive control groups.Conclusion
BAG and PAA-BAG surface treatments enhance enamel WSL remineralisation, assessed by the resultant improved mechanical properties, higher phosphate content and morphological changes within the artificial lesions. 相似文献100.