Abstract-In this article we introduce GMU, a genuine partial replication protocol for transactional systems, which exploits an innovative, highly scalable, distributed multiversioning scheme. Unlike existing multiversion-based solutions, GMU does not rely on a global logical clock, which represents a contention point and can limit system scalability. Also, GMU never aborts read-only transactions and spares them from distributed validation schemes. This makes GMU particularly efficient in presence of read-intensive workloads, as typical of a wide range of real-world applications.GMU guarantees the Extended Update Serializability (EUS) isolation level. This consistency criterion is particularly attractive as it is sufficiently strong to ensure correctness even for very demanding applications (such as TPC-C), but is also weak enough to allow efficient and scalable implementations, such as GMU. Further, unlike several relaxed consistency models proposed in literature, EUS has simple and intuitive semantics, thus being an attractive, scalable consistency model for ordinary programmers.We integrated the GMU protocol in a popular open source in-memory transactional data grid, namely Infinispan. On the basis of a large scale experimental study performed on heterogeneous experimental platforms and using industry standard benchmarks (namely TPC-C and YCSB), we show that GMU achieves linear scalability and that it introduces negligible overheads (less than 10%), with respect to solutions ensuring non-serializable semantics, in a wide range of workloads.
Natural products that contain ortho-quinones show great potential as anticancer agents but have been largely discarded from clinical development because their redox-cycling behaviour results in general systemic toxicity. Here we report conjugation of ortho-quinones to a carrier, which simultaneously masks their underlying redox activity. C-benzylation at a quinone carbonyl forms a redox-inactive benzyl ketol. Upon a specific enzymatic trigger, an acid-promoted, self-immolative C–C bond-cleaving 1,6-elimination mechanism releases the redox-active hydroquinone inside cells. By using a 5-lipoxygenase modulator, β-lapachone, we created cathepsin-B-cleavable quinone prodrugs. We applied the strategy for intracellular release of β-lapachone upon antibody-mediated delivery. Conjugation of protected β-lapachone to Gem-IgG1 antibodies, which contain the variable region of gemtuzumab, results in homogeneous, systemically non-toxic and conditionally stable CD33+-specific antibody–drug conjugates with in vivo efficacy against a xenograft murine model of acute myeloid leukaemia. This protection strategy could allow the use of previously overlooked natural products as anticancer agents, thus extending the range of drugs available for next-generation targeted therapeutics.
Introduction: Nanoparticles (NPs), as drug delivery systems, appear to be a promising tool for prolonged therapeutic strategies as they allow a controlled drug release over time. However, most of the studies found in the literature simply contemplate the use of a single or low number of dosages with low NPs concentrations. In the context of chronic diseases, like Alzheimer's disease, cancer or human immunodeficiency virus (HIV), where the therapeutic scheme is also chronic, studies with numerous repeated dosages are often neglected. Methods: We screened different NPs, polymeric and lipid-based, in a repeated-dose toxicity study, to evaluate the safety and tissue distribution of promising nanocarriers to be used in the treatment of long-lasting diseases. Results: After administrating 24 high concentrated doses of the selected NPs intraperitoneally (i.p.) (3 times a week for 2 months), animals have presented NPs accumulation in different tissues. However, neither toxicity, bodyweight changes nor clinical signs of disease were observed. Discussion: This work demonstrates no general adverse effects upon the studied NPs repeated-dose exposure, indicating the most promising NPs to be used in the different therapeutic circumstances, which may be useful in chronic diseases treatment.
In this article we introduce GMU, a genuine partial replication protocol for transactional systems, which exploits an innovative, highly scalable, distributed multiversioning scheme. Unlike existing multiversion-based solutions, GMU does not rely on any global logical clock, which may represent a contention point and a major impairment to system scalability. Also, GMU never aborts read-only transactions and spares them from undergoing distributed validation schemes. This makes GMU particularly efficient in presence of read-intensive workloads, as typical of a wide range of real-world applications. GMU guarantees the Extended Update Serializability (EUS) isolation level. This consistency criterion is particularly attractive as it is sufficiently strong to ensure correctness even for very demanding applications (such as TPC-C), but is also weak enough to allow efficient and scalable implementations, such as GMU. Further, unlike several relaxed consistency models proposed in literature, EUS shows simple and intuitive semantics, thus being an attractive consistency model for ordinary programmers. We integrated GMU in a popular open source in-memory transactional data grid, namely Infinispan. On the basis of a wide experimental study performed on heterogeneous platforms and using industry standard benchmarks (namely TPC-C and YCSB), we show that GMU achieves almost linear scalability and that it introduces reduced overhead, with respect to solutions ensuring non-serializable semantics, in a wide range of workloads. © 2015 IEEE
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